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

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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.

Original languageEnglish
Pages (from-to)60-66
Number of pages7
JournalChemical Biology and Drug Design
Volume93
Issue number1
DOIs
Publication statusPublished - 01-01-2019

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Antitubercular Agents
Phenyl Ethers
Tuberculosis
Derivatives
Vero Cells
Isoniazid
Hep G2 Cells
Mycobacterium tuberculosis
Pharmaceutical Preparations
Liver
Assays
High Pressure Liquid Chromatography
Safety
Acids
In Vitro Techniques
phenyl ether

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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title = "Design, synthesis, and evaluation of novel diphenyl ether derivatives against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis",
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.",
author = "Kar, {Sidhartha S.} and Bhat, {Varadaraj G.} and Shenoy, {Vishnu P.} and Indira Bairy and Shenoy, {G. Gautham}",
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AU - Bhat, Varadaraj G.

AU - Shenoy, Vishnu P.

AU - Bairy, Indira

AU - Shenoy, G. Gautham

PY - 2019/1/1

Y1 - 2019/1/1

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AB - 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.

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