Pharmacophore-based synthesis of pyrazole analogues as artificial antibiotics targeting Salmonella Typhi

Abstract

The pharmacological potential of the pyrazole moiety is demonstrated by their presence in a wide range of therapeutic agents spanning various categories. Notable examples include: Celecoxib: A potent anti-inflammatory drug, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB): An antipsychotic medication, Rimonabant: An anti-obesity drug, Difenamizole: An analgesic, Betazole: An H2-receptor agonist, Fezolamide: An antidepressant agent. These examples underscore the versatility and efficacy of the pyrazole nucleus in the development of pharmacologically active compounds across different therapeutic domains [1–12]. In our study, we computationally designed 23 different derivatives of pyrazole compounds and analysed their Pharmacokinetics (ADMET) properties in the QikProp module on Schrodinger's Maestro platform. Among them, high throughput optimised and promising analogues of 11 pyrazole compounds were synthesised and analysed by NMR and LCMS for structural configuration. The synthesised compounds were initially analysed for cytotoxicity by MTT assay and found to have lower toxicity profiling in 7 pyrazole derivatives. Further, the compounds were investigated for their antibacterial activity against Salmonella Typhi by broth dilution and disk diffusion methods, where four compounds (P4, P14, P19, and P20) exhibit a potential growth inhibitory activity as compared with standard antibiotics which commercially used for S. Typhi infection. Further, to explore the mode of action on the growth suppression of S. Typhi was investigated by performing molecular docking with outer membrane protein (cell wall inhibition) and DNA-dependant RNA polymerase (transcriptional arrest) of S. Typhi, wherein all four tested probes exhibited the binding interaction localised at the active domains of the foresaid target protein. The P14 compound exhibits the maximum score of least binding energy at -8.174 kcal/mol against OMP C, whereas the P4 remains at -5.575 kcal/mol against the DNA-dependent RNA polymerase. This observation is clearly evident in the antagonistic effects of the synthesised derivatives on the growth of S. Typhi.