Department Of Pharmaceutical Sciences and Natural Products
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Item 4,6-Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer's Disease(American Chemical Society, 2019) Kumar, B; Dwivedi, A.R; Sarkar, B; Gupta, S.K; Krishnamurthy, S; Mantha, Anil K; Parkash, Jyoti; Kumar, VinodAlzheimer's disease (AD) is a neurodegenerative disorder with multifactorial pathogenesis. Monoamine oxidase (MAO) and acetylcholinesterase enzymes (AChE) are potential targets for the treatment of AD. A total of 15 new propargyl containing 4,6-diphenylpyrimidine derivatives were synthesized and screened for the MAO and AChE inhibition activities along with ROS production inhibition and metal-chelation potential. All the synthesized compounds were found to be selective and potent inhibitors of MAO-A and AChE enzymes at nanomolar concentrations. VB1 was found to be the most potent MAO-A and BuChE inhibitor with IC 50 values of 18.34 ± 0.38 nM and 0.666 ± 0.03 μM, respectively. It also showed potent AChE inhibition with an IC 50 value of 30.46 ± 0.23 nM. Compound VB8 was found to be the most potent AChE inhibitor with an IC 50 value of 9.54 ± 0.07 nM and displayed an IC 50 value of 1010 ± 70.42 nM against the MAO-A isoform. In the cytotoxic studies, these compounds were found to be nontoxic to the human neuroblastoma SH-SY5Y cells even at 25 μM concentration. All the compounds were found to be reversible inhibitors of MAO-A and AChE enzymes. In addition, these compounds also showed good neuroprotective properties against 6-OHDA- and H 2 O 2 -induced neurotoxicity in SH-SY5Y cells. All the compounds accommodate nicely to the hydrophobic cavity of MAO-A and AChE enzymes. In the molecular dynamics simulation studies, both VB1 and VB8 were found to be stable in the respective cavities for 30 ns. Thus, 4,6-diphenylpyrimidine derivatives can act as promising leads in the development of dual-acting inhibitors targeting MAO-A and AChE enzymes for the treatment of Alzheimer's disease. © 2018 American Chemical Society.Item Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase(Elsevier, 2019) Kumar, Bhupinder; Kumar, V; Prashar, V; Saini, S; Dwivedi, A.R; Bajaj, B; Mehta, D; Parkash, Jyoti; Kumar, VinodAlzheimer's disease (AD) is a multifactorial neurological disorder involving complex pathogenesis. Single target directed drugs proved ineffective and since last few years' different pharmacological strategies including multi-targeting agents are being explored for the effective drug development for AD. A total of 19 dipropargyl substituted diphenylpyrimidines have been synthesized and evaluated for the monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibition potential. All the compounds were found to be selective and reversible inhibitors of MAO-B isoform. These compounds also displayed good AChE inhibition potential with IC50 values in low micromolar range. AVB4 was found to be the most potent MAO-B inhibitor with IC50 value of 1.49 ± 0.09 μM and AVB1 was found to be the most potent AChE inhibitor with IC50 value of 1.35 ± 0.03 μM. In the ROS protection inhibition studies, AVB1 and AVB4 displayed weak but interesting activity in SH-SY5Y cells. In the cytotoxicity studies involving SH-SY5Y cells, both AVB1 and AVB4 were found to be non-toxic to the tissue cells. In the molecular dynamic simulation studies of 30 ns, the potent compounds were found to be quite stable in the active site of MAO-B and AChE. The results suggested that AVB1 and AVB4 are promising dual inhibitors and have the potential to be developed as anti-Alzheimer's drug. © 2019