Bedi PMS

References (3)

Title : Pathogenesis of Alzheimer's Disease and Diversity of 1,2,3-Triazole Scaffold in Drug Development: Design Strategies, Structural Insights, and Therapeutic Potential - Singh_2023_ACS.Chem.Neurosci__
Author(s) : Singh A , Singh K , Kaur J , Kaur R , Sharma A , Kaur U , Chadha R , Bedi PMS
Ref : ACS Chem Neurosci , : , 2023
Abstract : Alzheimer's disease is a most prevalent form of dementia all around the globe and currently poses a significant challenge to the healthcare system. Currently available drugs only slow the progression of this disease rather than provide proper containment. Identification of multiple targets responsible for this disease in the last three decades established it as a multifactorial neurodegenerative disorder that needs novel multifunctional agents for its management and the possible reason for the failure of currently available single target clinical drugs. 1,2,3-Triazole is a miraculous nucleus in medicinal chemistry and the first choice for development of multifunctional hybrid molecules. Apart from that, it is an integral component of various drugs in clinical trials as well as in clinical practice. This review is focused on the pathogenesis of Alzheimer's disease and 1,2,3-triazole containing derivatives developed in recent decades as potential anti-Alzheimer's agents. The review will provide (A) precise insight of various established targets of Alzheimer's disease including cholinergic, amyloid, tau, monoamine oxidases, glutamate, calcium, and reactive oxygen species hypothesis and (B) design hypothesis, structure-activity relationships, and pharmacological outcomes of 1,2,3-triazole containing multifunctional anti-Alzheimer's agents. This review will provide a baseline for various research groups working on Alzheimer's drug development in designing potent, safer, and effective multifunctional anti-Alzheimer's candidates of the future.
ESTHER : Singh_2023_ACS.Chem.Neurosci__
PubMedSearch : Singh_2023_ACS.Chem.Neurosci__
PubMedID: 37683129

Title : Donepezil-Inspired Multitargeting Indanone Derivatives as Effective Anti-Alzheimer's Agents - Singh_2022_ACS.Chem.Neurosci__
Author(s) : Singh JV , Thakur S , Kumar N , Singh H , Mithu VS , Bhagat K , Gulati HK , Sharma A , Sharma S , Bedi PMS
Ref : ACS Chem Neurosci , : , 2022
Abstract : In continuous efforts to develop anti-Alzheimer's agents, we rationally designed and synthesized a series of multitargeting molecules by incorporating the essential molecular features of the standard drug donepezil. Among the series, compound 4b showed multitargeting properties to act as an anti-Alzheimer's agent, which is better tolerable in vivo than donepezil. Acetylcholinesterase (AChE) inhibition data showed that compound 4b inhibits the enzyme with a half-maximal inhibitory concentration (IC(50)) value of 0.78 microM and also showed DNA protection, which was confirmed through the DNA nicking assay, suggesting the protective effect of 4b against oxidative DNA damage. Compound 4b also showed 53.04% inhibition against Abeta(1-42) aggregations, which was found comparable to that of the standard compound curcumin. Molecular dynamics simulations were performed to check the stability of compound 4b with the enzyme AChE, which showed that the enzyme-ligand complex is stable enough to block the hydrolysis of acetylcholine in the brain. Its higher LD(50) cutoff value (50 mg/kg) in comparison to donepezil (LD(50): 25 mg/kg) made it safer, suggesting that it can be used in further clinical experiments. To evaluate its anti-Alzheimer property, a mice model with melamine-induced cognitive dysfunction was used, and Morris water maze and Rotarod tests were performed. A significant improvement in memory was observed after the treatment with compound 4b and donepezil. The study postulated that the introduction of important structural features of donepezil (dimethoxyindanone moiety as ring-A) embarked with terminal aromatic ether (ring-B and ring-C) made 4b a multitargeting molecule that offers a way for developing alternative therapeutics in the future against Alzheimer's disease (AD).
ESTHER : Singh_2022_ACS.Chem.Neurosci__
PubMedSearch : Singh_2022_ACS.Chem.Neurosci__
PubMedID: 35195392

Title : Rational Approaches, Design Strategies, Structure Activity Relationship and Mechanistic Insights for Esterase Inhibitors - Singh_2018_Mini.Rev.Med.Chem_18_837
Author(s) : Singh H , Singh JV , Kaur N , Sanduja M , Singh G , Bedi PMS , Sharma S
Ref : Mini Rev Med Chem , 18 :837 , 2018
Abstract : BACKGROUND: Esterase is an enzyme that splits esters into an acid and alcohol. Varieties of esterases are present in human body to control diverse set of cellular processes and execute their specific functions. It can be seen that any increase in metabolites produced by these enzymes lead to severe pathological conditions like Alzheimer disease, hypercholesterolemia etc. Objective: Numerous esterase inhibitors have been developed and reported by the researchers around the globe, but not systematically summarized yet. Therefore, this assemblage focuses on various reported esterase inhibitors during recent past with detailed account of the design strategies employed for the synthesis of novel drug entities. The article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of inhibitors as esterase inhibition. The interactions with the amino acid residues responsible for esterase inhibitory potential of molecules have also been discussed. This compilation will be of great interest for the researchers working in the area of esterase inhibitors. CONCLUSION: Rivastigmine derivatives (44-53), tacrine-piperazine hybrid (136), coumarin-benzofuran derivative (169), coumarin-benzylpiperidine hybrid (181) and phenylcinnamide derivative (220) found to be exerting cholinesterase inhibition with IC50 below the range of 1 nM. Whereas, flavone (258) has displayed anticholesterol esterase potential below 1 nM. Benzil like derivative, (273) has also been designed and reported to possess remarkable inhibitory potential (IC50 < 1 nM) against carboxylesterase. These representative results place them in forefront as potential future drug candidates to further develop potent and specific esterase inhibitors.
ESTHER : Singh_2018_Mini.Rev.Med.Chem_18_837
PubMedSearch : Singh_2018_Mini.Rev.Med.Chem_18_837
PubMedID: 28782481