Synthesis of benzimidazole-linked-1,3,4-oxadiazole carboxamides as GSK-3β inhibitors with in vivo antidepressant activity |
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| Institution: | 1. Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110062, India;2. CSIR – Unit for Research and Development of Information Products (URDIP), Pune 411038, India;3. Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110062, India;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110062, India;2. College of Pharmacy and Dentistry, Buraydah Private Colleges, Al-Qassim 31717, Saudi Arabia;3. School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India;4. Department of Medicinal Chemistry, Maharishi Arvind College of Pharmacy Jaipur, Rajasthan 301 039, India;5. College of Clinical Pharmacy, University of Dammam, Dammam 31441, Saudi Arabia;6. Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835 215, India;7. Department of Toxicology, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110062, India;1. Department of Chemistry, Art and Science Faculty, Recep Tayyip Erdogan University, Rize, Turkey;2. Department of Chemistry, Faculty of Arts and Sciences, Giresun University, 28049 Giresun, Turkey;3. Department of Nutrition and Dietetics, Faculty of Health Sciences, Karadeniz Technical University, Trabzon, Turkey;1. Department of Chemistry, Yuvaraja’s College (Autonomous), University of Mysore, Mysuru, Karnataka, India;2. Department of Biochemistry, Farooqia Dental College, Mysuru, Karnataka, India;1. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA, Puncak Alam Campus, Malaysia;2. Faculty of Applied Science, Universiti Teknologi MARA, 40450 Shah Alam, Selangor D. E., Malaysia;3. Department of Biochemistry, Computational Medicinal Chemistry Laboratory, UCSS, Abdul Wali Khan University Mardan, Pakistan;4. Department of Chemistry, Hazara University, Mansehra 21120, Pakistan;5. Center for Advanced Drug Research, COMSATS Institute of Information Technology, University Road, Abbottabad 22060, KPK, Pakistan;6. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;1. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China;2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China;3. State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, State Institute of Pharmaceutical Industry, Shanghai 201203, China |
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| Abstract: | Recent findings of potential implications of glycogen synthase kinase-3β (GSK-3β) dysfunction in psychiatric disorders like depression, have increased focus for development of GSK-3β inhibitors with possible anti-depressant activity. Keeping this in view, we synthesized a series of benzimidazole-linked-1,3,4-oxadiazole carboxamides and evaluated them for in vitro GSK-3β inhibition. Active compounds were investigated for in vivo antidepressant activity in Wistar rats. Docking studies of active compounds have also been performed. Among nineteen compounds synthesized, compounds 7a, 7r, 7j, and 7d exhibited significant potency against GSK-3β in sub-micromolar range with IC50 values of 0.13 μM, 0.14 μM, 0.20 μM, 0.22 μM respectively and significantly reduced immobility time (antidepressant-like activity) in rats compared to control group. Docking study showed key interactions of these compounds with GSK-3β. These compounds may thus serve as valuable candidates for subsequent development of effective drugs against depression and related disorders. |
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| Keywords: | Benzimidazole Oxadiazole Anti-depressant Forced swim test Tail suspension test |
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