Design, synthesis, and evaluation of novel diphenyl ether derivatives against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis

Kar, Sidhartha S and Bhat, Varadaraj G and Shenoy, Vishnu Prasad and Bairy, Indira and Shenoy, Gautham G (2019) Design, synthesis, and evaluation of novel diphenyl ether derivatives against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. Chemical Biology and Drug Design, 93 (1). pp. 60-66. ISSN 1747-0277

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: Antitubercular agents; diphenyl ether; human liver microsomal stability; physicochemical studies; safety profile.
Subjects: Medicine > MMMC Manipal > Microbiology
Medicine > KMC Manipal > Microbiology
Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Depositing User: KMC Library
Date Deposited: 05 Oct 2019 05:05
Last Modified: 05 Oct 2019 05:05
URI: http://eprints.manipal.edu/id/eprint/154686

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