title: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
authors.forename: Sidhartha S
authors.initials: SS
authors.lastname: Kar
authors.affiliation: Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
authors.forename: Varadaraj
authors.initials: V
authors.lastname: Bhat G
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, ON, Canada.
authors.forename: Praveen Pn
authors.initials: PP
authors.lastname: Rao
authors.affiliation: Department of Microbiology, Kasturba Medical College, Manipal.
authors.forename: Vishnu P
authors.initials: VP
authors.lastname: Shenoy
authors.affiliation: Melaka-Manipal Medical College, Manipal University, Manipal, India.
authors.forename: Indira
authors.initials: I
authors.lastname: Bairy
authors.affiliation: Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
authors.forename: G Gautham
authors.initials: GG
authors.lastname: Shenoy
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000187:drug effects; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010647:Phenyl Ethers / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D010647:Phenyl Ethers; C031538:phenyl ether
keywords: cytotoxicity; diphenyl ether; druglikeness; tuberculosis