Antibiotic resistance in bacteria exacerbates the issue of antimicrobial resistance. Bacteria that cause common or serious infections have evolved resistance to every new antibiotic that has been introduced into the market, to varying degrees, over several decades. Faced with this reality, one of society's most urgent needs is for new antimicrobial drugs with novel mechanisms of action. With this objective, we describe here the development of a novel set of compounds including piperazine‐ and thiophene‐based thiazolidinones (5a–i) and thiophene‐thiazolidinones (6a–i). Compounds (5a–i) and (6a–i) were developed, synthesized, and tested for their antimicrobial activity, and their structures were elucidated with the help of various analytical techniques. Compounds 5a and 5d showed excellent antibacterial efficacy against Pseudomonas aeruginosa, with MICs of 50 μg/ml, whereas compounds 6c and 6e showed similar potency against Staphylococcus aureus and Escherichia coli, respectively. The antifungal efficacy of compounds 5e and 6i against Candida albicans was outstanding (MIC = 50 μg/ml). The only compound that had excellent antifungal efficacy against Aspergillus niger was compound 5e (MIC = 50 μg/ml). The chemico‐in silico‐biology approach could provide valuable insights into the potential of this novel hybridized scaffold for the development of promising antimicrobial agents.
Background:
In the past few decades, mankind is suffering from tormented life-threatening infectious diseases caused by multidrug-resistant bacteria. As a result, new antimicrobial classes with distinct modes of action are required to combat multidrug-resistant infections.
Objective:
The pyrazole-based pyrimidine and pyrazolone motifs were synthesized, characterized, and screened for their antimicrobial activity. Molecular docking was carried out for the development of antimicrobial agents based on the results of biological activity obtained.
Methods:
: We have synthesized a new series of pyrazole containing pyrimidine-pyrazolone hybrids by using multi-step reactions in the search of antimicrobial agents (7a-o). The structures were determined by 1H NMR, 13C NMR, IR, and mass spectroscopy techniques. Moreover, synthesized compounds were evaluated for their antimicrobial activity by using serial Broth dilution method.
Results:
Antimicrobial activity of synthesized compounds has been tested against bacterial and fungal strains. Compound 7o was most effective against S. aureus with MIC = 0.096 M/mL. A molecular docking study against microbial DNA gyrase revealed important information about the mechanisms underlying antimicrobial efficacy. Through significant interactions with active site residues, all of the compounds were able to dock well into the enzyme's active site. Furthermore, Compounds 7a (0.531 M/mL), 7b (0.456 M/mL), and 7m (0.485 M/mL) showed excellent antifungal activity against C. albicans compared to the positive control griseofulvin.
Conclusion:
It has been concluded that compounds containing electron-donating groups are found to be most active against bacterial strains while compounds having both electron-donating as well as electron-withdrawing groups are most favorable for antifungal activity.
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