Synthesis and computational studies of new pyridine, pyrazole, pyran, and pyranopyrimidine-based derivatives of potential antimicrobial activity as DNA gyrase and topoisomerase IV inhibitors

• Published in: Journal of molecular structure Vol. 1319; p. 139528
• Main Authors: Alsfouk, Aisha A., Othman, Ismail M.M., Anwar, Manal M., Alshareef, Walaa A., Saleh, Asmaa, Nossier, Eman S.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05.01.2025
• Subjects: Antimicrobial; Cytotoxic activity; DNA gyrase B; Enaminone; Molecular docking; Topoisomerase IV; Antimicrobial; Topoisomerase IV; DNA gyrase B; Molecular docking; Enaminone; Cytotoxic activity
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.139528

•Design and synthesis of pyridine, pyrazole, pyran, and pyranopyrimidine derivatives 5–14.•All compounds were evaluated as in vitro antimicrobial agents.•5, 7a, and 7b exhibited the most promising activities.•Compound 5 showed promising dual suppression activity against both E. coli DNA gyrase and topoisomerase IV enzymes.•Compound 5 showed significant interactions with the active sites of both E. coli DNA gyrase and topoisomerase IV enzymes. In this study, new derivatives based on pyridine, pyrazole, pyran, and pyranopyrimidine scaffolds 5–14 were designed and synthesized. The newly synthesized compounds were characterized using microanalytical and spectral data. Using amoxicillin and amphotericin B, two common antibacterial and antifungal medications, respectively, the antimicrobial activity of the new compounds was assessed against a variety of strains of both Gram-positive and Gram-negative bacteria as well as fungal infections. The most promising activity was achieved by pyridine-based derivatives 5, 7a, and 7b, which exhibited MIC values ranging from 0.95 to 18.04 µM against the examined bacterial strains and ranging from 4.65 to 33.16 µM against the examined fungal strains. The later derivatives were also evaluated as E. coli DNA gyrase B/topoisomerase IV inhibitors in comparison with novobiocin as a standard drug. Although the assessed candidates 5, 7a, and 7b exhibited a promising suppression impact against E. coli DNA gyrase B (IC50 = 3.11 ± 0.14, 3.85 ± 0.20, and 4.05 ± 0.10, respectively, IC50 novobiocin= 3.64 ± 0.10 µM), they showed detectable less suppression impact against Topoisomerase IV than that of the reference drug with IC50 values of 19.72 ± 1.00, 79.33 ± 0.25, 85.14 ± 0.10, and 13.42 ± 0.05 µM, respectively. Additionally, the safety profiles of 5, 7a, and 7b against WI38 cells were significantly superior to that of novobiocin (IC50 = 138 ± 0.33, 170 ± 0.40, 163.3 ± 0.17, and 86.2 ± 0.03 µM, respectively). Lastly, molecular docking was used to examine the most active derivatives 5, 7a, and 7b's binding capacity to the target DNA gyrase B/topoisomerase IV. The molecules exhibited various H-interactions with the amino acid residues Asp73, Arg76, and Val71 in E. coli DNA gyrase, where compound 5 exhibited H-bonding with the Asp1069 side chain of E. coli Topoisomerase IV. Additional in silico ADMET studies were conducted to represent their oral bioavailability and drug-likeness characteristics. [Display omitted]