Affiliations 

  • 1 Department of Pharmaceutical Chemistry, Manipal Academy of Higher Education, Manipal College of Pharmaceutical Sciences, Manipal, India
  • 2 Department of Microbiology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
  • 3 Melaka-Manipal Medical College, Manipal Academy of Higher Education, Manipal, India
Chem Biol Drug Des, 2019 01;93(1):60-66.
PMID: 30118192 DOI: 10.1111/cbdd.13379

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.