1. QSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity.
- Author
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Gomes MN, Braga RC, Grzelak EM, Neves BJ, Muratov E, Ma R, Klein LL, Cho S, Oliveira GR, Franzblau SG, and Andrade CH
- Subjects
- Animals, Antitubercular Agents chemical synthesis, Antitubercular Agents chemistry, Chalcone chemical synthesis, Chalcone chemistry, Chlorocebus aethiops, Dose-Response Relationship, Drug, Drug Design, Microbial Sensitivity Tests, Molecular Structure, Vero Cells, Antitubercular Agents pharmacology, Chalcone pharmacology, Drug Discovery, Mycobacterium tuberculosis drug effects, Quantitative Structure-Activity Relationship, Tuberculosis, Multidrug-Resistant drug therapy
- Abstract
New anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis strains and to shorten the current 6-12-month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new heteroaryl chalcone compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation. As a result, 10 heteroaryl chalcone compounds (4, 8, 9, 11, 13, 17-20, and 23) were found to exhibit nanomolar activity against replicating mycobacteria, low micromolar activity against nonreplicating bacteria, and nanomolar and micromolar against rifampin (RMP) and isoniazid (INH) monoresistant strains (rRMP and rINH) (<1 μM and <10 μM, respectively). The series also show low activity against commensal bacteria and generally show good selectivity toward M. tuberculosis, with very low cytotoxicity against Vero cells (SI = 11-545). Our results suggest that our designed heteroaryl chalcone compounds, due to their high potency and selectivity, are promising anti-TB agents., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
- Published
- 2017
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