1. Design and development of ((4-methoxyphenyl)carbamoyl) (5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl)amide analogues as Mycobacterium tuberculosis ketol-acid reductoisomerase inhibitors.
- Author
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Krishna VS, Zheng S, Rekha EM, Nallangi R, Sai Prasad DV, George SE, Guddat LW, and Sriram D
- Subjects
- Amides chemical synthesis, Amides chemistry, Animals, Antitubercular Agents chemical synthesis, Antitubercular Agents chemistry, Biofilms drug effects, Cell Line, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, HEK293 Cells, Humans, Ketol-Acid Reductoisomerase metabolism, Macrophages drug effects, Macrophages microbiology, Mice, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Mycobacterium tuberculosis enzymology, Structure-Activity Relationship, Amides pharmacology, Antitubercular Agents pharmacology, Drug Development, Enzyme Inhibitors pharmacology, Ketol-Acid Reductoisomerase antagonists & inhibitors, Mycobacterium tuberculosis drug effects
- Abstract
Based on our previous finding that the titled compound possesses anti-tuberculosis activity, a series of novel ((4-methoxyphenyl)carbamoyl) (5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl)amide analogues have been synthesized. Amongst the 22 compounds synthesized and tested, 5b, 5c and 6c showed potent inhibitory activity with K
i values of 2.02, 5.48 and 4.72 μM for their target, Mycobacterium tuberculosis (Mt) ketol-acid reductoisomerase (KARI). In addition, these compounds have excellent in vitro activity against Mt H37Rv with MIC values as low as 1 μM. The mode of binding for these compounds to Mt KARI was investigated through molecular docking and dynamics simulations. Furthermore, these compounds were evaluated for their activity in Mt infected macrophages, and showed inhibitory activities with up to a 1.9-fold reduction in growth (at 10 μM concentration). They also inhibited Mt growth in a nutrient starved model by up to 2.5-fold. In addition, these compounds exhibited low toxicity against HEK 293T cell lines. Thus, these compounds are promising Mt KARI inhibitors that can be further optimized into anti-tuberculosis agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)- Published
- 2020
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