Design, Synthesis, and Molecular Docking of Novel Fluorine-Containing 1,2,3-Triazole-tethered Pyrazole-Chalcone Derivatives as Antimicrobial Agents

Abstract

Objective: A new series of fluorine-containing 1,2,3-triazole-pyrazole-chalcone derivatives (VIIIa–VIIIl) was synthesized via Claisen–Schmidt condensation of 1,4-disubstituted 1,2,3-triazole-tethered acetophenone derivatives with 1,3-diphenyl-1H-pyrazole-4-carbaldehyde derivatives in the presence of the base lithium hydroxide. Methods: All newly synthesized compounds were characterized by ¹H, ¹³C NMR, and HR-MS spectral techniques. Antibacterial activity was evaluated in vitro against Gram-positive Streptococcus pyogenes and Staphylococcus aureus, and Gram-negative Pseudomonas aeruginosa and Escherichia coli strains. Antifungal activity was screened against the fungal pathogens Aspergillus niger and Candida albicans, with MIC values determined for the novel compounds. Results and Discussion: Compounds (VIIIe), (VIIIf), and (VIIIg) exhibited good antibacterial activity against all tested bacterial strains. The majority of the compounds showed excellent antifungal activity. Among them, compounds (VIIIb) and (VIIId) showed twofold better antifungal activity (MIC of 250 µg/mL) than the reference drug griseofulvin, while compounds (VIIIa), (VIIIc), (VIIIg), and (VIIIl) exhibited antifungal activity comparable to that of griseofulvin (MIC of 500 µg/mL) against C. albicans strains. Molecular docking studies revealed that the newly synthesized compounds exhibited favorable binding affinities. The results from molecular docking correlate well with the experimental antifungal activity. Compounds (VIIIb) and (VIIId) showed the best binding affinity scores. Conclusions: These superior results are attributed to the development of hybrid molecules containing 1,4-disubstituted 1,2,3-triazole, pyrazole, and chalcone scaffolds, along with fluorine substitution(s), and the combined inductive and resonance effects of the substituents. These findings from the MIC activity data provide new insights for the design of lead molecules against microbial infections.