Two-Stage Synthesis and Antibacterial Profiling of Novel Symmetric and Unsymmetrical 1,2-Dialkylpyrazolium Salts

Abstract

An efficient two-stage synthetic approach to a novel series of symmetric and unsymmetrical 1,2-dialkylpyrazolium salts was developed via sequential N-alkylation and quaternization of pyrazoles. The quaternization step was found to be critically governed by both electronic and steric effects of substituents at positions 3 and 5 of the pyrazole core. Electron-donating methyl groups facilitate the reaction by enhancing the nucleophilicity of the N-2 pyridine-type nitrogen atom, whereas bulky phenyl rings and strongly electron-withdrawing trifluoromethyl groups arrest quaternization at the mono-alkylation stage. 1H and 13C NMR spectroscopy confirmed the electronic isolation of the pyrazole core from the acyl moiety via the aliphatic -CH2- linker and demonstrated that C-4 shielding is governed exclusively by the 3,5-substituents. In vitro biological evaluation revealed a narrow antibacterial spectrum with no activity against Candida albicans. The highest susceptibility was observed for Gram-positive Bacillus subtilis ATCC 6633. Compound 1,2-bis(2-(4-bromophenyl)-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-ium bromide exhibited potent antibacterial activity against B. subtilis (inhibition zone 20±1.5 mm), comparable to the reference drug Gentamicin, with a minimum inhibitory concentration (MIC) of 0.12 mg/mL, highlighting it as a promising lead for novel antibacterial agents.

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