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.
A series of triclosan mimic diphenyl ether derivatives have been synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The binding mode of the compounds at the active site of enoyl-acyl carrier protein reductase of M. tuberculosis has been explored. Among them, compound 10b was found to possess antitubercular activity (minimum inhibitory concentration =12.5 µg/mL) comparable to triclosan. All the synthesized compounds exhibited low levels of cytotoxicity against Vero and HepG2 cell lines, and three compounds 10a, 10b, and 10c had a selectivity index more than 10. Compound 10b was also evaluated for log P, pKa, human liver microsomal stability, and % protein binding, in order to probe its druglikeness. Based on the antitubercular activity and druglikeness profile, it may be concluded that compound 10b could be a lead for future development of antitubercular drugs.