Synthesis,crystal structure determination,biological screening and docking studies of N1-substituted derivatives of 2,3-dihydroquinazolin-4(1H)-one as inhibitors of cholinesterases |
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| Affiliation: | 1. Department of Chemistry, University of Sargodha, Sargodha, Pakistan;2. Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;3. School of Science & Engineering, Teesside University, Middlesbrough, Tees Valley TS1 3BA, UK;4. Department of Pharmacy, University of Malakand, Chakdara 18000 Dir (L), Pakistan;1. Key Laboratory of Small Fuctional Organic Molecule, Ministry of Education and College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China;2. Key Laboratory of Green Chemistry, Jiangxi Province, Nanchang, Jiangxi 330022, China;1. Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea;2. T&J Tech Inc., Kasan-Dong, Keumchun-Gu, Seoul 153-770, Republic of Korea;3. Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea;1. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), PuncakAlam Campus, 42300 Bandar PuncakAlam, Selangor, Malaysia;2. Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia;3. Department of Chemistry, COMSATS Institute of Information Technology, University Road, Abbottabad 22060, KPK, Pakistan;4. Batterje Medical College for Science & Technology, Jeddah 21442, Saudi Arabia;5. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;1. College of Chemistry and Environmental Science, Hebei University, Baoding 071002, PR China;2. College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding 071002, PR China;1. Department of Chemistry, Dibrugarh University, Dibrugarh-786004, Assam, India;2. AcSIR, Salt and Marine Chemicals Division, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar 364002, India;3. Analytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India |
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| Abstract: | Pursuing the strategy of developing potent AChE inhibitors, we attempted to carry out the N1-substitution of 2,3-dihydroquinazolin-4(1H)-one core. A set of 32 N-alkylated/benzylated quinazoline derivatives were synthesized, characterized and evaluated for their inhibition against cholinesterases. N-alkylation of the series of the compounds reported previously (N-unsubstituted) resulted in improved activity. All the compounds showed inhibition of both enzymes in the micromolar to submicromolar range. Structure activity relationship (SAR) of the 32 derivatives showed that N-benzylated compounds possess good activity than N-alkylated compounds. N-benzylated compounds 2ad and 2af were found very active with their IC50 values toward AChE in submicromolar range (0.8 µM and 0.6 µM respectively). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. Computational predictions of ADMET studies reveal that all the compounds have good pharmacokinetic properties with no AMES toxicity and carcinogenicity. Moreover, all the compounds are predicted to be absorbed in human intestine and also have the ability to cross blood brain barrier. Overall, the synthesized compounds have established a structural foundation for the design of new inhibitors of cholinesterase. |
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| Keywords: | Cholinesterases Alzheimer’s disease Benzylation Computational studies |
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