Exploration of Remarkably Potential Multitarget-Directed N-Alkylated-2-(substituted phenyl)-1H-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 1 H and 13 C 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.

Synthesis, Antimicrobial and Antibiofilm Activities, and Molecular Docking Investigations of 2-(1H-Indol-3-yl)-1H-benzo[d]imidazole Derivatives

“…Most of the compounds that have shown antibacterial activity against E. coli are the 5-substituted benzimidazoles 3q, 3r, 3v, and 3w. The low activity of benzimidazoles against Gram-negative bacteria was also observed in other studies [26,30]. This is probably due to the structure of the cell wall of this group of bacteria, which contains an outer membrane.…”

“…In continuation of our previous work on the development of an effective strategy for the synthesis of antibacterial compounds [25], we have become interested in finding the chemoselective pathway of 2-(1H-indol-3-yl)-1H-benzo[d]imidazole derivatives [26]. We have previously shown that the condensation of anthranilamides with aldehydes on heating in N,N-dimethylacetamide (DMAC) in the presence of sodium metabisulfite leads to the formation of antibacterial 2-(1H-indol-3-yl)quinazolin-4(3H)-ones and their analogs.…”

“…It is even more interesting that the synthesized library contains some substances 3j, 3y, and 3al with selective activity against staphylococci, which do not have an inhibitory effect against fungi, Gram-negative bacteria, or mycobacteria. Previously, the antistaphylococcal activity of benzimidazoles was registered in some studies; however, MIC values were 10s and 100s of µg/mL [26,30,37]. There are data on the activity of these compounds with MICs of 4 µg/mL [38], 3.12 µg/mL [39], and 6 µg/mL [40].…”

Isolation and Identification of Chemical Compounds from Agaricus blazei Murrill and Their In Vitro Antifungal Activities

“…Fungi stand out as exceptional creators of a broad spectrum of natural products, contributing to biodiversity and offering a treasure trove of compounds imbued with a wide range of biological functions [1,2]. Notably, mushrooms, a type of fungi [3], assume a pivotal role in traditional agriculture, cuisine, and medicinal practices [4][5][6].…”

A One-Pot Cascade Strategy toward Organocatalytic Enantioselective Construction of Fused Benzimidazoles

“…Benzimidazole is a privileged structural motif frequently found in marketed drug molecules, such as Omeprazole, Albendazole, Liarozole, Telmisartan, and Mibefradil . This heterocyclic pharmacophore exhibits diverse biological properties, including anti-inflammatory, anticancer, antimicrobial, antiviral, antifungal, and so on . Particularly, tricyclic and 1,2-disubstituted chiral benzimidazole derivatives demonstrate a broad spectrum of pharmaceutical, biological activities (Figure A) .…”