Design, synthesis and structural studies of meta-xylyl linked bis-benzimidazolium salts: potential anticancer agents against ‘human colon cancer’

Abstract

BackgroundBenzimidazole derivatives are structurally bioisosteres of naturally occurring nucleotides, which makes them compatible with biopolymers of living systems. This property gives benzimidazole a biological and clinical importance. In the last decade, this class of compounds has been reported to possess anti-allergic, anti-diabatic, anti-HIV, anti-hypertensive, anti-inflammatory, anti-mycobacterial, anti-oxidant, anti-protozoal, and anti-viral properties. The researchers are now interested to explore their potential as anti-cancer agents. In the present study, an effort was made to further explore this area of research. Furthermore, in order to increase the solubility and efficacy of these heterocycles, the interest is now shifted to the salts of these compounds. With this background, we planned to synthesize a series of meta-xylyl linked bis-benzimidazolium salts to assess their anti-proliferation efficacy on human colon cancer cell line (HCT 116).ResultsA number of N-alkylbenzimidazoles were synthesized by reactions of benzimidazole with alkyl halides (i-PrBr, PrBr, EthBr, Pent-2-ylBr, BuBr, BenzCl, HeptBr). The subsequent treatment of the resulting N-alkylbenzimidazoles with 1,3-(bromomethylene)benzene afforded corresponding bis-benzimidazolium salts. All synthesized compounds were characterized by spectroscopic techniques (Additional file 1: NMR & FT-IR) and microanalysis. Molecular structures of selected compounds were established through single crystal x-ray diffraction studies. All the compounds were assessed for their anti-proliferation test on human colorectal cancer cell line (HCT 116). Results showed that the compounds exhibited dose dependent cytotoxicity towards the colon cancer cells with IC50 ranges between 0.1 to 17.6 μM. The anti-proliferation activity of all compounds was more pronounced than that of standard reference drug 5-flourouracil (IC50 =19.2 μM).ConclusionsAll the synthesized bis-benzimidazolium salts showed potential anticancer activity. Out of them, some of these salts showed IC50 value as low as 0.1–0.2 μM. Based on the results it can be concluded that, the bis-benzimidazolium salts could probably be the potential source of chemotherapeutic drugs.

Potential of silver against human colon cancer: (synthesis, characterization and crystal structures of xylyl (Ortho, meta, & Para) linked bis-benzimidazolium salts and Ag(I)-NHC complexes: In vitroanticancer studies)

“…All the bis-benzimidazolium salts with bromide as counteranions ( 5-7 ) were found to be relatively active (IC 50 = 85, 0.2, & 157.52 μM for 5 , 6 , & 7 respectively) compare to the same benzimidazolium salts with hexaflourophosphate as counteranions (IC 50 = > 200 μM for compounds 8-10 ). This is in accordance with our previous reports [25-28] where we mentioned that halide salts of compounds with these structures are relatively active compare to the compounds with hexaflourophosphate as counter anions. The counteranions of these salts are usually exchanged from halide to PF 6 for the ease of handling and in some cases to achieve the purity because these compounds as PF 6 salts appear as white powder whereas in halide form these salts are mostly thick oily fluids before recystalization.…”

“…Possibly this is the reason that the bonding of silver cations to biologically compatible ligands enhances the bioavailability and ultimately the activity of silver cations. This is very obvious with our current and previously reported results [25,26,30,47], where ligands were found to be relatively less active compare to respective silver complexes. The photomicrograph of the cells treated with the silver complexes revealed the morphological features of apoptosis consist of membrane blebbing, nuclear condensation and formation of apoptotic bodies (Figure 10).…”

“…Unlike our previous reports [26-28,31], all the ligands were found inactive but respective silver complexes showed cytotoxicity in a dose dependent manner. All of our previous and current results indicate that silver metal ions practice a role in the death of cancer cells.…”

“…Interestingly, only bis-benzimidazolium salts, the precursors to form Ag-NHC, showed potential anticancer activity [25]. However, later on we reported that silver in bonding with these bis-benzimidazolium salts through Ag-NHC route, enhances the anticancer potential [26-29].…”

Synthesis and cytotoxicity studies of 1-propenyl-1,3-dihydro-benzimidazol-2-one

“…The biological importance of benzimidazole derivatives is due to their structural resemblance to the naturally occurring nucleotides. This has allowed them to interact with the biopolymers of the living system [16]. Substituted benzimidazole derivatives have lots of therapeutic applications in the areas including antimicrobial [17], antioxidant [18], antiviral [19], antihypertensive [20], antiprotozoal [21], anti-inflammatory [22], and molluscicidal [23] agents.…”