Exploration of Remarkably Potential Multitarget-Directed N-Alkylated-2-(substituted phenyl)-1 H-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)-1H-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 2g 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 Streptococcus faecalis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus compared with amikacin. The antifungal data of compounds 1b, 1c, 2e, and 2g revealed their moderate activities toward Candida albicans and Aspergillus niger, with MIC values of 64 μg mL^-1 for both strains. Finally, the molecular docking study found that 2g interacted with crucial amino acids in the binding site of complex dihydrofolate reductase with nicotinamide adenine dinucleotide phosphate.

Figure 1

Benzimidazole-based clinically approved anticancer drugs.

Figure 2

Benzimidazole derivatives (6–9) as antimicrobial agents.

Scheme 1. Synthesis of 2-(Substituted phenyl)-1H-benzimidazole (1–33)

Scheme 2. Synthesis of N-Alkylated-2-(substituted phenyl)-1H-benzimidazole (1a–g, 2a–g, and 3a–g)

(i) Dimethyl carbonate, reflux in 140 °C. (ii) Ethyl bromide in an ice bath. (iii) C3-C7 bromide, room temperature.

Figure 3

Illustration of the antiproliferative mechanism of action of synthesized compounds.

Figure 4

Antifungal mode of action of synthesized compounds.

Figure 5

Minimum inhibitory concentration of compound 2g against four strains of bacteria (E. coli, E; S. faecalis, S; S. aureus, SA; resistant-methicillin Staphylococcus aureus, MRSA).

Figure 6

2D and 3D interaction models of XCF (A and B), 2g (C and D), and amikacin (E and F) with the binding site of the DHFR–NADPH complex. NADPH is shown in green and DHFR in cyan ribbons, the hydrogen bonds are shown as dash lines, and the green curve lines illustrate the hydrophobic interactions.