Bhagat K

References (3)

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 : 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 : New coumarin-benzotriazole based hybrid molecules as inhibitors of acetylcholinesterase and amyloid aggregation - Singh_2020_Bioorg.Med.Chem.Lett_30_127477
Author(s) : Singh A , Sharma S , Arora S , Attri S , Kaur P , Kaur Gulati H , Bhagat K , Kumar N , Singh H , Vir Singh J , Mohinder Singh Bedi P
Ref : Bioorganic & Medicinal Chemistry Lett , 30 :127477 , 2020
Abstract : A novel series of triazole tethered coumarin-benzotriazole hybrids based on donepezil skeleton has been designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD). Among the synthesized compounds 13b showed most potent acetylcholinesterase (AChE) inhibition (IC(50) = 0.059 microM) with mixed type inhibition scenario. Structure-activity relationship revealed that three-carbon alkyl chain connecting coumarin and triazole is well tolerable for inhibitory potential. Hybrids obtained from 4-hydroxycoumarin and 1-benzotriazole were most potent AChE inhibitors. The inhibitory potential of all compounds against butyrylcholinesterase was also evaluated but all showed negligible activity suggesting that the hybrid molecules are selective AChE inhibitors. 13b (most potent AChE inhibitor) also showed copper-induced Abeta(1-42) aggregation inhibition (34.26% at 50 microM) and chelating properties for metal ions (Cu(2+), Fe(2+,) and Zn(2+)) involved in AD pathogenesis along with DNA protective potential against degenerative actions of OH radicals. Molecular modelling studies confirm the potential of 13b in blocking both PAS and CAS of AChE. In addition, interactions of 13b with Abeta(1-42) monomer are also streamlined. Therefore, hybrid 13b can act as an effective hit lead molecule for further development of selective AChE inhibitors as multifunctional anti-Alzheimer's agents.
ESTHER : Singh_2020_Bioorg.Med.Chem.Lett_30_127477
PubMedSearch : Singh_2020_Bioorg.Med.Chem.Lett_30_127477
PubMedID: 32781220