Synthesis and potent antimicrobial activities of 1 3 Dialkyl 2 arybenzimidazolium salts

Abstract

Background: Benzimidazolium salts include biologically active benzimidazole ring and are the structural analogue of ionic liquids(ILs) [1]. Some benzimidazolium salts and their metal complexes containing alkyl, aryl or silyl groups showed remarkable antibacterial, antifungal [2-4] and anticancer [5] effects. Since a variety of 2-unsubstituted imidazolium or benzimidazolium derivatives have been synthesized as carbene precursors and used for catalytic and microbiological purposes [3,4], there is not any study related to the 2-arylsubstituted benzimidazolium derivatives. In our previous works, we have reported the synthesis of 2-arylbenzimidazoles by various methods [6-8]. In order to enhance the efficacy of them in the biological systems, it is very important to overcome the insolubility problem in water. For this reason, we have focused on the 1,3-dialkyl halide salts of 2-arylbenzimidazoles in the present work. Methods: 1-Methyl-2-arylbenzimidazole derivatives were synthesized by using the previously reported method [6]. Novel 1,3-dialkyl-2-arylbenzimidazolium salts were synthesized via the N-alkylation of 1-methyl-2-arylbenzimidazole derivatives with various alkyl halides in CEM-Mars6 multimode microwave system (120 W) by using small amounts of DMF. Reactions were monitored by TLC. Structures of the products were confirmed by using 300 MHz 1H-13C NMR and FT-IR spectroscopic techniques. Antimicrobial activities of all synthesized compounds have been measured from DMSO solutions using microbroth tube dilution (NCCSL standards) and disc diffusion methods. MICs for each synthesized substances were investigated against S. aureus (ATCC 6535), B. subtilis (IMG 22), E. coli (W3110) P. vulgaris ( NRRLB 2643) and Candida albicans (clinical isolate). Results: We have already reported the microwave assisted synthesis of 1-methyl-2-arylbenzimidazole derivatives 1-7 before [6]. In the recent study N-alkylation of them with alkylhalides under microwave conditions afforded us 1,3-dialkyl-2-arylbenzimidazolium salts 8-28 which are the structural analogues of 1,3-dialkylimidazolium ionic liquids 29 (Figure 1). The yields in the range of 4-71 % under classical heating increased to the range of 64-96 % under microwave conditions. Considering the reactions repeated by classical heating, the reaction times were decreased 3-6 hours to 5-35 minutes by microwaves. MIC values of newly synthesized benzimidazolium salts 8-28 (1.95->1500 μg/ml) are remarkably smaller than starting benzimidazoles 1-7 (62.5->1500 μg/ml) on studied microorganisms. While they have little effect on gram-negative bacteria, they have remarkable effects on gram-positive and eukaryotic microorganisms. Especially 16, 18, 24, 25 and 27 were found to be the most effective compounds inhibiting the growth of both gram (+) bacteria and eukoryote. Conclusions: It is the first report that describes the microwave assisted synthesis and antimicrobial activity of 2-arylsubstituted benzimidazolium salts. The microwave method is advantageous regarding the usage of mild conditions and small amounts of solvent, easy purification and achieving high yields in short times. This study demonstrates that newly synthesized benzimidazolium salts (especially compounds 16, 18, 24, 25 and 27) have remarkable effects on microorganisms, especially in gram (+) bacteria and eukaryotes compared to benzimidazoles. Also, compounds 11 and 12 has considerable antifungal properties. Thus, the synthesized substances in this study may help in the treatment of fungal and bacterial diseases in developing pharmaceuticals.