Synthesis, antitubercular evaluation, molecular docking and molecular dynamics studies of 4,6-disubstituted-2-oxo-dihydropyridine-3-carbonitriles

• Published in: Journal of molecular structure 2019-12, Vol.1197, p.117-133
• Main Authors: Verma, Ruchi, Boshoff, Helena I.M., Arora, Kriti, Bairy, Indira, Tiwari, Mradul, Bhat, Varadaraj G., Shenoy, Gautham G.
• Format: Article
• Language: English
• Subjects: 2-Oxo-dihydropyridine; Anti-tubercular; Antibacterial; Diphenyl ether; InhA; Molecular dynamics
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2019.07.035

A new series of novel diphenyl ether based 2-oxo-dihydropyridine derivatives were synthesized and screened for their in vitro antimycobacterial and antibacterial activities. Most of the synthesized compounds showed significant activity against Mycobacterium tuberculosis H37Rv strain in comparison to triclosan. Among them, compounds 3k and 3q were found to be most active against Mycobacterium tuberculosis H37Rv strain with MIC of 31 and 32 μM respectively. All the compounds were found to be more active against Bacillus subtilis and Staphylococcus aureus than against Pseudomonas aeruginosa and Escherichia coli. Several compounds were found to safe against Vero and HepG2 cell lines. Molecular docking study was utilized to explore the binding mode of the synthesized compounds to the target enzyme InhA. The results showed reasonable binding interactions of synthesized molecules and good dock score. Molecular dynamics studies were performed in order to support the docking results. The compound 3k-InhA complex was found to be more stable and exhibited more interaction when compared to Triclosan. The compounds followed Lipinski rule of five and displayed acceptable pharmacokinetic properties depicted via in silico studies. [Display omitted] •4, 6-disubstituted-2-oxo-dihydropyridine-3-carbonitriles derivatives were synthesized and characterized.•Synthesized compounds were evaluated for their in vitro antimycobacterial potentials.•Compound 3k (MIC 31 μM) and 3q (32 μM) displayed significant antimycobacterial activity.•Molecular docking, molecular dynamics study, in silico ADME (absorption, distribution, metabolism and excretion) and drug likeness prediction.