Development of novel tetrahydrothieno[2,3-c]pyridine-3-carboxamide based Mycobacterium tuberculosis pantothenate synthetase inhibitors: Molecular hybridization from known antimycobacterial leads |
| |
| Institution: | 1. Cellular Biochemistry Laboratory, Methodist Research Institute, Indiana University Health, 1800 N. Capitol Ave., Room E504, Indianapolis, IN 46202, USA;2. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA;3. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Dr, West Lafayette, IN 47907, USA;1. Institute for Neurodegenerative Diseases, University of California, San Francisco, United States;2. Department of Neurology, University of California, San Francisco, United States;3. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States;4. Small Molecule Discovery Center, University of California, San Francisco, United States;5. Department of Pharmaceutical Chemistry, University of California, San Francisco, United States;1. School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport Bypass Road, Gandhi Nagar, Bhopal (MP) 462036, India;2. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark;3. Protein Phosphorylation and Human Disease Group, USR3151, Station Biologique, B.P. 74, 29682 Roscoff cedex, Bretagne, France;4. ManRos Therapeutics, Centre de Perharidy, 29680 Roscoff, Bretagne, France;1. Department of Biotechnology, National Formosa University, Yunlin 632, Taiwan;2. Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan;3. Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 401, Taiwan;4. Kunming Institute of Botany, Chinese Academy of Science, Kunming 650204, Yunnan, China;5. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA;6. Department of Pharmacy and Chinese Medicine Research and Development Center, China Medical University, Taichung 401, Taiwan;1. Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran;2. Pharmacology and Toxicology Department, Pharmaceutical Sciences Branch and Pharmaceutical Sciences Research Center, Islamic Azad University, Tehran, Iran;3. Department of Radiopharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;4. Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran;5. Department of Physiology & Pharmacology, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran;6. Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran, Iran;1. Department of Organic Chemistry, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation;2. Pasteur Institute of Epidemiology and Microbiology, 14 Mira St., 197101 St. Petersburg, Russian Federation;3. Department of Pre-clinical Trials, Influenza Research Institute, 15/17 Prof. Popova St., 197376 St. Petersburg, Russian Federation;4. Department of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India;5. Department of Organic Chemistry, Baku State University, Z. Khalilov str. 23, AZ 1148 Baku, Azerbaijan;6. Centro de QuímicaEstrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. RoviscoPais, 1049-001 Lisbon, Portugal |
| |
| Abstract: | Twenty six 2,6-disubstituted 4,5,6,7-tetrahydrothieno2,3-c]pyridine-3-carboxamide derivatives were designed by molecular hybridization approach using and synthesized from piperidin-4-one by five step synthesis. Compounds were evaluated for Mycobacterium tuberculosis (MTB) pantothenate synthetase (PS) inhibition study, in vitro activities against MTB, cytotoxicity against RAW 264.7 cell line. Among the compounds, 6-(4-nitrophenylsulfonyl)-2-(5-nitrothiophene-2-carboxamido)-4,5,6,7-tetrahydrothieno2,3-c]pyridine-3-carboxamide (11) was found to be the most active compound with IC50 of 5.87 ± 0.12 μM against MTB PS, inhibited MTB with MIC of 9.28 μM and it was non-cytotoxic at 50 μM. The binding affinity of the most potent inhibitor 11 was further confirmed biophysically through differential scanning fluorimetry. |
| |
| Keywords: | Tuberculosis Pantothenate synthetase Cytotoxicity |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
