Waiker DK

References (7)

Title : Design, synthesis, and biological evaluation of some 2-(3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-yl)-N-phenylacetamide hybrids as MTDLs for Alzheimer's disease therapy - Waiker_2024_Eur.J.Med.Chem_271_116409
Author(s) : Waiker DK , Verma A , Gajendra TA , Namrata , Roy A , Kumar P , Trigun SK , Srikrishna S , Krishnamurthy S , Davisson VJ , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 271 :116409 , 2024
Abstract : Inspite of established symptomatic relief drug targets, a multi targeting approach is highly in demand to cure Alzheimer's disease (AD). Simultaneous inhibition of cholinesterase (ChE), beta secretase-1 (BACE-1) and Dyrk1A could be promising in complete cure of AD. A series of 18 diaryl triazine based molecular hybrids were successfully designed, synthesized, and tested for their hChE, hBACE-1, Dyrk1A and Abeta aggregation inhibitory potentials. Compounds S-11 and S-12 were the representative molecules amongst the series with multi-targeted inhibitory effects. Compound S-12 showed hAChE inhibition (IC(50) value = 0.486 +/- 0.047 microM), BACE-1 inhibition (IC(50) value = 0.542 +/- 0.099 microM) along with good anti-Abeta aggregation effects in thioflavin-T assay. Only compound S-02 of the series has shown Dyrk1A inhibition (IC(50) value = 2.000 +/- 0.360 microM). Compound S-12 has also demonstrated no neurotoxic liabilities against SH-SY5Y as compared to donepezil. The in vivo behavioral studies of the compound S-12 in the scopolamine- and Abeta-induced animal models also demonstrated attanuation of learning and memory functions in rats models having AD-like characteristics. The ex vivo studies, on the rat hippocampal brain demonstrated reduction in certain biochemical markers of the AD brain with a significant increase in ACh level. The Western blot and Immunohistochemistry further revealed lower tau, APP and BACE-1 molecular levels. The drosophilla AD model also revealed improved eyephenotype after treatment with compound S-12. The molecular docking studies of the compounds suggested that compound S-12 was interacting with the ChE-PAS & CAS residues and catalytic dyad residues of the BACE-1 enzymes. The 100 ns molecular dynamics simulation studies of the ligand-protein complexed with hAChE and hBACE-1 also suggested stable ligand-protein confirmation throughout the simulation run.
ESTHER : Waiker_2024_Eur.J.Med.Chem_271_116409
PubMedSearch : Waiker_2024_Eur.J.Med.Chem_271_116409
PubMedID: 38663285

Title : Design, Synthesis, and Biological Investigation of Quinazoline Derivatives as Multitargeting Therapeutics in Alzheimer's Disease Therapy - Verma_2024_ACS.Chem.Neurosci__
Author(s) : Verma A , Waiker DK , Singh N , Roy A , Saraf P , Bhardwaj B , Krishnamurthy S , Trigun SK , Shrivastava SK
Ref : ACS Chem Neurosci , : , 2024
Abstract : An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer's disease (AD) is the multitarget-directed approach. Here in this work, a series of quinazoline derivatives (AV-1 to AV-21) were rationally designed, synthesized, and biologically evaluated as multitargeted directed ligands against human cholinesterase (hChE) and human beta-secretase (hBACE-1) that exhibit moderate to good inhibitory effects. Compounds AV-1, AV-2, and AV-3 from the series demonstrated balanced and significant inhibition against these targets. These compounds also displayed excellent blood-brain barrier permeability via the PAMPA-BBB assay. Compound AV-2 significantly displaced propidium iodide (PI) from the acetylcholinesterase-peripheral anionic site (AChE-PAS) and was found to be non-neurotoxic at the maximum tested concentration (80 microM) against differentiated SH-SY5Y cell lines. Compound AV-2 also prevented AChE- and self-induced Abeta aggregation in the thioflavin T assay. Additionally, compound AV-2 significantly ameliorated scopolamine and Abeta-induced cognitive impairments in the in vivo behavioral Y-maze and Morris water maze studies, respectively. The ex vivo and biochemical analysis further revealed good hippocampal AChE inhibition and the antioxidant potential of the compound AV-2. Western blot and immunohistochemical (IHC) analysis of hippocampal brain revealed reduced Abeta, BACE-1, APP/Abeta, and Tau molecular protein expressions levels. The pharmacokinetic analysis of compound AV-2 demonstrated significant oral absorption with good bioavailability. The in silico molecular modeling studies of lead compound AV-2 moreover demonstrated a reasonable binding profile with AChE and BACE-1 enzymes and stable ligand-protein complexes throughout the 100 ns run. Compound AV-2 can be regarded as the lead candidate and could be explored more for AD therapy.
ESTHER : Verma_2024_ACS.Chem.Neurosci__
PubMedSearch : Verma_2024_ACS.Chem.Neurosci__
PubMedID: 38327209

Title : Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment - Verma_2024_Eur.J.Med.Chem_271_116450
Author(s) : Verma A , Waiker DK , Singh N , Singh A , Saraf P , Bhardwaj B , Kumar P , Krishnamurthy S , Srikrishna S , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 271 :116450 , 2024
Abstract : The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and beta-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Abeta aggregation inhibition in a self- and AChE-induced Abeta aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Abeta-induced cognitive deficits in the Abeta-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the A-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Abeta and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.
ESTHER : Verma_2024_Eur.J.Med.Chem_271_116450
PubMedSearch : Verma_2024_Eur.J.Med.Chem_271_116450
PubMedID: 38701714

Title : Design, Synthesis, and Biological Evaluation of Piperazine and N-Benzylpiperidine Hybrids of 5-Phenyl-1,3,4-oxadiazol-2-thiol as Potential Multitargeted Ligands for Alzheimer's Disease Therapy - Waiker_2023_ACS.Chem.Neurosci__
Author(s) : Waiker DK , Verma A , Akhilesh , Gajendra TA , Singh N , Roy A , Dilnashin H , Tiwari V , Trigun SK , Singh SP , Krishnamurthy S , Lama P , Davisson VJ , Shrivastava SK
Ref : ACS Chem Neurosci , : , 2023
Abstract : Our present work demonstrates the successful design and synthesis of a new class of compounds based upon a multitargeted directed ligand design approach to discover new agents for use in Alzheimer's disease (AD). All the compounds were tested for their in vitro inhibitory potential against human acetylcholinesterase (hAChE), human butylcholinesterase (hBChE), beta-secretase-1 (hBACE-1), and amyloid beta (Abeta) aggregation. Compounds 5d and 5f have shown hAChE and hBACE-1 inhibition comparable to donepezil, while hBChE inhibition was comparable to rivastigmine. Compounds 5d and 5f also demonstrated a significant reduction in the formation of Abeta aggregates through the thioflavin T assay and confocal, atomic force, and scanning electron microscopy studies and significantly displaced the total propidium iodide, that is, 54 and 51% at 50 microM concentrations, respectively. Compounds 5d and 5f were devoid of neurotoxic liabilities against RA/BDNF (RA = retinoic acid; BDNF = brain-derived neurotrophic factor)-differentiated SH-SY5Y neuroblastoma cell lines at 10-80 microM concentrations. In both the scopolamine- and Abeta-induced mouse models for AD, compounds 5d and 5f demonstrated significant restoration of learning and memory behaviors. A series of ex vivo studies of hippocampal and cortex brain homogenates showed that 5d and 5f elicit decreases in AChE, malondialdehyde, and nitric oxide levels, an increase in glutathione level, and reduced levels of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) mRNA. The histopathological examination of mice revealed normal neuronal appearance in the hippocampal and cortex regions of the brain. Western blot analysis of the same tissue indicated a reduction in Abeta, amyloid precursor protein (APP)/Abeta, BACE-1, and tau protein levels, which were non-significant compared to the sham group. The immunohistochemical analysis also showed significantly lower expression of BACE-1 and Abeta levels, which was comparable to donepezil-treated group. Compounds 5d and 5f represent new lead candidates for developing AD therapeutics.
ESTHER : Waiker_2023_ACS.Chem.Neurosci__
PubMedSearch : Waiker_2023_ACS.Chem.Neurosci__
PubMedID: 37216500

Title : Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer's disease - Kiran_2023_Bioorg.Chem_139_106749
Author(s) : Kiran PVR , Waiker DK , Verma A , Saraf P , Bhardwaj B , Kumar H , Singh A , Kumar P , Singh N , Srikrishna S , Trigun SK , Shrivastava SK
Ref : Bioorg Chem , 139 :106749 , 2023
Abstract : Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Abeta-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 microM concentration which was comparable to donepezil and also demonstrated anti-Abeta aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 microM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Abeta-phenotypic drosophila AD model and amelioration of behavioral deficits in the Abeta-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy.
ESTHER : Kiran_2023_Bioorg.Chem_139_106749
PubMedSearch : Kiran_2023_Bioorg.Chem_139_106749
PubMedID: 37517157

Title : Development and Evaluation of Some Molecular Hybrids of N-(1-Benzylpiperidin-4-yl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio) as Multifunctional Agents to Combat Alzheimer's Disease - Waiker_2023_ACS.Omega_8_9394
Author(s) : Waiker DK , Verma A , Saraf P , T AG , Krishnamurthy S , Chaurasia RN , Shrivastava SK
Ref : ACS Omega , 8 :9394 , 2023
Abstract : A series of some novel compounds (SD-1-17) were designed following a molecular hybridization approach, synthesized, and biologically tested for hAChE, hBChE, hBACE-1, and Abeta aggregation inhibition potential to improve cognition and memory functions associated with Alzheimer's disease. Compounds SD-4 and SD-6 have shown multifunctional inhibitory profiles against hAChE, hBChE, and hBACE-1 enzymes in vitro. Compounds SD-4 and SD-6 have also shown anti-Abeta aggregation potential in self- and acetylcholinesterase (AChE)-induced thioflavin T assay. Both compounds have shown a significant propidium iodide (PI) displacement from the cholinesterase-peripheral active site (ChE-PAS) region with excellent blood-brain barrier (BBB) permeability and devoid of neurotoxic liabilities. Compound SD-6 ameliorates cognition and memory functions in scopolamine- and Abeta-induced behavioral rat models of Alzheimer's disease (AD). Ex vivo biochemical estimation revealed a significant decrease in malonaldehyde (MDA) and AChE levels, while a substantial increase of superoxide dismutase (SOD), catalase, glutathione (GSH), and ACh levels is seen in the hippocampal brain homogenates. The histopathological examination of brain slices also revealed no sign of neuronal or any tissue damage in the SD-6-treated experimental animals. The in silico molecular docking results of compounds SD-4 and SD-6 showed their binding with hChE-catalytic anionic site (CAS), PAS, and the catalytic dyad residues of the hBACE-1 enzymes. A 100 ns molecular dynamic simulation study of both compounds with ChE and hBACE-1 enzymes also confirmed the ligand-protein complex's stability, while quikprop analysis suggested drug-like properties of the compounds.
ESTHER : Waiker_2023_ACS.Omega_8_9394
PubMedSearch : Waiker_2023_ACS.Omega_8_9394
PubMedID: 36936338

Title : Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease - Shrivastava_2018_Bioorg.Chem_82_211
Author(s) : Shrivastava SK , Sinha SK , Srivastava P , Tripathi PN , Sharma P , Tripathi MK , Tripathi A , Choubey PK , Waiker DK , Aggarwal LM , Dixit M , Kheruka SC , Gambhir S , Shankar S , Srivastava RK
Ref : Bioorg Chem , 82 :211 , 2018
Abstract : Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE.
ESTHER : Shrivastava_2018_Bioorg.Chem_82_211
PubMedSearch : Shrivastava_2018_Bioorg.Chem_82_211
PubMedID: 30326403