Choudhary S

References (9)

Title : Design, Synthesis, and Pharmacological Evaluation of Embelin-Aryl\/alkyl Amine Hybrids as Orally Bioavailable Blood-Brain Barrier Permeable Multitargeted Agents with Therapeutic Potential in Alzheimer's Disease: Discovery of SB-1448 - Nuthakki_2023_ACS.Chem.Neurosci_14_1193
Author(s) : Nuthakki VK , Choudhary S , Reddy CN , Bhatt S , Jamwal A , Jotshi A , Raghuvanshi R , Sharma A , Thakur S , Jadhav HR , Bharate SS , Nandi U , Kumar A , Bharate SB
Ref : ACS Chem Neurosci , 14 :1193 , 2023
Abstract : The complex and multifaceted nature of Alzheimer's disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Embelia ribes Burm f., one of the oldest herbs in Indian traditional medicine. It is a micromolar inhibitor of cholinesterases (ChEs) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we synthesize a series of embelin-aryl/alkyl amine hybrids to improve its physicochemical properties and therapeutic potency against targeted enzymes. The most active derivative, 9j (SB-1448), inhibits human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE), and human BACE-1 (hBACE-1) with IC(50) values of 0.15, 1.6, and 0.6 microM, respectively. It inhibits both ChEs noncompetitively with k(i) values of 0.21 and 1.3 microM, respectively. It is orally bioavailable, crosses blood-brain barrier (BBB), inhibits Abeta self-aggregation, possesses good ADME properties, and protects neuronal cells from scopolamine-induced cell death. The oral administration of 9j at 30 mg/kg attenuates the scopolamine-induced cognitive impairments in C57BL/6J mice.
ESTHER : Nuthakki_2023_ACS.Chem.Neurosci_14_1193
PubMedSearch : Nuthakki_2023_ACS.Chem.Neurosci_14_1193
PubMedID: 36812360

Title : Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity - Kaur_2021_Bioorg.Chem_118_105479
Author(s) : Kaur Gulati H , Choudhary S , Kumar N , Ahmed A , Bhagat K , Vir Singh J , Singh A , Kumar A , Singh Bedi PM , Singh H , Mukherjee D
Ref : Bioorg Chem , 118 :105479 , 2021
Abstract : Tacrine is a known Acetylcholinesterase (AChE) inhibitors having hepatotoxicity as main liability associated with it. The present study aims to reduce its hepatotoxicity by synthesizing tacrine linked triazole glycoconjugates via Huisgen's [3 + 2] cycloaddition of anomeric azides and terminal acetylenes derived from tacrine. A series of triazole based glycoconjugates containing both acetylated (A-1 to A-7) and free sugar hydroxyl groups (A-8 to A-14) at the amino position of tacrine were synthesized in good yield taking aid from molecular docking studies and evaluated for their in vitro AChE inhibition activity as well as hepatotoxicity. All the hybrids were found to be non-toxic on HePG2 cell line at 200 microM (100 % cell viability) as compared to tacrine (35 % cell viability) after 24 h of incubation period. Enzyme kinetic studies carried out for one of the potent hybrids in the series A-1 (IC(50) 0.4 microM) revealed its mixed inhibition approach. Thus, compound A-1 can be used as principle template to further explore the mechanism of action of different targets involved in Alzheimer's disease (AD) which stands as an adequate chemical probe to be launched in an AD drug discovery program.
ESTHER : Kaur_2021_Bioorg.Chem_118_105479
PubMedSearch : Kaur_2021_Bioorg.Chem_118_105479
PubMedID: 34801945

Title : Role of Genetic Variants and Gene Expression in the Susceptibility and Severity of COVID-19 - Choudhary_2021_Ann.Lab.Med_41_129
Author(s) : Choudhary S , Sreenivasulu K , Mitra P , Misra S , Sharma P
Ref : Ann Lab Med , 41 :129 , 2021
Abstract : Since its first report in December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly emerged as a pandemic affecting nearly all countries worldwide. As the COVID-19 pandemic progresses, the need to identify genetic risk factors for susceptibility to this serious illness has emerged. Host genetic factors, along with other risk factors may help determine susceptibility to respiratory tract infections. It is hypothesized that the ACE2 gene, encoding angiotensin-converting enzyme 2 (ACE2), is a genetic risk factor for SARS-CoV-2 infection and is required by the virus to enter cells. Together with ACE2, transmembrane protease serine 2 (TMPRSS2) and dipeptidyl peptidase-4 (DPP4) also play an important role in disease severity. Evaluating the role of genetic variants in determining the direction of respiratory infections will help identify potential drug target candidates for further study in COVID-19 patients. We have summarized the latest reports demonstrating that ACE2 variants, their expression, and epigenetic factors may influence an individual's susceptibility to SARS-CoV-2 infection and disease outcome.
ESTHER : Choudhary_2021_Ann.Lab.Med_41_129
PubMedSearch : Choudhary_2021_Ann.Lab.Med_41_129
PubMedID: 33063674

Title : Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach - Choudhary_2020_Front.Immunol_11_1664
Author(s) : Choudhary S , Malik YS , Tomar S
Ref : Front Immunol , 11 :1664 , 2020
Abstract : The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) associated Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to cellular angiotensin converting enzyme 2 (ACE2) receptor. The virus specific molecular interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising molecules for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified molecules may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these molecules could save lives is justified.
ESTHER : Choudhary_2020_Front.Immunol_11_1664
PubMedSearch : Choudhary_2020_Front.Immunol_11_1664
PubMedID: 32754161

Title : Discovery of a New Donepezil-like Acetylcholinesterase Inhibitor for Targeting Alzheimer's Disease: Computational Studies with Biological Validation - Akhoon_2020_J.Chem.Inf.Model_60_4717
Author(s) : Akhoon BA , Choudhary S , Tiwari H , Kumar A , Barik MR , Rathor L , Pandey R , Nargotra A
Ref : J Chem Inf Model , 60 :4717 , 2020
Abstract : Alzheimer's disorder is one of the most common worldwide health problems, and its prevalence continues to increase, thereby straining the healthcare budgets of both developed and developing countries. So far, donepezil is the only Food and Drug Administration-approved dual-binding site inhibitor of acetylcholinesterase (AChE) that can amplify the cholinergic activity and also decrease Abeta aggregation in Alzheimer patients. We report herein a new donepezil-like natural compound derivative (D1) as a convincing AChE inhibitor. The in silico studies suggests that D1 exhibits a dual-binding mode of action and interacts with both the catalytic anionic site and peripheral anionic site (PAS) of human AChE. The biological studies confirm the dual-binding site character of D1 and revealed that D1 not only enhances the acetylcholine levels but also reduces the accumulation of Abeta plaques in Caenorhabditis elegans. In fact, 5 microM D1 was seen more potent in elevating the acetylcholine expression than 25 microM donepezil. While most of the non-cholinergic functions of donepezil, associated with the PAS of AChE, were gradually lost at higher concentrations, D1 was more functional at similar doses. Promisingly, D1 also exerted an agonistic effect on the alpha7 nicotinic acetylcholine receptor.
ESTHER : Akhoon_2020_J.Chem.Inf.Model_60_4717
PubMedSearch : Akhoon_2020_J.Chem.Inf.Model_60_4717
PubMedID: 32955256

Title : In silico guided designing of 4-(1H-benzo[d]imidazol-2-yl)phenol-based mutual-prodrugs of NSAIDs: synthesis and biological evaluation - Arora_2020_SAR.QSAR.Environ.Res__1
Author(s) : Arora M , Choudhary S , Silakari O
Ref : SAR QSAR Environ Research , :1 , 2020
Abstract : The free COOH group of conventional NSAIDs is a structural feature for non-selective cyclooxygenase (COX) inhibition and the molecular cause of their gastrointestinal (GI) toxicity. In this context, an in house database of synthesizable ester prodrugs of some well-known NSAIDs was developed by combining their -COOH group with -OH of a newly identified antioxidant 4-(1H-benzo[d]imidazol-2-yl)phenol (BZ). The antioxidant potential of BZ was unveiled through in silico PASS prediction and in vitro/in vivo evaluation. The in house database of NSAIDs-BZ prodrugs was first subjected to screening with our previously reported pharmacophore models of hCES1 (AAHRR.430) and hCES2 (AHHR.21) for determining hydrolytic susceptibility. Biotransformation behaviour of screened prodrugs was then assessed by using QM/MM and sterimol parameterization, followed by ADMET calculations to predict the drug likeness. On the basis of in silico results, five prodrugs were duly synthesized and the best three were subject to the in vivo evaluation for their anti-inflammatory, analgesic, antioxidant activities, and ulcerogenic index. Among these prodrugs, BN(2) and BN(5) displayed better anti-inflammatory and analgesics potential in comparison to their parent drugs. All the prodrugs were found to be gastro sparing in the rat model and significantly improved the levels of oxidative stress biomarkers in both blood plasma as well as gastric homogenate.
ESTHER : Arora_2020_SAR.QSAR.Environ.Res__1
PubMedSearch : Arora_2020_SAR.QSAR.Environ.Res__1
PubMedID: 32867537

Title : Mechanistic Insights into Strigolactone Biosynthesis, Signaling, and Regulation During Plant Growth and Development - Wani_2020_J.Plant.Growth.Regul__
Author(s) : Wani KI , Zehra A , Choudhary S , Naeem M , Khan MMA , Castroverde CDM , Aftab T
Ref : Journal of Plant Growth Regulation , : , 2020
Abstract : Strigolactones (SLs) constitute a group of carotenoid-derived phytohormones with butenolide moieties. These hormones are involved in various functions, including regulation of secondary growth, shoot branching and hypocotyl elongation, and stimulation of seed germination. SLs also control hyphal branching of arbuscular mycorrhizal (AM) fungi and mediate responses to both abiotic and biotic cues. Most of these functions stem from the interplay of SLs with other hormones, enabling plants to appropriately respond to changing environmental conditions. This dynamic interplay provides opportunities for phytohormones to modulate and augment one another. In this article, we review our current mechanistic understanding of SL biosynthesis, receptors, and signaling. We also highlight recent advances regarding the interaction of SLs with other hormones during developmental processes and stress conditions.
ESTHER : Wani_2020_J.Plant.Growth.Regul__
PubMedSearch : Wani_2020_J.Plant.Growth.Regul__

Title : Standardized extract of Lactuca sativa Linn. and its fractions abrogates scopolamine-induced amnesia in mice: A possible cholinergic and antioxidant mechanism - Malik_2017_Nutr.Neurosci__1
Author(s) : Malik J , Kaur J , Choudhary S
Ref : Nutr Neurosci , :1 , 2017
Abstract : OBJECTIVES: The present study was designed to evaluate the efficacy of Lactuca sativa (LS) Linn. (Asteraceae) against scopolamine- induced amnesia and to validate its traditional claim as memory enhancer.
METHODS: Ethanol extract of fresh LS leaves (LSEE), standardized on the basis of quercetin content, was successively partitioned using various solvents viz., hexane, ethyl acetate, and n-butanol in increasing order of polarity. LSEE (50, 100, and 200 mg/kg) and its various fractions (at a dose equivalent to dose of LSEE exhibiting maximum activity), administered orally for 14 days, were evaluated for their memory enhancing effect against scopolamine-induced (1 mg/kg, i.p.) amnesia in 3-4 months old male Laca mice (n = 6 in each group). The memory enhancing effect was evaluated using behavioural (elevated plus maze, novel object recognition and Morris water maze tests) and biochemical parameters (acetylcholinesterase activity, malonaldehyde, superoxide dismutase, nitrite, catalase, and reduced gultathione content). The results of the test substances were compared with both scopolamine and donepezil that was used as a standard memory enhancer and acetylcholinesterase inhibitor.
RESULTS: Scopolamine elicit marked deterioration of memory and alteration in biochemical parameters in comparison to the control group. LSEE and its n-butanol and aqueous fractions significantly (P < 0.05) attenuated the scopolamine- induced amnesia that was evident in all the behavioural and biochemical test parameters. LSEE (200 mg/kg) and n-butanol fraction (15 mg/kg) exhibited maximum anti-amnesic effect among various tested dose levels. DISCUSSION: The results exhibited that LS prophylaxis attenuated scopolamine- induced memory impairment through its acetylcholinesterase inhibitory and antioxidant activity validating its traditional claim.
ESTHER : Malik_2017_Nutr.Neurosci__1
PubMedSearch : Malik_2017_Nutr.Neurosci__1
PubMedID: 28245707

Title : Potential association of reduced cholinesterase activity with Trypanosoma evansi pathogenesis in buffaloes - Singh_2016_Vet.Parasitol_225_29
Author(s) : Singh SK , Singh VK , Yadav BK , Nakade UP , Kumari P , Srivastava MK , Sharma A , Choudhary S , Swain D , Garg SK
Ref : Vet Parasitol , 225 :29 , 2016
Abstract : The present study aimed to investigate the association of cholinesterase activity with trypanosomosis in buffaloes. Thirty-three clinical cases of trypanosomosis in water buffaloes, found positive for trypomastigotes of T. evansi on blood smear examination, were divided into two groups based on clinical manifestations. Twenty diseased buffaloes revealing only common clinical signs were allocated to Group I, while the remaining 13 buffaloes showing common clinical manifestations along with neurological disturbances were allocated to Group II. Twelve clinically healthy buffaloes, free from any haemoprotozoa infection, were kept as healthy control (Group III). Blood samples were collected from buffaloes of all three groups to determine serum cholinesterase activity. Compared to buffaloes of healthy control group, cholinesterase activity in T. evansi-infected buffaloes of Group I and II was significantly (P<0.001) lower. However, no significant difference was observed in cholinesterase activity between the T. evansi-infected buffaloes exhibiting neurological disorders and no neurological disorders. Summing up, reduced cholinesterase activity seems to be associated with the pathogenesis of natural T. evansi infection and its clinical manifestations in buffaloes possibly by evading immune response. Further studies are warranted on association of cholinesterase activity in T. evansi-infected buffaloes with neurological disorders.
ESTHER : Singh_2016_Vet.Parasitol_225_29
PubMedSearch : Singh_2016_Vet.Parasitol_225_29
PubMedID: 27369572