Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents

Ashutosh Prasad Tiwari, B. Sridhar, Helena I. Boshoff, Kriti Arora, G. Gautham Shenoy, K. E. Vandana, G. Varadaraj Bhat

Research output: Contribution to journalArticle

Abstract

Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4–7 µM) and Mycobacterium bovis (% inhibition at 10 µM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development. Graphic abstract: [Figure not available: see fulltext.].

Original languageEnglish
JournalMolecular Diversity
DOIs
Publication statusAccepted/In press - 01-01-2019

Fingerprint

Acyl Carrier Protein
Antitubercular Agents
tuberculosis
Molecular modeling
Mycobacterium tuberculosis
Computer Simulation
Ethers
ethers
Oxidoreductases
Cells
Derivatives
proteins
evaluation
drugs
synthesis
Cytotoxicity
Bioactivity
Fatty acids
Pharmaceutical Preparations
Fatty Acids

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Information Systems
  • Molecular Biology
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

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title = "Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents",
abstract = "Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4–7 µM) and Mycobacterium bovis ({\%} inhibition at 10 µM = 95.91{\%}). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development. Graphic abstract: [Figure not available: see fulltext.].",
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Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents. / Tiwari, Ashutosh Prasad; Sridhar, B.; Boshoff, Helena I.; Arora, Kriti; Gautham Shenoy, G.; Vandana, K. E.; Varadaraj Bhat, G.

In: Molecular Diversity, 01.01.2019.

Research output: Contribution to journalArticle

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T1 - Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents

AU - Tiwari, Ashutosh Prasad

AU - Sridhar, B.

AU - Boshoff, Helena I.

AU - Arora, Kriti

AU - Gautham Shenoy, G.

AU - Vandana, K. E.

AU - Varadaraj Bhat, G.

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AB - Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4–7 µM) and Mycobacterium bovis (% inhibition at 10 µM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development. Graphic abstract: [Figure not available: see fulltext.].

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