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Design, synthesis, and evaluation of novel diphenyl ether derivatives against drug‐susceptible and drug‐resistant strains of Mycobacterium tuberculosis
Author(s) -
Kar Sidhartha S.,
Bhat Varadaraj G.,
Shenoy Vishnu P.,
Bairy Indira,
Shenoy G. Gautham
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13379
Subject(s) - mycobacterium tuberculosis , chemistry , isoniazid , in vitro , diphenyl ether , drug , ether , druggability , microsome , vero cell , combinatorial chemistry , tuberculosis , stereochemistry , pharmacology , organic chemistry , biochemistry , biology , medicine , pathology , gene
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 ( CC 50 > 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. p K a 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.