Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents
Autor: | K. E. Vandana, Kriti Arora, Helena I. Boshoff, Gautham G. Shenoy, G. Varadaraj Bhat, Balasubramanian Sridhar, Ashutosh Prasad Tiwari |
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Rok vydání: | 2019 |
Předmět: |
In silico
Antitubercular Agents Microbial Sensitivity Tests Reductase 010402 general chemistry Crystallography X-Ray 01 natural sciences Catalysis Cell Line Inorganic Chemistry Mycobacterium tuberculosis chemistry.chemical_compound Structure-Activity Relationship Bacterial Proteins Cell Line Tumor Drug Discovery Humans Tuberculosis Computer Simulation Physical and Theoretical Chemistry Molecular Biology ADME Mycobacterium bovis biology 010405 organic chemistry Chemistry INHA Phenyl Ethers Organic Chemistry Diphenyl ether Biological activity General Medicine biology.organism_classification 0104 chemical sciences Molecular Docking Simulation HEK293 Cells Biochemistry Drug Design PC-3 Cells MCF-7 Cells Information Systems HeLa Cells |
Zdroj: | Molecular diversity. 24(4) |
ISSN: | 1573-501X |
Popis: | 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. |
Databáze: | OpenAIRE |
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