Design, synthesis, and in-silico studies of pyrazolylpyridine analogues: A futuristic antibacterial contender against coagulase positive superbug-MRSA

Abstract

In the coagulation cascade during host infection by MRSA, staphylococci are blocked within a fibrin clot mesh, and very hard to clear these pathogens by host tissues and also enable the pathogen to cause lethal sepsis. To overcome this complication, this work aimed at synthesis of pyrazolylpyridine analogs as potential anti-superbug agents and using a simple synthetic protocol. The synthesized pyrazolylpyridine analogs were characterized using spectroscopic techniques like FTIR, NMR, and mass spectroscopy. All synthesized pyrazolylpyridine analogs were evaluated for the in-vitro antibacterial activity. The antibacterial activity was further confirmed with cellular content leakage and measurement of potassium efflux. The anti-biofilm activity was studied qualitatively and quantitatively with crystal violet dye technique. The compounds binding ability with 1NU7 and 1MWT proteins were tested using molecular docking and further analogs were exposed to dynamic simulations. The synthesized compounds were also inspected for their ADMET analysis. It was observed that 4(a g) series showed a potential antibacterial activity compared to 3(a g) analogs to standard drug vancomycin. The MIC value of 4e was found to 30±0.4 µg/mL and also showed an excellent anti-biofilm activity. The revealed data was strongly correlated with molecular docking studies on staphylocoagulase enzyme (PDB: 1NU7) and Penicillin-binding protein 2a (PBP2a) (PDB: 1MWT) with a good docking score, and glide score with high binding energy. By dynamic simulation it was obtained that 4d exhibit stable interaction with staph-coagulase enzyme up to 20 ns with PBP2a protein, and compound 4e exhibited stable interaction at both active and allosteric site. The potent pyrazolylpyridine was designed and synthesized to treat infectious agent MRSA. Among the analogs synthesized, compound 4e showed antibacterial activity validated by insilico studies. In this study, experimental results show significant anti-coagulase, anti-biofilm and antimicrobial activity against MRSA by synthesised compound 4e. This leads to the compound 4e can serve as a potent drug against MRSA in upcoming days.