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- Title
Design, synthesis, and evaluation of novel diphenyl ether derivatives against drug‐susceptible and drug‐resistant strains of Mycobacterium tuberculosis.
- Authors
Kar, Sidhartha S.; Bhat, Varadaraj G.; Shenoy, G. Gautham; Shenoy, Vishnu P.; Bairy, Indira
- Abstract
In our efforts to develop druggable diphenyl ethers as potential antitubercular agents, a series of novel diphenyl ether derivatives (5a–f, 6a–f) were designed and synthesized. The representative compounds showed promising in vitro activity against drug‐susceptible, isoniazid‐resistant, and multidrug‐resistant strains of Mycobacterium tuberculosis with MIC values of 1.56 μg/ml (6b), 6.25 μg/ml (6a–d), and 3.125 μg/ml (6b–c), respectively. All the synthesized compounds exhibited satisfactory safety profile (CC50 > 300 μg/ml) against Vero and HepG2 cells. Reverse phase HPLC method was used to probe the physicochemical properties of the synthesized compounds. This series of compounds demonstrated comparatively low logP values. pKa values of representative compounds indicated that they were weak acids. Additionally, in vitro human liver microsomal stability assay confirmed that the synthesized compounds possessed acceptable stability under study conditions. The present study thus establishes compound 6b as the most promising antitubercular agent with acceptable drug‐likeness. Twelve new compounds with diphenyl ether scaffold were designed and synthesized. Compounds 6b showed better activity against drug‐susceptible and drug‐resistant strains of Mycobacterium tuberculosis. All the compounds exhibited an acceptable safety profile in Vero and HepG2 cells. Compounds also demonstrated comparatively low logP. pKa study of the representative compounds showed that they are weak acids. Liver microsomal stability of the synthesized compounds confirmed their druggability.
- Subjects
MYCOBACTERIUM tuberculosis; ANTITUBERCULAR agents; PHENYL ethers; CHEMICAL derivatives; CHEMICAL synthesis; DRUG resistance
- Publication
Chemical Biology & Drug Design, 2019, Vol 93, Issue 1, p60
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.13379