Structure-based design, synthesis and biological evaluation of a newer series of pyrazolo[1,5-a]pyrimidine analogues as potential anti-tubercular agents

• Published in: Bioorganic chemistry 2019-06, Vol.87, p.240-251
• Main Authors: Modi, Palmi, Patel, Shivani, Chhabria, Mahesh
• Format: Article
• Language: English
• Subjects: Molecular docking; Molecular dynamics; Mycobacterium tuberculosis; Pyrazolo[1,5-a]pyrimidine hybrids
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.02.044

[Display omitted] •Based on molecular docking study a series of pyrazolo[1,5-a]pyrimidine analogues were synthesized and screened for its anti-tubercular potential.•Based on the preliminary screening Structure Activity Relationship (SAR) was generated.•Compound 6g, 6h, 6n and 6p were found to be the most potent further opted for MDR-TB, XDR-TB and cytotoxicity study. In-depth study of structure-based drug designing can provide vital leads for the development of novel, clinically active molecules. In this present study, twenty six novel pyrazolo[1,5-a]pyrimidine analogues (6a-6z) were designed using molecular docking studies. The designed molecules were synthesized in good yields. Structural elucidation of the synthesized molecules was carried out using IR, MS, 1H NMR and 13C NMR spectroscopy. All the synthesized compounds were evaluated for their in-vitro anti-tubercular activity against H37Rv strain by Alamar Blue assay method. Most of the synthesized compounds displayed potent anti-tubercular activities. Amongst all the tested compounds 6p, 6g, 6n and 6h exhibited promising anti-tubercular activity. Further, these potent compounds were gauged for MDR-TB, XDR-TB and cytotoxic study. None of these compounds exhibited potent cytotoxicity. Stability of protein ligand complex was further evaluated by molecular dynamics simulation for 10 ns. All these results indicate that the synthesized compounds could be potential leads for further development of new potent anti-tubercular agents.