Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors |
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| Institution: | 1. School of Biological Science and Technology, University of Jinan, Jinan 250022, China;2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;3. Institute of Biological Sciences, University of Brasília, Brasilia 70910900, Brazil;4. Faculty of Ceilandia, University of Brasília, Brasilia 72220275, Brazil;5. Cambrian Discovery Inc., Dover, MA 02115, USA;6. Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA;1. Department of Chemistry, Khuzestan Science and Research Branch, Islamic Azad University, Ahvaz, Iran;2. Department of Chemistry, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran;3. Marine Pharmaceutical Science Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran;4. Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran;1. Laboratory of Synthesis of Molecules with Biological Interest, Frères Mentouri-Constantine University, 25000 Constantine, Algeria;2. SRSMC, Lorraine University, 1 Boulevard Arago, 57070, France;3. Chemistry of Natural Compounds Department, National Research Centrer, El-Behoos St. 33, Dokki, Cairo 12622, Egypt;4. Faculty of Technology, Batna 2 University, 05000 Batna, Algeria;5. Biotechnology Research Center, Constantine, Algeria;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon;3. Noha Gouda, Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, 35040 Izmir, Turkey;2. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, 35040 Izmir, Turkey;3. Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany;1. National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic;2. Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic;3. Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic;4. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic;5. Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, I-40126, Bologna, Italy;6. Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park - Basovizza, S.S. n° 14-Km 163.5, I-34149, Trieste, Italy;7. Institut de Recherche Biomédicale des Armées, Département de Toxicologie et Risques Chimiques, 1 Place Général Valérie André, 91220, Brétigny-sur-Orge, France;8. Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic;9. Institute of Clinical Biochemistry and Diagnosis, University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic;10. Department of Analytical Chemistry, University of Chemistry and Technology Prague, Technicka 5, 166 28, Prague, Czech Republic;11. Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic;12. Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Kralove and University Hospital, Simkova 870, 500 03, Hradec Kralove, Czech Republic;1. Division of Chemistry, Department of Science and Humanities, Vignan''s Foundation for Science, Technology and Research University-VFSTRU (Vignan''s University), Vadlamudi, Guntur 522 213, Andhra Pradesh, India;2. Department of Biotechnology and Microbiology and Inter-University Centre for Bioscience, Kannur University, Thalassery Campus, Kerala, India;3. Molecular Neurobiology Division, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Trivandrum, Kerala 695014, India;4. Research Scholar, University of Kerala, India;5. Post Graduate and Research Department of Chemistry, Kasargod Govt. College, Kannur University, Kasaragod, India |
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| Abstract: | A series of new indole-3-acetic acid (IAA)-tacrine hybrids as dual acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitors were designed and prepared based on the molecular docking mode of AChE with an IAA derivative (1a), a moderate AChE inhibitor identified by screening our compound library for anti-Alzheimer’s disease (AD) drug leads. The enzyme assay results revealed that some hybrids, e.g. 5d and 5e, displayed potent dual in vitro inhibitory activities against AChE/BChE with IC50 values in low nanomolar range. Molecular modeling studies in tandem with kinetic analysis suggest that these hybrids target both catalytic active site and peripheral anionic site of cholinesterase (ChE). Molecular dynamic simulations and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations indicate that 5e has more potent binding affinity than hit 1a, which may explain the stronger inhibitory effect of 5e on AChE. Furthermore, their predicted pharmacokinetic properties and in vitro influences on mouse brain neural network electrical activity were discussed. Taken together, compound 5e can be highlighted as a lead compound worthy of further optimization for designing new anti-AD drugs. |
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| Keywords: | Alzheimer’s disease IAA-tacrine hybrids Dual AChE/BChE inhibitor Molecular docking Neural network electrical activity |
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