Exploration of Remarkably Potential Multitarget-Directed N-Alkylated-2-(substituted phenyl)-1<i>H</i>-benzimidazole Derivatives as Antiproliferative, Antifungal, and Antibacterial Agents

Abstract

Improving lipophilicity for drugs to penetrate the lipid membrane and decreasing bacterial and fungal coinfections for patients with cancer pose challenges in the drug development process. Here, a series of new N-alkylated-2-(substituted phenyl)-1<i>H</i>-benzimidazole derivatives were synthesized and characterized by ¹H and ¹³C NMR, FTIR, and HRMS spectrum analyses to address these difficulties. All the compounds were evaluated for their antiproliferative, antibacterial, and antifungal activities. Results indicated that compound <b>2g</b> exhibited the best antiproliferative activity against the MDA-MB-231 cell line and also displayed significant inhibition at minimal inhibitory concentration (MIC) values of 8, 4, and 4 μg mL^-1 against <i>Streptococcus faecalis</i>, <i>Staphylococcus aureus</i>, and methicillin-resistant <i>Staphylococcus aureus</i> compared with amikacin. The antifungal data of compounds <b>1b</b>, <b>1c</b>, <b>2e</b>, and <b>2g</b> revealed their moderate activities toward <i>Candida albicans</i> and <i>Aspergillus niger</i>, with MIC values of 64 μg mL^-1 for both strains. Finally, the molecular docking study found that <b>2g</b> interacted with crucial amino acids in the binding site of complex dihydrofolate reductase with nicotinamide adenine dinucleotide phosphate.