Sadiq A

References (40)

Title : Pregnenolone derivatives for the treatment of Alzheimer's disease: synthesis, and in vitro inhibition of amyloid beta(1-42) peptide aggregation, acetylcholinesterase and carbonic anhydrase-II - Tahir_2024_RSC.Adv_14_14742
Author(s) : Tahir A , Mobeen B , Hussain F , Sadiq A , Rashid U
Ref : RSC Adv , 14 :14742 , 2024
Abstract : The amyloid state, which is a specific conformation of proteins, offers valuable information about both functional protein structures and the pathological assemblies associated with various diseases. One of the major hallmarks of Alzheimer's disease includes primarily the extracellular build-up of a peptide known as amyloid-beta, which has a sequence consisting of 39 to 42 amino acid residues, and the formation of intracellular neurofibrillary tangles mostly consisting of hyperphosphorylated tau protein. Drugs that are expected to reduce Abeta production, prevent Abeta aggregation, and promote Abeta clearance are promising approaches for treating AD. Current work is focused on identifying the compounds that have balanced even mild biological activities against multiple targets instead of finding one-target compound with high potency. We synthesized pregnenolone derivatives and evaluated their potential against inhibition of eeAChE/eqBChE, hCA-II and self-mediated Abeta(1-42) peptide aggregation. Our synthesized derivatives 23, and 25-27 exhibited concomitant inhibition of all the tested macromolecular targets. All the active compounds were found to be BBB penetrants in the PAMPA assay. Furthermore, these selected compounds were found to be non-neurotoxic in the MTT assay on neuroblastoma SH-SY5Y cells. Docking studies support dual binding site (PAS and CAS) inhibition of AChE which showed Abeta(1-42) aggregation and AChE inhibition. Moreover, docking studies carried out on the 3D crystallographic structure of Abeta(1-42) peptide (PDB ID = 1IYT) showed significant interactions with amino acid residues Asp 23 and Lys 28, and hydrophobic interactions with the Phe19, Phe20, and Ala 30 effectively impeding the formation of beta-sheet structures.
ESTHER : Tahir_2024_RSC.Adv_14_14742
PubMedSearch : Tahir_2024_RSC.Adv_14_14742
PubMedID: 38716099

Title : Quantitative-HPLC-DAD polyphenols analysis, anxiolytic and cognition enhancing potentials of Sorbaria tomentosa Lindl. Rehder - Mahnashi_2023_J.Ethnopharmacol_317_116786
Author(s) : Mahnashi MH , Ayaz M , Alqahtani YS , Alyami BA , Shahid M , Alqahtani O , Kabrah SM , Zeb A , Ullah F , Sadiq A
Ref : J Ethnopharmacol , 317 :116786 , 2023
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants of the family Rosaceae have a long history of traditional uses in the management of neurological disorders. Sorbaria tomentosa Lindl. Rehder is composed of antioxidant and neuroprotective polyphenolics. AIMS OF THE STUDY: The current study was designed to explore phenolics profile via high performance liquid chromatography-photodiode array detector (HPLC-DAD) and validated the neuroprotective and anxiolytic potentials of S. tomentosa by applying in vitro and in vivo approaches. MATERIALS AND METHODS: The plant crude methanolic extract (St.Crm) and fractions were subjected to HPLC-DAD analysis for qualitative and quantitative assessment of phytochemicals. Samples were screened for in vitro free radicals scavenging assays by using 2,2-diphenylpicrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) along with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibition assays. For cognitive and anxiolytic studies, mice were subjected to open field, elevated plus maze (EPM), light-dark model, Y-maze, shallow water maze (SWM), and novel object recognition (NOR) tests. RESULTS: HPLC-DAD analysis revealed the presence of high concentrations of phenolic compounds. For instance, in St.Cr, 21 phenolics were quantified, among which apigenin-7-glucoside (291.6 mg/g), quercetin (122.1 mg/g), quercetin-3-feruloylsophoroside-7-glucoside (52.6 mg/g), quercetin-7-glucoside (51.8 mg/g), ellagic acid (42.7 mg/g), luteolin (45.0 mg/g), kaempferol (40.5 mg/g), 5-feruloylquinic acid (43.7 mg/g) were present in higher concentrations. Likewise, in ethyl acetate fraction (St.Et.Ac), 21 phenolics were identified as 3,5-di-caffeoylquinic acid (177.4 mg/g) and 5-hydroxybenzoylquinic acid (46.9 mg/g) were most abundant phytochemicals. Highly valuable phenolics were also identified in other fractions including butanol (St.Bt), chloroform (St.Chf), and n-hexane (St.Hex). The various fractions exhibited concentration dependent inhibition of free radicals in DPPH and ABTS assays. Potent AChE inhibitory potentials were revealed by the test samples with St.Chf, St.Bt and St.EtAc being the most active having an IC(50) of 298.1, 580.1, and 606.47 microg mL(-1), respectively. Similarly, St.Chf, St.Bt, St.EtAc and St.Cr exhibited potent BChE inhibitory activity and was observed as 59.14, 54.73, 51.35 and 49.44%, respectively. A significant improvement in the exploratory behavior was observed in open field test and stress/anxiety was relieved effectively at 50-100 mg/kg. Likewise, EPM, light-dark and NOR tests revealed an anxiolytic and memory enhancing behaviors. These effects were further corroborated from the Y-maze and SWM transgenic studies that showed considerable improvement in cognition retention. CONCLUSIONS: These findings concluded that S. tomentosa possessed potential anxiolytic and nootropic efficacies and may have therapeutic potential in neurodegenerative disorders.
ESTHER : Mahnashi_2023_J.Ethnopharmacol_317_116786
PubMedSearch : Mahnashi_2023_J.Ethnopharmacol_317_116786
PubMedID: 37328081

Title : Evaluation of pyrimidine\/pyrrolidine-sertraline based hybrids as multitarget anti-Alzheimer agents: In-vitro, in-vivo, and computational studies - Javed_2023_Biomed.Pharmacother_159_114239
Author(s) : Javed MA , Jan MS , Shbeer AM , Al-Ghorbani M , Rauf A , Wilairatana P , Mannan A , Sadiq A , Farooq U , Rashid U
Ref : Biomed Pharmacother , 159 :114239 , 2023
Abstract : Alzheimer's disease (AD) is a complex, multifactorial and most prevalent progressive neurodegenerative ailment. Its multifactorial and complex nature causes the lack of disease modifying drugs. Hence, multi-target drug design strategies have been adopted to halt the progression of AD. In current research, we applied multitarget strategy to tackle multifactorial nature of AD. Rational design and synthesis of framework of hybrids containing Pyrimidine/pyrrolidine-sertraline scaffolds were carried out. The synthesized compounds were further evaluated for their in-vitro enzyme inhibition potential against cholinesterases, monoamine oxidases and beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1). Compound 19 emerged as an optimal multipotent hybrid with IC(50) values of 0.07smicroM, 0.09smicroM, 0.63smicroM, 0.21smicroM and 0.73smicroM against AChE, BChE, MAO-A, MAO-B and BACE-1 respectively. After in-vivo cytotoxicity and in-vitro PAMPA blood brain barrier permeation assays, a number of widely used behavioral assessment tests were also performed for the evaluation of memory and learning.Determination of biochemical parameters showed low levels of acetylcholinesterase by the treatment with synthesized compounds. Furthermore, levels of neurotransmitters such as serotonin, dopamine and noradrenaline were also analyzed. Increased neurotransmitter levels showed the improved short and long-term memory as well as enhanced learning behavior. Docking studies on the target enzymes showed correlation with the experimental in-vitro enzyme inhibition results.
ESTHER : Javed_2023_Biomed.Pharmacother_159_114239
PubMedSearch : Javed_2023_Biomed.Pharmacother_159_114239
PubMedID: 36638595

Title : Pharmacological evaluations of amide carboxylates as potential anti-Alzheimer agents: anti-radicals, enzyme inhibition, simulation and behavioral studies in animal models - Mahnashi_2023_J.Biomol.Struct.Dyn__1
Author(s) : Mahnashi MH , Ali S , O MA , Almazni IA , Asiri SA , Sadiq A , Zafar R , Jan MS
Ref : J Biomol Struct Dyn , :1 , 2023
Abstract : Alzheimer's disease (AD) is a neurological disorder that progresses gradually but irreversibly leading to dementia and is difficult to prevent and treat. There is a considerable time window in which the progression of the disease can be intervened. Scientific advances were required to help the researchers to identify the effective methods for the prevention and treatment of disease. This research was designed to investigate potential mediators for the remedy of AD, five new carboxylate amide zinc complexes (AAZ9-AAZ13) were synthesized and characterized by spectroscopic and physicochemical techniques. The biological evaluation was carried out based on the cholinesterase inhibitory mechanism. The preparation methodology provided the effective synthesis of targeted moieties. The in vitro pharmacological activities were evaluated involving AChE/BChE inhibition and antioxidant potential. All synthesized compounds displayed activity against both enzymes in higher or comparable to the standard drug Galantamine, a reversible inhibitor but the results displayed by compound AAZ10 indicated IC(50) of 0.0013 microM (AChE) and 0.061 microM (BChE) as high values for dual AChE/BChE inhibition with potent anti-oxidant results. Structure activity relationship (SAR) indicated that the potent activity of compound AAZ10 appeared due to the presence of nitro clusters at the ortho position of an aromatic ring. The potent synthesized compound AAZ10 was also explored for the in-vivo Anti-Alzheimer activity and anti-oxidant activity. Binding approaches of all synthesized compounds were revealed through molecular docking studies concerning binding pockets of enzymes that analyzed the best posture interaction with amino acid (AA) residues providing an appreciable understanding of enzyme inhibitory mechanisms. Results indicate that synthesized zinc (II) amide carboxylates can behave as an effective remedy in the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.
ESTHER : Mahnashi_2023_J.Biomol.Struct.Dyn__1
PubMedSearch : Mahnashi_2023_J.Biomol.Struct.Dyn__1
PubMedID: 37642974

Title : Succinimide Derivatives as Antioxidant Anticholinesterases, Anti-alpha-Amylase, and Anti-alpha-Glucosidase: In Vitro and In Silico Approaches - Alshehri_2022_Evid.Based.Complement.Alternat.Med_2022_6726438
Author(s) : Alshehri OM , Mahnashi MH , Sadiq A , Zafar R , Jan MS , Ullah F , Alshehri MA , Alshamrani S , Hassan EE
Ref : Evid Based Complement Alternat Med , 2022 :6726438 , 2022
Abstract : Based on the diverse pharmacological potency and the structural features of succinimide, this research considered to synthesize succinimide derivatives. Moreover, these compounds were estimated for their biological potential in terms of anti-diabetic, anti-cholinesterase, and anti-oxidant capacities. The compounds were synthesized through Michael addition of various ketones to N-aryl maleimides. Similarly, the MOE software was used for the molecular docking study to explore the binding mode of the potent compounds against different enzymes. In the anti-cholinesterase activity, the compounds MSJ2 and MSJ10 exhibited outstanding activity against acetylcholinesterase (AChE), i.e., 91.90, 93.20%, and against butyrylcholinesterase (BChE), i.e., 97.30, 91.36% inhibitory potentials, respectively. The compounds MSJ9 and MSJ10 exhibited prominent alpha-glucosidase inhibitory potentials, i.e., 87.63 and 89.37 with IC(50) value of 32 and 28.04 microM, respectively. Moreover, the compounds MSJ2 and MSJ10 revealed significant scavenging activity against DPPH free radicals with IC(50) values of 2.59 and 2.52, while against ABTS displayed excellent scavenging potential with IC(50) values 7.32 and 3.29 microM, respectively. The tentative results are added with molecular docking studies in the active sites of enzymes to predict the theoretical protein-ligand binding modes. Further detailed mechanism-based studies in animal models are essential for the in vivo evaluation of the potent compound.
ESTHER : Alshehri_2022_Evid.Based.Complement.Alternat.Med_2022_6726438
PubMedSearch : Alshehri_2022_Evid.Based.Complement.Alternat.Med_2022_6726438
PubMedID: 35942378

Title : Inhibitory potential of nitrogen, oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase - Obaid_2022_RSC.Adv_12_19764
Author(s) : Obaid RJ , Naeem N , Mughal EU , Al-Rooqi MM , Sadiq A , Jassas RS , Moussa Z , Ahmed SA
Ref : RSC Adv , 12 :19764 , 2022
Abstract : Heterocycles are the key structures in organic chemistry owing to their immense applications in the biological, chemical, and pharmaceutical fields. Heterocyclic compounds perform various noteworthy functions in nature, medication, innovation etc. Most frequently, pure nitrogen heterocycles or various positional combinations of nitrogen, oxygen, and sulfur atoms in five or six-membered rings can be found. Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes is a popular strategy for the management of numerous mental diseases. In this context, cholinesterase inhibitors are utilized to relieve the symptoms of neurological illnesses like dementia and Alzheimer's disease (AD). The present review focuses on various heterocyclic scaffolds and their role in designing and developing new potential AChE and BChE inhibitors to treat AD. Moreover, a detailed structure-activity relationship (SAR) has been established for the future discovery of novel drugs for the treatment of AD. Most of the heterocyclic motifs have been used in the design of new potent cholinesterase inhibitors. In this regard, this review is an endeavor to summarize the biological and chemical studies over the past decade (2010-2022) describing the pursuit of new N, O and S containing heterocycles which can offer a rich supply of promising AChE and BChE inhibitory activities.
ESTHER : Obaid_2022_RSC.Adv_12_19764
PubMedSearch : Obaid_2022_RSC.Adv_12_19764
PubMedID: 35919585

Title : Diclofenac derivatives as concomitant inhibitors of cholinesterase, monoamine oxidase, cyclooxygenase-2 and 5-lipoxygenase for the treatment of Alzheimer's disease: synthesis, pharmacology, toxicity and docking studies - Javed_2022_RSC.Adv_12_22503
Author(s) : Javed MA , Bibi S , Jan MS , Ikram M , Zaidi A , Farooq U , Sadiq A , Rashid U
Ref : RSC Adv , 12 :22503 , 2022
Abstract : Targeting concomitantly cholinesterase (ChEs) and monoamine oxidases (MAO-A and MAO-B) is a key strategy to treat multifactorial Alzheimer's disease (AD). Moreover, it is reported that the expression of cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) is increased significantly in the brain of AD patients. Using the triazole of diclofenac 12 as a lead compound, we synthesized a variety of analogs as multipotent inhibitors concomitantly targeting COX-2, 5-LOX, AChE, BChE, MAO-A and MAO-B. A number of compounds showed excellent in vitro inhibition of the target biological macromolecules in nanomolar concentration. Compound 39 emerged as the most potent multitarget ligand with IC(50) values of 0.03 microM, 0.91 microM, 0.61 microM, 0.01 microM 0.60 microM and 0.98 microM towards AChE, BChE, MAO-A, MAO-B, COX-2 and 5-LOX respectively. All the biologically active compounds were found to be non-neurotoxic and blood-brain barrier penetrant by using PAMPA assay. In a reversibility assay, all the studied active compounds showed reversibility and thus were found to be devoid of side effects. MTT assay results on neuroblastoma SH-SY5Y cells showed that the tested compounds were non-neurotoxic. An in vivo acute toxicity study showed the safety of the synthesized compounds up to a 2000 mg kg(-1) dose. In docking studies three-dimensional construction and interaction with key residues of all the studied biological macromolecules helped us to explain the experimental results.
ESTHER : Javed_2022_RSC.Adv_12_22503
PubMedSearch : Javed_2022_RSC.Adv_12_22503
PubMedID: 36105972

Title : Prospective Evaluation of an Amide-Based Zinc Scaffold as an Anti-Alzheimer Agent: In Vitro, In Vivo, and Computational Studies - Waseem_2022_ACS.Omega_7_26723
Author(s) : Waseem W , Anwar F , Saleem U , Ahmad B , Zafar R , Anwar A , Saeed Jan M , Rashid U , Sadiq A , Ismail T
Ref : ACS Omega , 7 :26723 , 2022
Abstract : Alzheimer's disease is the most common progressive neurodegenerative mental disorder associated with loss of memory, decline in cognitive function, and dysfunction of language. The prominent pathogenic causes of this disease involve deposition of amyloid-beta plaques, acetylcholine neurotransmitter deficiency, and accumulation of neurofibrillary tangles. There are multiple pathways that have been targeted to treat this disease. The inhibition of the intracellular cyclic AMP regulator phosphodiesterase IV causes the increase in CAMP levels that play an important role in the memory formation process. Organometallic chemistry works in a different way in treating pharmacological disorders. In the field of medicinal chemistry and pharmaceuticals, zinc-based amide carboxylates have been shown to be a preferred pharmacophore. The purpose of this research work was to investigate the potential of zinc amide carboxylates in inhibition of phosphodiesterase IV for the Alzheimer's disease management. Swiss Albino mice under controlled conditions were divided into seven groups with 10 mice each. Group I was injected with carboxymethylcellulose (CMC) at 1 mL/100 g dose, group II was injected with Streptozotocin (STZ) at 3 mg/kg dose, group III was injected with Piracetam acting as a standard drug at 200 mg/kg dosage, while groups IV-VII were injected with a zinc scaffold at the dose regimen of 10, 20, 40, and 80 mg/kg through intraperitoneal injection. All groups except group I were injected with Streptozotocin on the first day and third day of treatment at the dose of 3 mg/kg through an intracerebroventricular route to induce Alzheimer's disease. Afterward, respective treatment was continued for all groups for 23 days. In between the treatment regimen, groups were analyzed for memory and learning improvement through various behavioral tests such as open field, elevated plus maze, Morris water maze, and passive avoidance tests. At the end of the study, different biochemical markers in the brain were estimated like neurotransmitters (dopamine, serotonin and adrenaline), oxidative stress markers (superoxide dismutase, glutathione, and catalase), acetylcholinesterase (AchE), tau proteins, and amyloid-beta levels. A PCR study was also performed. Results showed that the LD(50) of the zinc scaffold is greater than 2000 mg/kg. Research indicated that the zinc scaffold has the potential to improve the memory impairment and learning behavior in Alzheimer's disease animal models in a dose-dependent manner. At the dose of 80 mg/kg, a maximum response was observed for the zinc scaffold. Maximum reduction in the acetylcholinesterase enzyme was observed at 80 mg/kg dose, which was further strengthened and verified by the PCR study. Oxidative stress was restored by the zinc scaffold due to the significant activation of the endogenous antioxidant enzymes. This research ended up with the conclusion that the zinc-based amide carboxylate scaffold has the potential to improve behavioral disturbances and vary the biochemical markers in the brain.
ESTHER : Waseem_2022_ACS.Omega_7_26723
PubMedSearch : Waseem_2022_ACS.Omega_7_26723
PubMedID: 35936440

Title : In-Vitro, In-Vivo, Molecular Docking and ADMET Studies of 2-Substituted 3,7-Dihydroxy-4H-chromen-4-one for Oxidative Stress, Inflammation and Alzheimer's Disease - Mahnashi_2022_Metabolites_12_
Author(s) : Mahnashi MH , Alshahrani MA , Nahari MH , Hassan SSU , Jan MS , Ayaz M , Ullah F , Alshehri OM , Alshehri MA , Rashid U , Sadiq A
Ref : Metabolites , 12 : , 2022
Abstract : Plants' bioactives are well-known safe drugs for vital diseases. Flavones and Flavonoid-rich dietary supplements are known to exhibit neuroprotective potential. In this study, we isolated a flavone 2-(3,4-dimethoxyphenyl)-3,7-dihydroxy-4H-chromen-4-one from Notholirion thomsonianum and it was evaluated against various targets of the oxidative stress-related neurological disorders. The compound showed excellent acetyl and butyrylcholinesterase inhibitions in its profile, giving IC(50) values of 1.37 and 0.95 M, respectively. Similarly, in in-vitro MAO-B assay, our flavone exhibited an IC(50) value of 0.14 M in comparison to the standard safinamide (IC(50) 0.025 M). In in-vitro anti-inflammatory assay, our isolated compound exhibited IC(50) values of 7.09, 0.38 and 0.84 M against COX-1, COX-2 and 5-LOX, respectively. The COX-2 selectivity (SI) of the compound was 18.70. The compound was found safe in animals and was very effective in carrageenan-induced inflammation. Due to the polar groups in the structure, a very excellent antioxidant profile was observed in both in-vitro and in-vivo models. The compound was docked into the target proteins of the respective activities and the binding energies confirmed the potency of our compound. Furthermore, absorption, distribution, metabolism, excretion, and toxicity (ADMET) results showed that the isolated flavone has a good GIT absorption ability and comes with no hepatic and cardiotoxicity. In addition, the skin sensitization test, in-vitro human cell line activation test (h-CLAT) and KeratinoSens have revealed that isolated flavone is not skin sensitive with a confidence score of 59.6% and 91.6%. Herein, we have isolated a natural flavone with an effective profile against Alzheimer's, inflammation and oxidative stress. The exploration of this natural flavone will provide a baseline for future research in the field of drug development.
ESTHER : Mahnashi_2022_Metabolites_12_
PubMedSearch : Mahnashi_2022_Metabolites_12_
PubMedID: 36355138

Title : Neuroprotective potentials of selected natural edible oils using enzyme inhibitory, kinetic and simulation approaches - Mahnashi_2021_BMC.Complement.Med.Ther_21_248
Author(s) : Mahnashi MH , Alyami BA , Alqahtani YS , Alqarni AO , Jan MS , Ayaz M , Ullah F , Shahid M , Rashid U , Sadiq A
Ref : BMC Complement Med Ther , 21 :248 , 2021
Abstract : BACKGROUND: Edible oils have proven health benefits in the prevention and treatment of various disorders since the establishment of human era. This study was aimed to appraise neuropharmacological studies on the commonly used edible oils including Cinnamomum verum (CV), Zingiber officinale (ZO) and Cuminum cyminum (CC). METHODS: The oils were analyzed via GC-MS for identifications of bioactive compounds. Anti-radicals capacity of the oils were evaluated via 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals scavenging assays. The samples were also tested against two important acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are among the important drug targets in Alzheimer's disease. Lineweaver-Burk plots were constructed for enzyme inhibition studies which correspond to velocity of enzymes (V(max)) against the reciprocal of substrate concentration (K(m)) in the presence of test samples and control drugs following Michaelis-Menten kinetics. Docking studies on AChE target were also carried out using Molecular Operating Environment (MOE 2016.0802) software. RESULTS: (Gas chromatography-mass spectrometry GC-MS) analysis revealed the presence of thirty-four compounds in Cinnamon oil (Cv.Eo), fourteen in ginger oil (Zo.Eo) and fifty-six in cumin oil (Cc.Eo). In the antioxidant assays, Cv.Eo, Zo.Eo and Cc.Eo exhibited IC(50) values of 85, 121, 280 microg/ml sequentially against DPPH radicals. Whereas, in ABTS assay, Cv.Eo, Zo.Eo and Cc.Eo showed considerable anti-radicals potentials with IC(50) values of 93, 77 and 271 microg/ml respectively. Furthermore, Cv.Eo was highly active against AChE enzyme with IC(50) of 21 microg/ml. Zo.Eo and Cc.Eo exhibited considerable inhibitory activities against AChE with IC(50) values of 88 and 198 microg/ml respectively. In BChE assay, Cv.Eo, Zo.Eo and Cc.Eo exhibited IC(50) values of 106, 101 and 37 microg/ml respectively. Our results revealed that these oils possess considerable antioxidant and cholinesterase inhibitory potentials. As functional foods these oils can be effective remedy for the prevention and management of neurological disorders including AD. Synergistic effect of all the identified compounds was determined via binding energy values computed through docking simulations. Binding orientations showed that all the compounds interact with amino acid residues present in the peripheral anionic site (PAS) and catalytic anionic site (CAS) amino acid residues, oxyanion hole and acyl pocket via Pi-Pi stacking interactions and hydrogen bond interactions.
ESTHER : Mahnashi_2021_BMC.Complement.Med.Ther_21_248
PubMedSearch : Mahnashi_2021_BMC.Complement.Med.Ther_21_248
PubMedID: 34600509

Title : Prospective Application of Two New Pyridine-Based Zinc (II) Amide Carboxylate in Management of Alzheimer's Disease: Synthesis, Characterization, Computational and in vitro Approaches - Zafar_2021_Drug.Des.Devel.Ther_15_2679
Author(s) : Zafar R , Naureen H , Zubair M , Shahid K , Saeed Jan M , Akhtar S , Ahmad H , Waseem W , Haider A , Ali S , Tariq M , Sadiq A
Ref : Drug Des Devel Ther , 15 :2679 , 2021
Abstract : BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative illness described predominantly by dementia. Even though Alzheimer's disease has been known for over a century, its origin remains a mystery, and researchers are exploring many therapy options, including the cholinesterase technique. A decreased acetylcholine ACh neurotransmitter level is believed to be among the important factors in the progression of Alzheimer's disease. METHODS: In continuation of synthesizing potential anti-Alzheimer agents and known appreciative pharmacological potential of amide-containing compounds, this study presents the synthesis of two novel amide-based transition metal zinc (II) complexes, AAZ7 and AAZ8, attached with a heterocyclic pyridine ring, which was synthesized and characterized by Fourier transform infrared spectroscopy (FT-IR), elemental analysis, (1)H_NMR, and (13)C_NMR. FT-IR spectroscopic records showed the development of bidentate ligand as deltav value was decreased in both complexes when compared with the free ligand. Both of the synthesized complexes were analyzed for acetylcholinesterase and butyrylcholinesterase inhibitory potential along with the antioxidizing activity. RESULTS: Importantly, the complex of AAZ8 exhibited more potent activity giving IC(50) values of 14 microg/mL and 18microg/mL as AChE and BChE cholinesterase inhibitors, respectively, when compared with standard positive control galantamine. Interestingly, AAZ8 also displayed promising antioxidant potential by showing IC(50) values of 35 microg/mL for DPPH and 29 microg/mL for ABTS in comparison with positive control ascorbic acid. CONCLUSION: Herein, we report two new amide carboxylate zinc (II) complexes which were potentially analyzed for various biological applications like acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory potentials, and antioxidant assays. Computational docking studies also simulated results to understand the interactions. Additionally, thermodynamic parameters utilizing molecular dynamic simulation were performed to determine the ligand protein stability and flexibility that supported the results. Studies have shown that these compounds have the potential to be good anti-Alzheimer candidates for future studies due to inhibition of cholinesterase enzymes and display of free radical scavenging potential against DPPH as well as ABTS free radicals.
ESTHER : Zafar_2021_Drug.Des.Devel.Ther_15_2679
PubMedSearch : Zafar_2021_Drug.Des.Devel.Ther_15_2679
PubMedID: 34188447

Title : Structural Modification, In Vitro, In Vivo, Ex Vivo, and In Silico Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer's Disease - Javed_2021_ACS.Chem.Neurosci__
Author(s) : Javed MA , Ashraf N , Saeed Jan M , Mahnashi MH , Alqahtani YS , Alyami BA , Alqarni AO , Asiri YI , Ikram M , Sadiq A , Rashid U
Ref : ACS Chem Neurosci , : , 2021
Abstract : To obtain a multipotent framework that can target simultaneously COX-2, 5-LOX, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) to treat neuroinflammation, a series of derivatives containing pyrimidine and pyrrolidine cores were rationally synthesized and evaluated. Pyrazoline-pyrimidine hybrid (23g), (3-acetylcoumarin derivative of pyrrolidin-1-yl)benzenesulfonamide (27), and tacrine derivatives of (pyrrolidin-1-yl)benzenesulfonamide (31, 38) displayed excellent in vitro COX-2 inhibition having IC(50) value in the nanomolar range. Tacrine-pyrrolidine hybrids 36 and 38, and tacrine-pyrimidine hybrid (46) emerged as the most potent eeAChE inhibitors with IC(50) values of 23, 16, and 2 nM, respectively. However, compounds 27, 31, and 38 possessed excellent simultaneous and balanced inhibitory activity against all of the four tested targets and thus emerged as optimal multipotent hybrid compounds among all of the synthesized series of the compounds. In the ex vivo, transgenic animal models treated with compounds 36 and 46 displayed a significant decline in both AChE and BChE potentials in the hippocampus and cortical tissues. In anti-inflammatory activities, animals treated with compounds 36 and 46 displayed a significant % inhibition of edema induced by carrageenan and arachidonic acid. Biochemical analysis and histopathological examination of mice liver indicate that tacrine derivatives are devoid of hepatotoxicity and neurotoxicity against SH-SY5Y neuroblastoma cell lines. In vivo acute toxicity study showed the safety of synthesized compounds up to 1000 mg/kg dose. The inhibitory manner of interaction of these potent drugs on all of the studied in vitro targets was confirmed by molecular docking investigations.
ESTHER : Javed_2021_ACS.Chem.Neurosci__
PubMedSearch : Javed_2021_ACS.Chem.Neurosci__
PubMedID: 34643082

Title : Neuroprotective Studies on Polygonum hydropiper L. Essential Oils Using Transgenic Animal Models - Tong_2020_Front.Pharmacol_11_580069
Author(s) : Tong X , Li X , Ayaz M , Ullah F , Sadiq A , Ovais M , Shahid M , Khayrullin M , Hazrat A
Ref : Front Pharmacol , 11 :580069 , 2020
Abstract : Polygonum hydropiper L. and related species are reported to possess neuroprotective potentials. In an attempt to validate its anti-Alzheimer's potentials, leaf oils (Ph. Lo) were extensively evaluated in this study against several in vitro and in vivo models of Alzheimer's disease. The Ph. Lo were tested against pathological targets of Alzheimer's diseases (ADs). The in vitro and in vivo assays were done for cholinesterase inhibition, anti-radical properties and cognitive assessments using transgenic animal models. In preliminary cholinesterase inhibition assays, Ph. Lo were more active against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2-azinobis (3-ethylbenzthiazoline)-6-sulfonic acid (ABTS), and hydrogen peroxide (H(2)O(2)) radicals. Subsequently, Ph. Lo was evaluated for its effects on special memory, exploratory behavior, and coordination using shallow water maze (SWM), Y-maze, open filed, and balance beam tests. Animal pre-genotyping was done via polymerase chain reaction (PCR) to confirm amyloid precursor protein (APP) transgene, and after completion of drug therapy, brain homogenates from the cortex and hippocampus were evaluated for cholinesterase and free radical studies. In SWM task, disease control animals treated with 10 mg/kg of Ph. Lo for 5 days exhibited significant improvement in cognitive performance indicated by low escape times on 5th day compared with normal animals. In the Y-maze test, transgenic animals showed higher spontaneous alternation behavior than disease control animals and standard control group animals. Ph. Lo therapy has improved the exploratory behavior and declined anxiety behavior in diseased animals as accessed via open field test. Ph. Lo administration significantly augmented the motor and coordination abilities of transgenic animals when compared to other groups of animals and declined AChE, BChE activities as well as free radicals load in the cortex and hippocampus tissues. Based on our finding, it is concluded that Ph. Lo exhibit significant neuroprotective potentials preliminary due to their anti-radicals and cholinesterase inhibitory activities. Ph. Lo need further detailed studies as potential aromatherapy against neurodegenerative disorders.
ESTHER : Tong_2020_Front.Pharmacol_11_580069
PubMedSearch : Tong_2020_Front.Pharmacol_11_580069
PubMedID: 33584260

Title : Exploring 3-Benzyloxyflavones as new lead cholinesterase inhibitors: synthesis, structure-activity relationship and molecular modelling simulations - Mughal_2020_J.Biomol.Struct.Dyn__1
Author(s) : Mughal EU , Sadiq A , Ayub M , Naeem N , Javid A , Sumrra SH , Zafar MN , Khan BA , Malik FP , Ahmed I
Ref : J Biomol Struct Dyn , :1 , 2020
Abstract : In this protocol, a series of 3-benzyloxyflavone derivatives have been designed, synthesized, characterized and investigated in vitro as cholinesterase inhibitors. The findings showed that all the synthesized target compounds (1-10) are potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes with varying IC(50) values. In comparison, they are more active against AChE than BChE. Remarkably, amongst the series, the compound 2 was identified as the most active inhibitor of both AChE (IC(50) = 0.05 +/- 0.01 muM) and BChE (IC(50) = 0.09 +/- 0.02 muM) relative to the standard Donepezil (IC(50) = 0.09 +/- 0.01 for AChE and 0.13 +/- 0.04 muM for BChE). Moreover, the derivatives 5 (IC(50) = 0.07 +/- 0.02 muM) and 10 (0.08 +/- 0.02 muM) exhibited the highest selective inhibition against AChE as compared to the standard. Preliminary structure-activity relationship was established and thus found that cholinesterase inhibitory activities of these compounds are highly dependent on the nature and position of various substituents on Ring-B of the 3-Benzyloxyflavone scaffolds. In order to find out the nature of binding interactions of the compounds and active sites of the enzymes, molecular docking studies were carried out. HIGHLIGHTS 3-benzyloxyflavone analogues were designed, synthesized and characterized. The target molecules (1-10) were evaluated for their inhibitory potential against AChE and BChE inhibitory activities. Limited structure-activity relationship was developed based on the different substituent patterns on aryl part. Molecular docking studies were conducted to correlate the in vitro results and to identify possible mode of interactions at the active pocket site of the enzyme.
ESTHER : Mughal_2020_J.Biomol.Struct.Dyn__1
PubMedSearch : Mughal_2020_J.Biomol.Struct.Dyn__1
PubMedID: 32752941

Title : SAR based in-vitro anticholinesterase and molecular docking studies of nitrogenous progesterone derivatives - Amin_2020_Steroids__108599
Author(s) : Amin MJ , Miana GA , Rashid U , Miraz Rahman K , Khan HU , Sadiq A
Ref : Steroids , :108599 , 2020
Abstract : Progesterone is a steroidal hormone that has been described with pathogenic features of brain dysfunction, realized with advanced age-related neurodegenerative diseases such as Alzheimer's disease. In this study, sixteen nitrogenous derivatives of progesterone which we previously synthesized have been used for Alzheimer targets. The progesterone derivatives (1-16) were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potentials in a dose-dependent manner. All the compounds exhibited overwhelming AChE inhibitions, with IC50 values ranging from 14.40 to 40.37 muM. Similarly, the BChE inhibitory potentials of our compounds were also dominant with IC50values between 20.08 and 46.84 muM. In comparison to our compounds, the standard drug galantamine attain IC50 values of 12.03 and 18.20 muM against AChE and BChE respectively. Molecular docking studies suggested that the compounds exerted their inhibitory activity by binding to the active site of the enzyme. The cholinergic system plays an important role in the regulation of learning and memory processes and has been a major target for the design of anti-Alzheimer's drugs. Therefore, these nitrogen-containing progesterone derivatives will be of potential interest to researchers working in AD for developing new drugs or chemical tools to study the disease.
ESTHER : Amin_2020_Steroids__108599
PubMedSearch : Amin_2020_Steroids__108599
PubMedID: 32126219

Title : Zinc metal carboxylates as Potential anti-Alzheimer's candidate: In-vitro anticholinesterase, antioxidant and molecular docking studies - Zafar_2020_J.Biomol.Struct.Dyn__1
Author(s) : Zafar R , Zubair M , Ali S , Shahid K , Waseem W , Naureen H , Haider A , Saeed Jan M , Ullah F , Sirajuddin M , Sadiq A
Ref : J Biomol Struct Dyn , :1 , 2020
Abstract : In search of suitable therapy for the management of Alzheimer's disease, this study was designed to evaluate metal complexes against its biochemical targets. Zinc metal carboxylates (AAZ1 - AAZ6) were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The antioxidant in combination with anticholinesterase activity can be considered as an important target in the management of Alzheimer's disease. Therefore, these compounds were also screened for ABTS and DPPH free radicals scavenging activity. In AChE inhibition assay, we noticed encouraging IC50 values of 33.07 and 59.52 microM for compounds AAZ5 and AAZ3 respectively. However, when we tested BChE activity, we observed an outstanding IC50 of 0.056 microM for compound AAZ6. Amazingly all of our compounds (AAZ1 - AAZ6) were proved to be strong antioxidants which actively supplement the anti-Alzheimer's activity. Majority of our compounds exhibited lower IC50 values than the standard ascorbic acid both in DPPH and ABTS assays. We also correlated our results with molecular docking studies. Results elaborated that AAZ 1 and AAZ 5 exhibits strong interactions with amino acids HIS 362, HIS 398, GLU 306 ARG 289 and SER 237 inside binding pocket of targeted protein. In remarks, we can claim that our synthesized zinc metal carboxylates have strong potency to manage Alzheimer's disease on both anticholinesterase and antioxidant targets.
ESTHER : Zafar_2020_J.Biomol.Struct.Dyn__1
PubMedSearch : Zafar_2020_J.Biomol.Struct.Dyn__1
PubMedID: 32013770

Title : Comparative Cholinesterase, alpha-Glucosidase Inhibitory, Antioxidant, Molecular Docking, and Kinetic Studies on Potent Succinimide Derivatives - Ahmad_2020_Drug.Des.Devel.Ther_14_2165
Author(s) : Ahmad A , Ullah F , Sadiq A , Ayaz M , Saeed Jan M , Shahid M , Wadood A , Mahmood F , Rashid U , Ullah R , Sahibzada MUK , Alqahtani AS , Mahmood HM
Ref : Drug Des Devel Ther , 14 :2165 , 2020
Abstract : Introduction: The current study was designed to synthesize derivatives of succinimide and compare their biological potency in anticholinesterase, alpha-glucosidase inhibition, and antioxidant assays. Methods: In this research, two succinimide derivatives including (S)-1-(2,5-dioxo-1-phenylpyrrolidin-3-yl) cyclohexanecarbaldehyde (Compound 1) and (R)-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-phenylpropanal (Compound 2) were synthesized using Michael addition. Both the compounds, ie, 1 and 2 were evaluated for in-vitro acetylcholinesterase (AChE), butyrylctcholinesterase (BChE), antioxidant, and alpha-glucosidase inhibitory potentials. Furthermore, molecular docking was performed using Molecular Operating Environment (MOE) to explore the binding mode of both the compounds against different enzymes. Lineweaver-Burk plots of enzyme inhibitions representing the reciprocal of initial enzyme velocity versus the reciprocal of substrate concentration in the presence of synthesized compounds and standard drugs were constructed using Michaelis-Menten kinetics. Results: In AChE inhibitory assay, compounds 1 and 2 exhibited IC50 of 343.45 and 422.98 microM, respectively, against AChE enzyme. Similarly, both the compounds showed IC50 of 276.86 and 357.91 microM, respectively, against BChE enzyme. Compounds 1 and 2 displayed IC50 of 157.71 and 471.79 microM against alpha-glucosidase enzyme, respectively. In a similar pattern, compound 1 exhibited to be more potent as compared to compound 2 in all the three antioxidant assays. Compound 1 exhibited IC50 values of 297.98, 332.94, and 825.92 microM against DPPH, ABTS, and H2O2 free radicals, respectively. Molecular docking showed a triple fold in the AChE and BChE activity for compound 1 compared with compound 2. The compound 1 revealed good interaction against both the AChE and BChE enzymes which revealed the high potency of this compound compared to compound 2. Conclusion: Both succinimide derivatives exhibited considerable inhibitory activities against cholinesterases and alpha-glucosidase enzymes. Of these two, compound 1 revealed to be more potent against all the in-vitro targets which was supported by molecular docking with the lowest binding energies. Moreover, compound 1 also proved to have antiradical properties.
ESTHER : Ahmad_2020_Drug.Des.Devel.Ther_14_2165
PubMedSearch : Ahmad_2020_Drug.Des.Devel.Ther_14_2165
PubMedID: 32606589

Title : Flavonols and 4-thioflavonols as potential acetylcholinesterase and butyrylcholinesterase inhibitors: Synthesis, structure-activity relationship and molecular docking studies - Mughal_2019_Bioorg.Chem_91_103124
Author(s) : Mughal EU , Sadiq A , Ashraf J , Zafar MN , Sumrra SH , Tariq R , Mumtaz A , Javid A , Khan BA , Ali A , Javed CO
Ref : Bioorg Chem , 91 :103124 , 2019
Abstract : To explore new scaffolds for the treat of Alzheimer's disease appears to be an inspiring goal. In this context, a series of varyingly substituted flavonols and 4-thioflavonols have been designed and synthesized efficiently. All the newly synthesized compounds were characterized unambiguously by common spectroscopic techniques (IR, (1)H-, (13)C NMR) and mass spectrometry (EI-MS). All the derivatives (1-24) were evaluated in vitro for their inhibitory potential against cholinesterase enzymes. The results exhibited that these derivatives were potent selective inhibitors of acetylcholinesterase (AChE), except the compound 11 which was selective inhibitor of butyrylcholinesterase (BChE), with varying degree of IC50 values. Remarkably, the compounds 20 and 23 have been found the most potent almost dual inhibitors of AChE and BChE amongst the series with IC50 values even less than the standard drug. The experimental results in silico were further validated by molecular docking studies in order to find their binding modes with the active pockets of AChE and BChE enzymes.
ESTHER : Mughal_2019_Bioorg.Chem_91_103124
PubMedSearch : Mughal_2019_Bioorg.Chem_91_103124
PubMedID: 31319297

Title : Pharmacological Evaluation of Aldehydic-Pyrrolidinedione Against HCT-116, MDA-MB231, NIH\/3T3, MCF-7 Cancer Cell Lines, Antioxidant and Enzyme Inhibition Studies - Ahmad_2019_Drug.Des.Devel.Ther_13_4185
Author(s) : Ahmad A , Ullah F , Sadiq A , Ayaz M , Rahim H , Rashid U , Ahmad S , Jan MS , Ullah R , Shahat AA , Mahmood HM
Ref : Drug Des Devel Ther , 13 :4185 , 2019
Abstract : Purpose: The current work was designed to synthesize a bioactive derivative of succinimide and evaluate it for anti-Alzheimer, anticancer and anti-diabetic potentials. Methods: The compound was synthesized by Michael addition of butyraldehyde with N-phenylmaleimide. The synthesized compound was screened for biological potentials including anti-cholinesterase, in-vitro anti-diabetic, antioxidant and anthelmintic potentials. The anti-cholinesterase potential was evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), anti-diabetic potential against alpha-glucosidase, antioxidant potential against ABTS, DPPH and H2O2 and anthelmintic potential against Perethima posthuma and Ascaridia galli respectively. Results: The compound demonstrated significant AChE and BChE inhibition i.e., 71.34+/-1.92 and 73.42 +/-1.92 at the concentration of 1000 microg/mL respectively. Other dilutions exhibited concentration-dependent inhibitory activity against both enzymes. In the MTT assay, the newly synthesized compound was found active against all of the cell lines viz, HCT-116, MDA-MB231, NIH/3T3 and MCF-7 and the highest cytotoxicity potential was observed against the colon cancer cell line (HCT-116) with an IC50 value of 78 microg/mL exhibiting its highest potential. Moreover, the compound exhibited prominent alpha-glucosidase inhibitory potentials (79.86+/-2.54% at 1000 microg/mL) with IC50 value of 156.23 microg/mL. Further, our test compound exhibited considerable scavenging activity against DPPH, ABTS and H2O2 free radicals with percent inhibitions of 75.84+/-1.58, 72.85+/-1.17 and 54.82+/-1.82 and IC50 values of 84.36, 139.74 and 752.21 microg/mL respectively. Our test sample exhibited significant anthelmintic potentials. It demonstrated significant paralysis and death of the test worms in an unbelievably short time in comparison with albendazole. Conclusion: Going into the detail of all observations, it may be deduced that the newly synthesized succinimide derivative could be an important drug candidate against neurodegenerative disorders like Alzheimer's disease, cancer, diabetes mellitus and worms. Further detailed studies in animal models are required for in-vivo analysis of the compound.
ESTHER : Ahmad_2019_Drug.Des.Devel.Ther_13_4185
PubMedSearch : Ahmad_2019_Drug.Des.Devel.Ther_13_4185
PubMedID: 31849450

Title : Flavonoids as Prospective Neuroprotectants and Their Therapeutic Propensity in Aging Associated Neurological Disorders - Ayaz_2019_Front.Aging.Neurosci_11_155
Author(s) : Ayaz M , Sadiq A , Junaid M , Ullah F , Ovais M , Ullah I , Ahmed J , Shahid M
Ref : Front Aging Neurosci , 11 :155 , 2019
Abstract : Modern research has revealed that dietary consumption of flavonoids and flavonoids-rich foods significantly improve cognitive capabilities, inhibit or delay the senescence process and related neurodegenerative disorders including Alzheimer's disease (AD). The flavonoids rich foods such as green tea, cocoa, blue berry and other foods improve the various states of cognitive dysfunction, AD and dementia-like pathological alterations in different animal models. The mechanisms of flavonoids have been shown to be mediated through the inhibition of cholinesterases including acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), beta-secretase (BACE1), free radicals and modulation of signaling pathways, that are implicated in cognitive and neuroprotective functions. Flavonoids interact with various signaling protein pathways like ERK and PI3-kinase/Akt and modulate their actions, thereby leading to beneficial neuroprotective effects. Moreover, they enhance vascular blood flow and instigate neurogenesis particularly in the hippocampus. Flavonoids also hamper the progression of pathological symptoms of neurodegenerative diseases by inhibiting neuronal apoptosis induced by neurotoxic substances including free radicals and beta-amyloid proteins (Abeta). All these protective mechanisms contribute to the maintenance of number, quality of neurons and their synaptic connectivity in the brain. Thus flavonoids can thwart the progression of age-related disorders and can be a potential source for the design and development of new drugs effective in cognitive disorders.
ESTHER : Ayaz_2019_Front.Aging.Neurosci_11_155
PubMedSearch : Ayaz_2019_Front.Aging.Neurosci_11_155
PubMedID: 31293414

Title : Isolation of bioactive compounds from Bergenia ciliata (haw.) Sternb rhizome and their antioxidant and anticholinesterase activities - Zafar_2019_BMC.Complement.Altern.Med_19_296
Author(s) : Zafar R , Ullah H , Zahoor M , Sadiq A
Ref : BMC Complement Altern Med , 19 :296 , 2019
Abstract : BACKGROUND: Bergenia ciliata is a medicinal plant used for the treatment of diarrhea, vomiting, fever, cough, diabetes, cancer, pulmonary disorders and wound healing. METHODS: In this study, Bergenia ciliata crude extract, subfractions, and isolated compounds were evaluated for their antioxidant and anticholinesterase potential. The free radical scavenging capacities of the extracts determined using DPPH and ABTS assays. The anticholinesterase potentials were determined using acetylcholine esterase and butyryl choline esterase enzymes. To determine the phytochemical composition, the extracts were subjected to HPLC analysis and silica gel column isolation. Based on HPLC fingerprinting results, the ethyl acetate fraction was found to have more bioactive compounds and was therefore subjected to silica gel column isolation. As a result, three compounds; pyrogallol, rutin, and morin were isolated in the pure state. The structures of the isolated compounds were elucidated using spectroscopic techniques like (1)H-NMR, IR and UV-Visible. RESULTS: The crude extract showed maximum anticholinesterase (acetylcholinesterase = 90.22 +/- 1.15% and butyrylcholinesterase = 88.22 +/- 0.71%) and free radical scavenging (87.37 +/- 2.45 and 83.50 +/- 0.70% respectively against DPPH and ABTS radicals) potentials. The total phenolic contents (expressed as equivalent of gallic acid; mgGAE/g) were higher in ethyl acetate fraction (80.96 +/- 1.74) followed by crude extract (70.65 +/- 0.86) while the flavonoid contents (expressed as quercetin equivalent; mgQE/g) and were higher in crude extract (88.40 +/- 1.12) followed by n-butanol fraction (60.10 +/- 1.86). The isolated bioactive compounds pyrogallol, rutin, and morin were found active against ABTS and DPPH free radicals. Amongst them, pyrogallol was more active against both free radicals. Reasonable anticholinesterase activities were recorded for pyrogallol against selected enzymes. CONCLUSION: The extracts and isolated compounds showed antioxidant and acetylcholinesterase inhibitory potentials. It was concluded that this plant could be helpful in the treatment of oxidative stress and neurological disorders if used in the form of extracts.
ESTHER : Zafar_2019_BMC.Complement.Altern.Med_19_296
PubMedSearch : Zafar_2019_BMC.Complement.Altern.Med_19_296
PubMedID: 31694704

Title : Synthesis, in-vitro cholinesterase inhibition, in-vivo anticonvulsant activity and in-silico exploration of N-(4-methylpyridin-2-yl)thiophene-2-carboxamide analogs - Ahmad_2019_Bioorg.Chem_92_103216
Author(s) : Ahmad G , Rasool N , Rizwan K , Imran I , Zahoor AF , Zubair M , Sadiq A , Rashid U
Ref : Bioorg Chem , 92 :103216 , 2019
Abstract : In our current research, a diverse effect of acetylcholinesterase inhibitors was studied on BALB-C mice by using pentylenetetrazole (PTZ) seizure model. A series of carboxamide analogs (4a-4i) have been synthesized via Suzuki coupling reaction in moderate to good yields (35-84%). To study the efficacy of the synthesized compounds against AD, in-vitro inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) was performed. A number of compounds showed inhibition in low micromolar range. Subsequently, these compounds were evaluated for anticonvulsive effects in BALB-C mice by using pentylenetetrazole (PTZ) seizure model. The compound 4e displayed potential anticonvulsive effect and displayed 50% and 80% protection from mortality at the dose of 10mg/kg, and 30mg/kg respectively. The compound 4h showed some protection (33%) from mortality at 10mg/kg and was not further explored based on non-significant delay in onset of myoclonic seizures. While, other compounds from the series did not show any anticonvulsive activity. To rationalize the observed biological activity, we performed docking studies against AChE and BChE targets. To explore the rationale of the mechanism of in-vivo anticonvulsant activity, docking studies were performed on GABAergic receptors. Moreover, in order to establish a relationship between physiochemical data of the synthesized compounds and their in-vivo performance, we employed in-silico pharmacokinetic predictions. Our in-silico predictions suggest that the plasma protein binding, low to moderate blood brain barrier penetration and low solubility are the main attributes of low in-vivo performance.
ESTHER : Ahmad_2019_Bioorg.Chem_92_103216
PubMedSearch : Ahmad_2019_Bioorg.Chem_92_103216
PubMedID: 31491567

Title : Synthesis, structure-activity relationship and molecular docking studies of 3-O-flavonol glycosides as cholinesterase inhibitors - Mughal_2018_Bioorg.Med.Chem_26_3696
Author(s) : Mughal EU , Javid A , Sadiq A , Murtaza S , Zafar MN , Khan BA , Sumrra SH , Tahir MN , Kanwal , Khan KM
Ref : Bioorganic & Medicinal Chemistry , 26 :3696 , 2018
Abstract : The prime objective of this research work is to prepare readily soluble synthetic analogues of naturally occurring 3-O-flavonol glycosides and then investigate the influence of various substituents on biological properties of synthetic compounds. In this context, a series of varyingly substituted 3-O-flavonol glycosides have been designed, synthesized and characterized efficiently. The structures of synthetic molecules were unambiguously corroborated by IR, (1)H, (13)C NMR and ESI-MS spectroscopic techniques. The structure of compound 22 was also analyzed by X-ray diffraction analysis. All the synthetic compounds (21-30) were evaluated for in vitro inhibitory potential against cholinesterase enzymes. The results displayed that most of the derivatives were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with varying degree of IC50 values. The experimental results were further encouraged by molecular docking studies in order to explore their binding behavior with the active pocket of AChE and BChE enzymes. The experimental and theoretical results are in parallel with one another.
ESTHER : Mughal_2018_Bioorg.Med.Chem_26_3696
PubMedSearch : Mughal_2018_Bioorg.Med.Chem_26_3696
PubMedID: 29886083

Title : Chemical Characterization, Analgesic, Antioxidant, and Anticholinesterase Potentials of Essential Oils From Isodon rugosus Wall. ex. Benth - Sadiq_2018_Front.Pharmacol_9_623
Author(s) : Sadiq A , Zeb A , Ullah F , Ahmad S , Ayaz M , Rashid U , Muhammad N
Ref : Front Pharmacol , 9 :623 , 2018
Abstract : Isodon rugosus Wall. ex. Benth is an important species and is used in folk medicine for different types of pains such as abdominal pain, earache, toothache, gastric, and generalized body pain. Recently, we also have reported the antinociceptive potential of chloroform fraction of I. rugosus. In this research, we have investigated the antinociceptive, antioxidant and anti-cholinesterase potentials of essential oils from I. rugosus (Ir.EO), and have determined a possible mechanism of anti-nociception. The Ir.EO was subjected to gas chromatography-mass spectroscopy analysis to find out its chemical constituents. The Ir.EO was assayed for analgesic potential following acetic acid induced writhing, formalin test and hot plate method in animal models. The antioxidant activity was conducted against DPPH and ABTS free radicals following spectroscopic analysis. The cholinesterase inhibitory assays were performed using Ellman's assay. The GC-MS analysis of Ir.EO revealed the identification of 141 compounds. Ir.EO demonstrated strong antinociceptive potential in all three in-vivo models. With the use of nalaxone, it was confirmed that the essential oil was acting on the central pathway of nociception. The Ir.EO also exhibited strong free radicals scavenging potential, exhibiting IC50 values of 338 and 118 mug/ml for DPPH and ABTS free radicals respectively. In AChE and BChE inhibitory assays, the observed IC50 values were 93.56 and 284.19 mug/ml respectively. The encouraging antinociceptive, antioxidant and anticholinesterase results revealed that Ir.EO is a rich source of bioactive compounds as obvious from the GC-MS results.
ESTHER : Sadiq_2018_Front.Pharmacol_9_623
PubMedSearch : Sadiq_2018_Front.Pharmacol_9_623
PubMedID: 29950997

Title : Design, synthesis and bioevaluation of tricyclic fused ring system as dual binding site acetylcholinesterase inhibitors - Tanoli_2018_Bioorg.Chem_83_336
Author(s) : Tanoli ST , Ramzan M , Hassan A , Sadiq A , Jan MS , Khan FA , Ullah F , Ahmad H , Bibi M , Mahmood T , Rashid U
Ref : Bioorg Chem , 83 :336 , 2018
Abstract : Due to recently discovered non-classical acetylcholinesterase (AChE) function, dual binding-site AChE inhibitors have acquired a paramount attention of drug designing researchers. The unique structural arrangements of AChE peripheral anionic site (PAS) and catalytic site (CAS) joined by a narrow gorge, prompted us to design the inhibitors that can interact with dual binding sites of AChE. Eighteen homo- and heterodimers of desloratadine and carbazole (already available tricyclic building blocks) were synthesized and tested for their inhibition potential against electric eel acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBChE). We identified a six-carbon tether heterodimer of desloratadine and indanedione based tricyclic dihydropyrimidine (4c) as potent and selective inhibitor of eeAChE with IC50 value of 0.09+/-0.003muM and 1.04+/-0.08muM (for eqBChE) with selectivity index of 11.1. Binding pose analysis of potent inhibitors suggest that tricyclic ring is well accommodated into the AChE active site through hydrophobic interactions with Trp84 and Trp279. The indanone ring of most active heterodimer 4b is stabilized into the bottom of the gorge and forms hydrogen bonding interactions with the important catalytic triad residue Ser200.
ESTHER : Tanoli_2018_Bioorg.Chem_83_336
PubMedSearch : Tanoli_2018_Bioorg.Chem_83_336
PubMedID: 30399465

Title : Neurologically Potent Molecules from Crataegus oxyacantha\; Isolation, Anticholinesterase Inhibition, and Molecular Docking - Ali_2017_Front.Pharmacol_8_327
Author(s) : Ali M , Muhammad S , Shah MR , Khan A , Rashid U , Farooq U , Ullah F , Sadiq A , Ayaz M , Ahmad M , Latif A
Ref : Front Pharmacol , 8 :327 , 2017
Abstract : Crataegus oxyacantha is an important herbal supplement and famous for its antioxidant potential. The antioxidant in combination with anticholinesterase activity can be considered as an important target in the management of Alzheimer's disease. The compounds isolated from C. oxyacantha were evaluated for cholinesterases inhibitory activity using Ellman's assay with Galantamine as standard drug. Total of nine (1-9) compounds were isolated. Compounds 1 and 2 were isolated for the first time from natural source. Important natural products like beta-Sitosterol-3-O-beta-D-Glucopyranoside (3), lupeol (4), beta-sitosterol (5), betulin (6), betulinic acid (7), oleanolic acid (8), and chrysin (9) have also been isolated from C. oxyacantha. Overall, all the compounds exhibited an overwhelming acetylcholinesterase (AChE) inhibition potential in the range 5.22-44.47 muM. The compound 3 was prominent AChE inhibitor with IC50 value of 5.22 muM. Likewise, all the compounds were also potent in butyrylcholinesterase (BChE) inhibitions with IC50s of up to 0.55-15.36 muM. All the compounds, except 3, were selective toward BChE. Mechanism of the inhibition of both the enzymes were further studied by docking procedures using Genetic Optimization for Ligand Docking suit v5.4.1. Furthermore, computational blood brain barrier prediction of the isolated compounds suggest that these are BBB+.
ESTHER : Ali_2017_Front.Pharmacol_8_327
PubMedSearch : Ali_2017_Front.Pharmacol_8_327
PubMedID: 28638340

Title : Synthesis, crystal structure determination, biological screening and docking studies of N1-substituted derivatives of 2,3-dihydroquinazolin-4(1H)-one as inhibitors of cholinesterases - Sultana_2017_Bioorg.Chem_72_256
Author(s) : Sultana N , Sarfraz M , Tanoli ST , Akram MS , Sadiq A , Rashid U , Tariq MI
Ref : Bioorg Chem , 72 :256 , 2017
Abstract : Pursuing the strategy of developing potent AChE inhibitors, we attempted to carry out the N1-substitution of 2,3-dihydroquinazolin-4(1H)-one core. A set of 32 N-alkylated/benzylated quinazoline derivatives were synthesized, characterized and evaluated for their inhibition against cholinesterases. N-alkylation of the series of the compounds reported previously (N-unsubstituted) resulted in improved activity. All the compounds showed inhibition of both enzymes in the micromolar to submicromolar range. Structure activity relationship (SAR) of the 32 derivatives showed that N-benzylated compounds possess good activity than N-alkylated compounds. N-benzylated compounds 2ad and 2af were found very active with their IC50 values toward AChE in submicromolar range (0.8microM and 0.6microM respectively). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. Computational predictions of ADMET studies reveal that all the compounds have good pharmacokinetic properties with no AMES toxicity and carcinogenicity. Moreover, all the compounds are predicted to be absorbed in human intestine and also have the ability to cross blood brain barrier. Overall, the synthesized compounds have established a structural foundation for the design of new inhibitors of cholinesterase.
ESTHER : Sultana_2017_Bioorg.Chem_72_256
PubMedSearch : Sultana_2017_Bioorg.Chem_72_256
PubMedID: 28495556

Title : Synthesis, biological evaluation and docking studies of 2,3-dihydroquinazolin-4(1H)-one derivatives as inhibitors of cholinesterases - Sarfraz_2017_Bioorg.Chem_70_237
Author(s) : Sarfraz M , Sultana N , Rashid U , Akram MS , Sadiq A , Tariq MI
Ref : Bioorg Chem , 70 :237 , 2017
Abstract : In search of potent inhibitors of cholinesterases, we have synthesized and evaluate a number of 2,3-dihydroquinazolin-4(1H)-one derivatives. The synthetic approach provided an efficient synthesis of the target molecules with excellent yield. All the tested compounds showed activity against both the enzymes in micromolar range. In many case, the inhibition of both enzymes are higher than or comparable to the standard drug galatamine. With the selectivity index of 2.3 for AChE, compound 5f can be considered as a potential lead compound with a feature of dual AChE/BChE inhibition with IC50=1.6+/-0.10muM (AChE) and 3.7+/-0.18muM (BChE). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. The computed binding modes of these compounds in the active site of AChE and BChE provide an insight into the mechanism of inhibition of these two enzyme.
ESTHER : Sarfraz_2017_Bioorg.Chem_70_237
PubMedSearch : Sarfraz_2017_Bioorg.Chem_70_237
PubMedID: 28126287

Title : Anticholinesterase and antioxidant potentials of Nonea micrantha Bioss. & Reut along with GC-MS analysis - Imran_2017_BMC.Complement.Altern.Med_17_499
Author(s) : Imran M , Ullah F , Ayaz M , Sadiq A , Shah MR , Jan MS
Ref : BMC Complement Altern Med , 17 :499 , 2017
Abstract : BACKGROUND: Nonea micrantha Boiss. & Reut . being an unexplored member of Boraginaceae was investigated for GC/MS analysis, acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory and antioxidant activities in an attempt to find its effectiveness in neurological disorders.
METHODS: The AChE and BChE inhibitory activities of crude methanolic extract (Nm.Cr), subsequent fractions; n-hexane (Nm.Hex), chloroform (Nm.Cf), ethyl acetate (Nm.EtAc), aqueous (Nm.Aq) and crude saponins (Nm.Sp) from N. micrantha were conducted using Ellman's assay. The antioxidant activity of the plant samples using DPPH and ABTS free radical scavenging potential following quantitative spectrophotometric and qualitative TLC method were also studied. Moreover the total reducing power (TRP) of all the samples was also figured out.
RESULTS: The GC/Ms analysis confirmed that the plant is rich in bioactive molecules. Among different fractions, Nm.Hex, Nm.EtAc and Nm.Cf exhibited highest AChE inhibitory activities causing 75.51 +/- 0.73, 68.54 +/- 0.59 and 63.48 +/- 0.59% enzyme inhibition respectively and IC50 of 44, 100 and 144 mug/mL respectively. In BChE inhibiton assay, Nm.Aq, Nm.Sp and Nm.Cr showed highest activity causing 83.49 +/- 0.27, 81.49 +/- 0.89 and 75.31 +/- 0.56% enzyme inhibition with IC50 of 90, 110 and 44 mug/mL respectively. In DPPH assay, Nm.Aq, Nm.Cf, Nm.Hex and Nm.Cr were most potent exhibiting IC50 values of 3, 5, 93 and 120 mug/ml respectively. In ABTS assay Nm.EtAc, Nm.Aq, Nm.Sp and Nm.Cr showed IC50 values of 60, 95, 100 and 150 mug/mL respectively. Likewise ABTS inhibition was most prominent for Nm.Sp, Nm.EtAc and Nm.Aq causing 78.26 +/- 0.49, 67.67 +/- 0.73 and 63.58 +/- 0.45% inhibition respectively at 1 mg/mL. These results were further confirmed by qualitative screening using DPPH and ABTS staining.
CONCLUSIONS: Our anticholinesterase and antioxidant results signify the N. micrantha as a potential source of natural bioactive compounds. Moreover isolation of natural bioactive compounds from this plant may lead to novel drug candidates against neurodegenerative disorders.
ESTHER : Imran_2017_BMC.Complement.Altern.Med_17_499
PubMedSearch : Imran_2017_BMC.Complement.Altern.Med_17_499
PubMedID: 29169349

Title : Anti-Alzheimer's Studies on beta-Sitosterol Isolated from Polygonum hydropiper L - Ayaz_2017_Front.Pharmacol_8_697
Author(s) : Ayaz M , Junaid M , Ullah F , Subhan F , Sadiq A , Ali G , Ovais M , Shahid M , Ahmad A , Wadood A , El-Shazly M , Ahmad N , Ahmad S
Ref : Front Pharmacol , 8 :697 , 2017
Abstract : The family Polygonaceae is known for its traditional use in the management of various neurological disorders including Alzheimer's disease (AD). In search of new anti-AD drugs, beta-sitosterol isolated from Polygonum hydropiper was subjected to in vitro, in vivo, behavioral and molecular docking studies to confirm its possibility as a potential anti-Alzheimer's agent. The in vitro AChE, BChE inhibitory potentials of beta-sitosterol were investigated following Ellman's assay. The antioxidant activity was tested using DPPH, ABTS and H2O2 assays. Behavioral studies were performed on a sub-strain of transgenic mice using shallow water maze (SWM), Y-maze and balance beam tests. beta-sitosterol was tested for in vivo inhibitory potentials against cholinesterase's and free radicals in the frontal cortex (FC) and hippocampus (HC). The molecular docking study was performed to predict the binding mode of beta-sitosterol in the active sites of AChE and BChE as inhibitor. Considerable in vitro and in vivo cholinesterase inhibitory effects were observed in the beta-sitosterol treated groups. beta-sitosterol exhibited an IC50 value of 55 and 50 mug/ml against AChE and BChE respectively. Whereas, the activity of these enzymes were significantly low in FC and HC homogenates of transgenic animals. Molecular docking studies also support the binding of beta-sitosterol with the target enzyme and further support the in vitro and in vivo results. In the antioxidant assays, the IC50 values were observed as 140, 120, and 280 mug/ml in the DPPH, ABTS and H2O2 assays respectively. The free radicals load in the brain tissues was significantly declined in the beta-sitosterol treated animals as compared to the transgenic-saline treated groups. In the memory assessment and coordination tasks including SWM, Y-maze and balance beam tests, beta-sitosterol treated transgenic animals showed gradual improvement in working memory, spontaneous alternation behavior and motor coordination. These results conclude that beta-sitosterol is a potential compound for the management of memory deficit disorders like AD.
ESTHER : Ayaz_2017_Front.Pharmacol_8_697
PubMedSearch : Ayaz_2017_Front.Pharmacol_8_697
PubMedID: 29056913

Title : Synthesis, structure-activity relationship and molecular docking of 3-oxoaurones and 3-thioaurones as acetylcholinesterase and butyrylcholinesterase inhibitors - Mughal_2017_Bioorg.Med.Chem_25_100
Author(s) : Mughal EU , Sadiq A , Murtaza S , Rafique H , Zafar MN , Riaz T , Khan BA , Hameed A , Khan KM
Ref : Bioorganic & Medicinal Chemistry , 25 :100 , 2017
Abstract : The present study describes efficient and facile syntheses of varyingly substituted 3-thioaurones from the corresponding 3-oxoaurones using Lawesson's reagent and phosphorous pentasulfide. In comparison, the latter methodology was proved more convenient, giving higher yields and required short and simple methodology. The structures of synthetic compounds were unambiguously elucidated by IR, MS and NMR spectroscopy. All synthetic compounds were screened for their inhibitory potential against in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Molecular docking studies were also performed in order to examine their binding interactions with AChE and BChE human proteins. Both studies revealed that some of these compounds were found to be good inhibitors against AChE and BChE.
ESTHER : Mughal_2017_Bioorg.Med.Chem_25_100
PubMedSearch : Mughal_2017_Bioorg.Med.Chem_25_100
PubMedID: 27780618

Title : Neuroprotective and Anti-Aging Potentials of Essential Oils from Aromatic and Medicinal Plants - Ayaz_2017_Front.Aging.Neurosci_9_168
Author(s) : Ayaz M , Sadiq A , Junaid M , Ullah F , Subhan F , Ahmed J
Ref : Front Aging Neurosci , 9 :168 , 2017
Abstract : The use of essential oils (EOs) and their components is known since long in traditional medicine and aromatherapy for the management of various diseases, and is further increased in the recent times. The neuroprotective and anti-aging potentials of EOs and their possible mechanism of actions were evaluated by numerous researchers around the globe. Several clinically important EOs and their components from Nigella sativa, Acorus gramineus, Lavandula angustifolia, Eucalyptus globulus, Mentha piperita, Rosmarinus officinalis, Jasminum sambac, Piper nigrum and so many other plants are reported for neuroprotective effects. This review article was aimed to summarize the current finding on EOs tested against neurodegenerative disorders like Alzheimer disease (AD) and dementia. The effects of EOs on pathological targets of AD and dementia including amyloid deposition (Abeta), neurofibrillary tangles (NFTs), cholinergic hypofunction, oxidative stress and glutamatergic abnormalities were focused. Furthermore, effects of EOs on other neurological disorders including anxiety, depression, cognitive hypofunction epilepsy and convulsions were also evaluated in detail. In conclusion, EOs were effective on several pathological targets and have improved cognitive performance in animal models and human subjects. Thus, EOs can be developed as multi-potent agents against neurological disorders with better efficacy, safety and cost effectiveness.
ESTHER : Ayaz_2017_Front.Aging.Neurosci_9_168
PubMedSearch : Ayaz_2017_Front.Aging.Neurosci_9_168
PubMedID: 28611658

Title : Chemical composition, antioxidant and anticholinesterase potentials of essential oil of Rumex hastatus D. Don collected from the North West of Pakistan - Ahmad_2016_BMC.Complement.Altern.Med_16_29
Author(s) : Ahmad S , Ullah F , Sadiq A , Ayaz M , Imran M , Ali I , Zeb A , Shah MR
Ref : BMC Complement Altern Med , 16 :29 , 2016
Abstract : BACKGROUND: Ethnomedicinally Rumex hastatus D. Don has been used since long for various ailments especially in neurological disorders. The reported data and the importance of Rumex genus demonstrate the vital medicinal value of R. hastatus.
METHODS: In the current investigational study, isolation of essential oil and its antioxidant and anticholinesterase assays were performed. The essential oil of R. hastatus was analyzed by GC-MS for the first time. The essential oil was evaluated for anticholinesterase and antioxidant assays. The anticholinesterase assay was conducted at various concentrations (62.5 to 1000 mug/ml) against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Similarly, the antioxidant potential was determined using DPPH and ABTS free radicals.
RESULTS: The GC-MS analysis of essential oil showed 123 components. The result recorded for the anticholinesterase assays demonstrated a marked potential against AChE and BChE with IC50 values of 32.54 and 97.38 mug/ml respectively which were comparable with the positive control i.e., galanthamine (AChE, IC50 = 4.73 mug/ml and BChE, IC50 = 11.09 mug/ml). The antioxidant assays against DPPH and ABTS free radicals also exhibited significant scavenging potential with IC50 values of 3.71 and 6.29 mug/ml respectively, while for ascorbic acid the IC50 value was <0.1 mug/ml against both free radicals.
CONCLUSIONS: Based on the current investigational studies, it may be concluded that R. hastatus is an effective source of essential oil's components having anticholinesterase and antioxidant potentials, which after subjecting to drug development may lead to novel drug candidates against neurodegenerative disorders.
ESTHER : Ahmad_2016_BMC.Complement.Altern.Med_16_29
PubMedSearch : Ahmad_2016_BMC.Complement.Altern.Med_16_29
PubMedID: 26810212

Title : Phenolic, flavonoid contents, anticholinesterase and antioxidant evaluation of Iris germanica var\; florentina - Ullah_2015_Nat.Prod.Res__1
Author(s) : Ullah F , Ayaz M , Sadiq A , Hussain A , Ahmad S , Imran M , Zeb A
Ref : Nat Prod Res , :1 , 2015
Abstract : This study was designed to investigate antioxidant and anticholinesterase potential of Iris germanica var; florentina. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential of plant samples were investigated by Ellman's assay. Antioxidant activity was performed using DPPH, H2O2 and ABTS free radical scavenging assays. Total phenolics and flavonoids contents were expressed in mg GAE/g dry weight and mg RTE/g, respectively. In AChE inhibition assay, Ig.Fl, Ig.Sp and Ig.Cf fractions exhibited highest activity with IC50 values of < 0.1, 5.64 and 19 mug/mL, respectively. In BChE inhibitory assay, Ig.Fl, Ig.Sp, Ig.Cf and Ig.Cr were most active with IC50 of < 0.1, < 0.1, 31 and 78 mug/mL, respectively. In DPPH assay, Ig.Fl and Ig.Cf exhibited highest inhibition of free radicals, 80.52% (IC50 = 9 mug/mL) and 78.30% (IC50 = 8 mug/mL), respectively. In ABTS assay Ig.Cr, Ig.Cf, Ig.Fl and Ig.Sp exhibited IC50 values of < 0.1, 2, 2 and 3 mug/mL, respectively.
ESTHER : Ullah_2015_Nat.Prod.Res__1
PubMedSearch : Ullah_2015_Nat.Prod.Res__1
PubMedID: 26166432

Title : Antioxidant and anticholinesterase investigations of Rumex hastatus D. Don: potential effectiveness in oxidative stress and neurological disorders - Ahmad_2015_Biol.Res_48_20
Author(s) : Ahmad S , Ullah F , Ayaz M , Sadiq A , Imran M
Ref : Biol Res , 48 :20 , 2015
Abstract : BACKGROUND: Rumex species are traditionally used for the treatment of neurological disorders including headache, migraine, depression, paralysis etc. Several species have been scientifically validated for antioxidant and anticholinestrase potentials. This study aims to investigate Rumex hastatus D. Don crude methanolic extract, subsequent fractions, saponins and flavonoids for acetylcholinestrase, butyrylcholinestrase inhibition and diverse antioxidant activities to validate its folkloric uses in neurological disorders. Rumex hastatus crude methanolic extract (Rh. Cr), subsequent fractions; n-hexane (Rh. Hex), chloroform (Rh. Chf), ethyl acetate (Rh. EtAc), aqueous fraction (Rh. Aq), crude saponins (Rh. Sp) and flavonoids (Rh. Fl) were investigated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) at various concentrations (125, 250, 500, 1000 mug/mL) using Ellman's spectrophotometric analysis. Antioxidant potentials of Rh. Sp and Rh. Fl were evaluated using DPPH, H2O2 and ABTS free radical scavenging assays at 62.5, 125, 250, 500, 1000 mug/mL.
RESULTS: All the test samples showed concentration dependent cholinesterase inhibition and radicals scavenging activity. The AChE inhibition potential of Rh. Sp and Rh. Fl were most prominent i.e., 81.67 +/- 0.88 and 91.62 +/- 1.67 at highest concentration with IC50 135 and 20 mug/mL respectively. All the subsequent fractions exhibited moderate to high AChE inhibition i.e., Rh. Cr, Rh. Hex, Rh. Chf, Rh. EtAc and Rh. Aq showed IC50 218, 1420, 75, 115 and 1210 mug/mL respectively. Similarly, against BChE various plant extracts i.e., Rh. Sp, Rh. Fl, Rh. Cr, Rh. Hex, Rh. Chf, Rh. EtAc and Rh. Aq resulted IC50 165, 175, 265, 890, 92, 115 and 220 mug/mL respectively. In DPPH free radical scavenging assay, Rh. Sp and Rh. Fl showed comparable results with the positive control i.e., 63.34 +/- 0.98 and 76.93 +/- 1.13% scavenging at 1 mg/mL concentration (IC50 312 and 104 mug/mL) respectively. The percent ABTS radical scavenging potential exhibited by Rh. Sp and Rh. Fl (1000 mug/mL) were 82.58 +/- 0.52 and 88.25 +/- 0.67 with IC50 18 and 9 mug/mL respectively. Similarly in H2O2 scavenging assay, the Rh. Sp and Rh. Fl exhibited IC50 175 and 275 mug/mL respectively. CONCLUSION: The strong anticholinesterase and antioxidant activities of Rh. Sp, Rh. Fl and various fractions of R. hastatus support the purported ethnomedicinal uses and recommend R. hastatus as a possible remedy for the treatment of AD and neurodegenerative disorders.
ESTHER : Ahmad_2015_Biol.Res_48_20
PubMedSearch : Ahmad_2015_Biol.Res_48_20
PubMedID: 25857346

Title : Anticholinesterse and antioxidant investigations of crude extracts, subsequent fractions, saponins and flavonoids of atriplex laciniata L.: potential effectiveness in Alzheimer's and other neurological disorders - Kamal_2015_Biol.Res_48_21
Author(s) : Kamal Z , Ullah F , Ayaz M , Sadiq A , Ahmad S , Zeb A , Hussain A , Imran M
Ref : Biol Res , 48 :21 , 2015
Abstract : BACKGROUND: Atriplex laciniata L. was investigated for phenolic, flavonoid contents, antioxidant, anticholinesterase activities, in an attempt to explore its effectiveness in Alzheimer's and other neurological disorders. Plant crude methanolic extract (Al.MeF), subsequent fractions; n-hexane (Al.HxF), chloroform (Al.CfF), ethyl acetate (Al.EaF), aqueous (Al.WtF), Saponins (Al.SPF) and Flavonoids (Al.FLVF) were investigated for DPPH, ABTS and H2O2 free radical scavenging activities. Further these extracts were subjected to acetylcholinesterase (AChE) & butyrylcholinesterase (BChE) inhibitory activities using Ellman's assay. Phenolic and Flavonoid contents were determined and expressed in mg Gallic acid GAE/g and Rutin RTE/g of samples respectively.
RESULTS: In DPPH free radicals scavenging assay, Al.FLVF, Al.SPF and Al.MeF showed highest activity causing 89.41 +/- 0.55, 83.37 +/- 0.34 and 83.37 +/- 0.34% inhibition of free radicals respectively at 1 mg/mL concentration. IC50 for these fractions were 33, 83 and 82 mug/mL respectively. Similarly, plant extracts showed high ABTS scavenging potential, i.e. Al.FLVF (90.34 +/- 0.55), Al.CfF (83.42 +/- 0.57), Al.MeF (81.49 +/- 0.60) with IC50 of 30, 190 and 70 mug/ml respectively. further, H2O2 percent scavenging was highly appraised in Al.FLVF (91.29 +/- 0.53, IC50 75), Al.SPF (85.35 +/- 0.61, IC50 70) and Al.EaF (83.48 +/- 0.67, IC50 270 mug/mL). All fractions exhibited concentration dependent AChE inhibitory activity as; Al.FLVF, 88.31 +/- 0.57 (IC50 70 mug/mL), Al.SPF, 84.36 +/- 0.64 (IC50 90 mug/mL), Al.MeF, 78.65 +/- 0.70 (IC50 280 mug/mL), Al.EaF, 77.45 +/- 0.46 (IC50 270 mug/mL) and Al.WtF 72.44 +/- 0.58 (IC50 263 mug/mL) at 1 mg/mL. Likewise the percent BChE inhibitory activity was most obvious in Al.FLVF 85.46 +/- 0.62 (IC50 100 mug/mL), Al.CfF 83.49 +/- 0.46 (IC50 160 mug/mL), Al.MeF 82.68 +/- 0.60 (IC50 220 mug/mL) and Al.SPF 80.37 +/- 0.54 (IC50 120 mug/mL).
CONCLUSIONS: These results stipulate that A. laciniata is enriched with phenolic and flavonoid contents that possess significant antioxidant and anticholinestrase effects. This provide pharmacological basis for the presence of compounds that may be effective in Alzheimer's and other neurological disorders.
ESTHER : Kamal_2015_Biol.Res_48_21
PubMedSearch : Kamal_2015_Biol.Res_48_21
PubMedID: 25889712

Title : Comparative chemical profiling, cholinesterase inhibitions and anti-radicals properties of essential oils from Polygonum hydropiper L: A Preliminary anti- Alzheimer's study - Ayaz_2015_Lipids.Health.Dis_14_141
Author(s) : Ayaz M , Junaid M , Ullah F , Sadiq A , Khan MA , Ahmad W , Shah MR , Imran M , Ahmad S
Ref : Lipids Health Dis , 14 :141 , 2015
Abstract : BACKGROUND: Cholinesterase inhibition is a vital target for the development of novel and mechanism based inhibitors, owing to their role in the breakdown of acetylcholine (ACh) neurotransmitter to treat various neurological disorders including Alzheimer's disease (AD). Similarly, free radicals are implicated in the progression of various diseases like neurodegenerative disorders. Due to lipid solubility and potential to easily cross blood brain barrier, this study was designed to investigate the anticholinesterase and antioxidant potentials of the standardized essential oils from the leaves and flowers of Polygonum hydropiper.
METHODS: Essential oils from the leaves (Ph.LO) and flowers (Ph.FO) of P. hdropiper were isolated using Clevenger apparatus. Oil samples were analyzed by GC-MS to identify major components and to attribute the antioxidant and anticholinesterase activity to specific components. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potentials of the samples were determined following Ellman's assay. Antioxidant assays were performed using 1,1-diphenyl,2-picrylhydrazyl (DPPH), 2,2-azinobis[3-ethylbenzthiazoline]-6-sulfonic acid (ABTS) and hydrogen peroxide (H2O2) free radical scavenging assays.
RESULTS: In the GC-MS analysis 141 and 122 compounds were indentified in Ph.LO and Ph.FO respectively. Caryophylene oxide (41.42 %) was the major component in Ph.FO while decahydronaphthalene (38.29 %) was prominent in Ph.LO. In AChE inhibition, Ph.LO and Ph.FO exhibited 87.00** and 79.66***% inhibitions at 1000 mug/ml with IC50 of 120 and 220 mug/ml respectively. The IC50 value for galanthamine was 15 mug/ml. In BChE inhibitory assay, Ph.LO and Ph.FO caused 82.66*** (IC50 130 mug/ml) and 77.50***% (IC50 225 mug/ml) inhibitions respectively at 1000 mug/ml concentration. In DPPH free radical scavenging assay, Ph.LO and Ph.FO exhibited IC50 of 20 and 200 mug/ml respectively. The calculated IC50s were 180 & 60 mug/ml for Ph.LO, and 45 & 50 mug/ml for Ph.FO in scavenging of ABTS and H2O2 free radicals respectively.
CONCLUSIONS: In the current study, essential oils from leaves and flowers of P. hydropiper exhibited dose dependent anticholinesterase and antioxidant activities. Leaves essential oil were more effective and can be subjected to further in-vitro and in-vivo anti-Alzheimer's studies.
ESTHER : Ayaz_2015_Lipids.Health.Dis_14_141
PubMedSearch : Ayaz_2015_Lipids.Health.Dis_14_141
PubMedID: 26530857

Title : Synthesis, anticholinesterase and antioxidant potentials of ketoesters derivatives of succinimides: a possible role in the management of Alzheimer's - Sadiq_2015_Chem.Cent.J_9_31
Author(s) : Sadiq A , Mahmood F , Ullah F , Ayaz M , Ahmad S , Haq FU , Khan G , Jan MS
Ref : Chem Cent J , 9 :31 , 2015
Abstract : BACKGROUND: Based on the pharmacological potency and structural features of succinimides, this study was designed to synthesize new ketoesters derivatives of succinimides. Furthermore, the synthesized compounds were evaluated for their possible anticholinesterase and antioxidant potentials. The compounds were synthesized by organocatalytic Michael additions of alpha-ketoesters to N-aryl maleimides. Acetyl and butyrylcholinesterase inhibitory activities were determined using Ellman's spectrophotometric assay. The antioxidant activity was performed with DPPH and ABTS free radicals scavenging assay.
RESULTS: The Michael additions of alpha-ketoesters to maleimides was promoted by 8-hydroxyquinoline. The organocatalyst (8-hydroxyquinoline, 20 mol %) produced the compounds in relatively shorter time (20-24 h) and with excellent isolated yields (84-98 %). The synthesized compounds (1-4) showed outstanding acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potentials, i.e., 98.75 and 90.00 % respectively for compound 2, with IC50 < 0.1 mug/mL. Additionally, compounds 1-4 revealed moderate antioxidant activity at different concentrations. In DPPH free radical scavenging assay, compound 1 showed dominant result with 72.41 +/- 0.45, 52.49 +/- 0.78 and 35.60 +/- 0.75 % inhibition at concentrations of 1000, 500 and 250 mug/mL respectively, IC50 value of 440 mug/mL. However, the free radical scavenging was better when used ABTS free radicals. In ABTS free radicals scavenging assay compound 1 exhibited 88.51 +/- 0.62 % inhibition at highest tested concentration i.e., 1000 mug/mL.
CONCLUSIONS: Herein, we have synthesized four ketoesters derivatives of succinimides in a single step reaction and high yields. As a highlight, we have showed a first report on the anticholinesterase and antioxidant potentials of succinimides. All the compounds showed overwhelming enzyme inhibitions and moderate antioxidant potentials. Graphical AbstractGraphical representation of synthesis, anticholinesterase and antioxidant potentials of ketoester derivatives of succinimides.
ESTHER : Sadiq_2015_Chem.Cent.J_9_31
PubMedSearch : Sadiq_2015_Chem.Cent.J_9_31
PubMedID: 26064188

Title : Phenolic contents, antioxidant and anticholinesterase potentials of crude extract, subsequent fractions and crude saponins from Polygonum hydropiper L - Ayaz_2014_BMC.Complement.Altern.Med_14_145
Author(s) : Ayaz M , Junaid M , Ahmed J , Ullah F , Sadiq A , Ahmad S , Imran M
Ref : BMC Complement Altern Med , 14 :145 , 2014
Abstract : BACKGROUND: We investigated Polygonum hydropiper L. (P. hydropiper) for phenolic contents, antioxidant, anticholinesterase activities, in an attempt to rationalize its use in neurological disorders.
METHODS: Plant crude extract (Ph.Cr), its subsequent fractions: n-hexane (Ph.Hex), chloroform (Ph.Chf), ethyl acetate (Ph.EtAc), n-Butanol (Ph.Bt), aqueous (Ph.Aq) and saponins (Ph.Sp) were evaluated for 1,1-diphenyl,2-picrylhydrazyl (DPPH), 2,2-azinobis[3-ethylbenzthiazoline]-6-sulfonic acid (ABTS) free radical scavenging potential. Further, acetylcholinesterase (AChE) & butyrylcholinesterase (BChE) inhibitory activities were performed using Ellman's assay. Moreover, total phenolic contents of plant extracts were determined and expressed in mg of gallic acid equivalent per gram of dry sample (mg GAE/g dry weight).
RESULTS: Among different fractions, Ph.Cr (90.82), Ph.Chf (178.16), Ph.EtAc (203.44) and Ph.Bt (153.61) exhibited high phenolic contents. All fractions showed concentration dependent DPPH scavenging activity, with Ph.EtAc 71.33% (IC50 15 mug/ml), Ph.Bt 71.40% (IC50 3 mug/ml) and Ph.Sp 71.40% (IC50 35 mug/ml) were most potent. The plant extracts exhibited high ABTS scavenging ability i.e. Ph.Bt (91.03%), Ph.EtAc (90.56%), Ph.Sp (90.84%), Ph.Aq (90.56%) with IC50 < 0.01 mug/ml. All fractions showed moderate to high AChE inhibitory activity as; Ph.Cr, 86.87% (IC50 330 mug/ml), Ph.Hex, 87.49% (IC50 35 mug/ml), Ph.Chf, 84.76% (IC50 55 mug/ml), Ph.Sp, 87.58% (IC50 108 mug/ml) and Ph.EtAc 79.95% (IC50 310 mug/ml) at 1 mg/ml). Furthermore the BChE inhibitory activity was most prominent in Ph.Hex 90.30% (IC50 40 mug/ml), Ph.Chf 85.94% (IC50 215 mug/ml), Ph.Aq 87.62% (IC50 3 mug/ml) and Ph.EtAc 81.01% (IC50 395 mug/ml) fractions.
CONCLUSIONS: In this study, for the first time, we determined phenolic contents, isolated crude saponins, investigated antioxidant and anticholinestrase potential of P. hydropiper extracts. The results indicate that P. hydropiper is enriched with potent bioactive compounds and warrant further investigation by isolation and structural elucidation to find novel and affordable compounds for the treatment of various neurological disorders.
ESTHER : Ayaz_2014_BMC.Complement.Altern.Med_14_145
PubMedSearch : Ayaz_2014_BMC.Complement.Altern.Med_14_145
PubMedID: 24884823

Title : Investigations of anticholinestrase and antioxidant potentials of methanolic extract, subsequent fractions, crude saponins and flavonoids isolated from Isodon rugosus - Zeb_2014_Biol.Res_47_76
Author(s) : Zeb A , Sadiq A , Ullah F , Ahmad S , Ayaz M
Ref : Biol Res , 47 :76 , 2014
Abstract : BACKGROUND: Based on the ethnomedicinal uses and the effective outcomes of natural products in various diseases, this study was designed to evaluate Isodon rugosus as possible remedy in oxidative stress, alzheimer's and other neurodegenerative diseases. Acetylecholinestrase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of crude methanolic extract (Ir.Cr), resultant fractions (n-hexane (Ir.Hex), chloroform (Ir.Cf), ethyl acetate (Ir.EtAc), aqueous (Ir.Aq)), flavonoids (Ir.Flv) and crude saponins (Ir.Sp) of I. rugosus were investigated using Ellman's spectrophotometric method. Antioxidant potential of I. rugosus was determined using DPPH, H2O2 and ABTS free radicals scavenging assays. Total phenolic and flavonoids contents of plant extracts were determined and expressed in mg GAE/g dry weight and mg RTE/g of dry sample respectively.
RESULTS: Among different fractions Ir.Flv and Ir.Cf exhibited highest inhibitory activity against AChE (87.44 +/- 0.51, 83.73 +/- 0.64%) and BChE (82.53 +/- 0.71, 88.55 +/- 0.77%) enzymes at 1 mg/ml with IC50 values of 45, 50 for AChE and 40, 70 mug/ml for BChE respectively. Activity of these fractions were comparable to galanthamine causing 96.00 +/- 0.30 and 88.61 +/- 0.43% inhibition of AChE and BChE at 1 mg/ml concentration with IC50 values of 20 and 47 mug/ml respectively. In antioxidant assays, Ir.Flv, Ir.Cf, and Ir.EtAc demonstrated highest radicals scavenging activities in DPPH and H2O2 assays which were comparable to ascorbic acid. Ir.Flv was found most potent with IC50 of 19 and 24 mug/ml against DPPH and H2O2 radicals respectively. Whereas antioxidant activates of plant samples against ABTS free radicals was moderate. Ir.Cf, Ir.EtAc and Ir.Cr showed high phenolic and flavonoid contents and concentrations of these compounds in different fractions correlated well to their antioxidant and anticholinestrase activities. CONCLUSION: It may be inferred from the current investigations that the Ir.Sp, Ir.Flv and various fractions of I. rugosus are good sources of anticholinesterase and antioxidant compounds. Different fractions can be subjected to activity guided isolation of bioactive compounds effective in neurological disorders.
ESTHER : Zeb_2014_Biol.Res_47_76
PubMedSearch : Zeb_2014_Biol.Res_47_76
PubMedID: 25723481