Rational design and synthesis of novel diphenyl ether derivatives as antitubercular agents

Abstract

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.

Keywords:

• diphenyl ether
• tuberculosis
• cytotoxicity
• druglikeness

Acknowledgments

This research was funded by the Indian Council of Medical Research, New Delhi. The authors thank Schrodinger Inc. for providing software to carry out molecular modeling studies. The authors are grateful to AICTE, New Delhi, DST, New Delhi, and Manipal University, Manipal, for providing necessary facilities to carry out the research work.

Disclosure

The authors report no conflicts of interest in this work.