Design,synthesis and biological evaluation of novel pyrrole derivatives as potential ClpP1P2 inhibitor against Mycobacterium tuberculosis |
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| Institution: | 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China;2. State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China;3. Institute of Physical Science and Information Technology, Anhui University, Hefei 230601, China;4. Guangdong Zhongsheng Pharmaceutical Co., Ltd, Dongguan, Guangdong 523325, China;1. Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India;2. Dr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India;3. Zephase Therapeutics (An Incubated Company at the Dr Reddy’s Institute of Life Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India;1. State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China;2. Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China;1. Crop Protection Chemicals, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India;2. Chemical Biology, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India;3. Department of Chemistry, Vikrama Simhapuri University, Nellore 524001, India;4. Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, India;5. Natural Product Chemistry, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India;6. Biology Division Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India;1. Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India;2. Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, Telangana, India;3. Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India;1. Medicinal Chemistry and Molecular Modelling Lab, Dept. of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 62, India;2. Dept. of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia;3. From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115,;4. Department of Biochemistry, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts 02139,;5. Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts 02111, and;6. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115 |
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| Abstract: | In an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6-fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)-1H-pyrrole-3-carboxylate was found to display inhibitory effects against H37Ra with an MIC value of 77 µM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis, a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated for in vitro studies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)-N-((1-(2-chloro-6-fluorophenyl)-2, 5-dimethyl-1H- pyrrolyl)methyl)ethan-1-aminehydrochloride 7d, ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13i, ethyl 1-(4-chlorophenyl)-4-(((2-fluorophenethyl)amino)methyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 µM against Mtb H37Ra, respectively. |
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| Keywords: | Anti-tubercular ClpP1P2 peptidase Pyrrole derivatives |
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