Design, synthesis, and evaluation of novel diphenyl ether derivatives against drug ‐susceptible and drug‐resistant strains of Mycobacterium tuberculosis

Twelve new compounds with diphenyl ether scaffold were designed and synthesized. Compounds6b showed better activity against drug ‐susceptible and drug‐resistant strains ofMycobacterium 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. 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 promisingin vitro activity against drug ‐susceptible, isoniazid‐resistant, and multidrug‐resistant strains ofMycobacterium 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. Th...

Source: Chemical Biology and Drug Design - November 28, 2018 Category: Biology Authors: Sidhartha S. Kar, Varadaraj G. Bhat, Vishnu P. Shenoy, Indira Bairy, G. Gautham Shenoy Tags: RESEARCH ARTICLE Source Type: research