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

Authors Sankar Kar S, Bhat V, Rao P N P, P Shenoy V, Bairy I, Gautham G

Received 11 January 2016

Accepted for publication 16 March 2016

Published 18 July 2016 Volume 2016:10 Pages 2299—2310

DOI https://doi.org/10.2147/DDDT.S104037

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Rammohan Devulapally

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Wei Duan


Sidhartha S Kar,1 Varadaraj Bhat G,1 Praveen PN Rao,2 Vishnu P Shenoy,3 Indira Bairy,4 G Gautham Shenoy1

1Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India; 2School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, ON, Canada; 3Department of Microbiology, Kasturba Medical College, Manipal, 4Melaka-Manipal Medical College, Manipal University, Manipal, India

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: dihenyl ether, tuberculosis, cytotoxicity, druglikeness

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