Novel Benzimidazole-Pyridine-Phenylalkanesulfonate Hybrids: Design, Synthesis, Antimicrobial Screening, Lanosterol 14α-Demethylase Inhibition Properties and in Silico Studies

Abstract

A newly designed benzimidazole-pyridine-pheylalkanesulfonate hybrids (3a-r) were synthesized through the regioselective Michael addition reaction between 2-acetyl-1-substituted-benzimidazole (1) and dicyano vinyl alkanesulfonate (2) to evaluate their activity against diverse microbial pathogens including Candida albicans (a unicellular fungus), Bacillus subtilis and Staphylococcus aureus (Gram-positive bacteria), as well as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Salmonella typhimurium (Gram-negative bacteria). Although most of the tested hybrids showed promising antimicrobial potentiality, the MIC was calculated for the two precursors 1a,b in addition to derivatives 3b, 3 g, 3k, 3 m and 3p that found to prevent the proliferation of all microbial pathogens with different ratios in comparison to the reference drug used. Compound 3k demonstrated the best anti-candida properties with MIC = 5 μg/mL (amphotericin B, MIC = 20 μg/mL), and it was of equal efficacy to ciprofloxacin against Staphylococcus aureus with MIC = 20 μg/mL. Derivatives 3b and 3 m displayed equipotent activity to ciprofloxacin with MICs = 10 μg/mL against S. typhimurium and B. subtilis, respectively. Moreover, derivative 3 m exhibited 42.1% biofilm inhibition against P. aeruginosa (compared with 39.8% for Ciprofloxacin). An acceptable safety profile of the most potent derivatives was detected. The impact of the 3b and 3k hybrids on the tested microbial pathogens was visualized using CLSM. Furthermore, 3k inhibited the Lanosterol 14α-demethylase (CYP51) with IC₅₀ = 4.2 μM (fluconazole IC₅₀ = 0.6 μM). Furthermore, in silico studies including ADME prediction for the five promising hits and molecular docking simulation of 3k in the demethylase binding site were performed.