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Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities
Institution:1. Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia;2. New Drug Discovery Research, Department of Medicinal Chemistry, Alwar Pharmacy College, Alwar 301030, Rajasthan, India;3. New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar 301030, Rajasthan, India;4. School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia;5. Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, United States;1. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia;2. Faculty of Applied Science, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor, Malaysia;3. Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia;4. Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia;5. Department of Chemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa, Pakistan;6. Pharmacology and Toxicology Research Laboratory, Faculty of Pharmacy, University Technology MARA (UiTM), 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia;7. Department of Chemistry, COMSATS Institute of Information Technology, University Road, Abbottabad 22060, KPK, Pakistan;8. Center for Advanced Drug Research, COMSATS Institute of Information Technology, University Road, Abbottabad 22060, KPK, Pakistan;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 Pharmaceutical Chemistry, Gokulakrishna College of Pharmacy, Andhra Pradesh 524121, India;2. Department of Pharmacology, SSM College of Pharmacy, Tamil Nadu 638312, India;3. Department of Pharmaceutical Biotechnology, Srikrupa Institute of Pharmaceutical Sciences, Andhra Pradesh 502277, India;1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;2. Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Sakaka, Aljouf 2014, Saudi Arabia;3. Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates;4. Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;1. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor D. E., Malaysia;2. Faculty of Applied Science, UiTM Shah Alam, 40450 Shah Alam, Selangor D.E., Malaysia;3. Department of Chemistry, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan;4. Department of Chemistry, Hazara University Mansehra, 21300 Khyber Pakhtunkhwa, Pakistan;5. Department of Bioinformatics, Quaide-e-Azam University, Islamabad, Pakistan
Abstract:A total of 15 novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. All compounds showed better inhibition on SIRT2 as compared to SIRT1. Among these, compound 5j displayed the best inhibitory activity for SIRT1 (IC50 = 58.43 μM) as well as for SIRT2 (IC50 = 45.12 μM). Cell cytotoxicity assays also showed that compound 5j possesses good antitumor activity against two different cancer cell lines derived from breast cancer (MCF-7 and MDA-MB-468). A simple structure–activity-relationship (SAR) study of the newly synthesized benzimidazole derivatives was also discussed.
Keywords:Sirtuin  Benzimidazole  Electron donating  Anti-proliferative  Breast cancer
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