2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase |
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| Affiliation: | 1. Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia;2. Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia;3. Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abd. Aziz, 50300 Kuala Lumpur, Malaysia;4. Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia;1. Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy;2. Department of Organic Chemistry, University of Santiago de Compostela, Santiago de Compostela, Spain;3. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy;4. Biomedicine Department, Center for Advanced Studies, Research and Development in Sardinia (CRS4), Pula, Italy;5. Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Cagliari, Italy;1. Instituto de Química, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Campus do Vale, 91501-970, Porto Alegre, RS, Brazil;2. Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Prédio Anexo, 90035-003, Porto Alegre, RS, Brazil;3. Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av Ipiranga, 2752, Santana, 90610000, Porto Alegre, RS, Brazil;4. Laboratório Nacional De Computação Científica-LNCC, Av. Getulio Vargas, 333, Petrópolis, 25651-075, RJ, Brazil;1. Department of Organic Chemistry, Institute of Chemical Sciences, Faculty of Science, P. J. Safarik University, Moyzesova 11, SK-041 67 Kosice, Slovak Republic;2. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic;3. Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanského 62, 500 03 Hradec Kralove, Czech Republic;4. Department of Toxicology and Military Pharmacy, Faculty Military Helath Sciences, University of Defense, Trebesska 1575, 500 05 Hradec Kralove, Czech Republic;1. Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal;2. Institut für Physik, Photobiophysik, Humboldt-Universität zu Berlin, Newtonstrasse 15, 12489 Berlin, Germany;1. Department of Chemistry and Biochemistry, California State University, Long Beach, 1250 Bellflower Blvd., Long Beach, CA 90840, USA;2. Department of Physics, California State University, Long Beach, 1250 Bellflower Blvd., Long Beach, CA 90840, USA;1. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;2. Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA;3. Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;4. School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia 4072, Queensland, Australia |
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| Abstract: | In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6 μM and 0.6 μM, respectively. Further structure–activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes’ inhibition. The Lineweaver–Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer. |
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| Keywords: | Acetylcholinesterase Butyrylcholinesterase 2-Benzoyl-6-benzylidenecyclohexanone Kinetic studies Molecular docking |
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