Synthesis and biological evaluation of benzimidazole-linked 1,2,3-triazole congeners as agents

Background Benzimidazoles and triazoles are useful structures for research and development of new pharmaceutical molecules and have received much attention in the last decade because of their highly potent medicinal activities. Findings A simple and efficient synthesis of triazole was carried out by treatment of 2-(4-azidophenyl)-1H-benzo[d]imidazole (6) with different types of terminal alkynes in t-BuOH/H2O, sodium ascorbate, and Zn(OTf)2, screened for cytotoxicity assay and achieved good results. A series of new benzimidazole-linked 1,2,3-triazole (8a-i) congeners were synthesized through cyclization of terminal alkynes and azide. These synthesized congeners 8a-i were evaluated for their cytotoxicity against five human cancer cell lines. These benzimidazole-linked 1,2,3-triazole derivatives have shown promising activity with IC50 values ranging from 0.1 to 43 μM. Among them, the compounds (8a, 8b, 8c, and 8e) showed comparable cytotoxicity with adriamycin control drug. Conclusions In conclusion, we have developed a simple, convenient, and an efficient convergent approach for the synthesis of benzimidazole-linked 1,2,3-triazole congeners as agents. Graphical Abstract Synthesis of 1,2,3-triazole derivatives Electronic supplementary material The online version of this article (doi:10.1186/s13588-014-0014-x) contains supplementary material, which is available to authorized users.


Findings
Cancer is one of the terrible diseases which cause uncontrolled growth of group of cells. It remains a mean threat to human beings and cause death [1,2]. Recently, many researchers developed safe and effective ways of treating this disease and to search for novel chemotherapeutic agents. The benzimidazole nucleus is an important pharmacophore in medicinal chemistry. The synthesis of novel benzimidazole derivatives remains a main focus of modern drug discovery. The versatility of new generation benzimidazole would represent a fruitful pharmacophore for further development of better medicinal agents. Many researchers have been attracted to benzimidazole derivatives because of their wide range of biological activity. Over the past years, there is a considerable interest in the development and pharmacology of benzimidazole. They are of wide interest because of their diverse biological activity and clinical applications [3].
In addition, triazoles also display wide spectrum of biological activities and are widely employed as pharmaceuticals and agrochemicals. Triazoles are reported to possess antibacterial, antifungal, and antihelminthic activities [16][17][18][19][20][21]. They have been regarded as an interesting unit in terms of biological activity [22,23], and some of them have also shown significant anticancer activity in many of the human cell lines [24].
In view of the biological importance of benzimidazole and 1,2,3-triazoles, to know the combined effect of both benzimidazole and 1,2,3-triazole moieties, it was considered worthwhile to synthesize certain new chemical entities having benzimidazole and 1,2,3-triazole pharmacophores in a single molecular framework, and here we have used Zn (OTf) 2 catalyst instead of CuSO 4 . All of these congeners have been evaluated for their anticancer activity against a panel of five human cancer cell lines ( Figure 1).

Experimental section
All chemicals and reagents were obtained from Aldrich (Sigma-Aldrich, St. Louis, MO, USA) and Lancaster (Alfa Aesar, Johnson Matthey Company, Ward Hill, MA, USA) and were used without further purification. Reactions were monitored by TLC and performed on silica gel glass plates containing 60 F-254, and visualization on TLC was achieved by UV light or iodine indicator. 1
The product was either worked up by filtration, followed by rinsing with aqueous 5% NH 3 (×3) and cold ether (×2), or by extraction with dichloromethane (4 × 100 mL). The combined organic layers were washed with aqueous 5% NH 3 (3 × 100 mL) and brine (100 mL) and dried over anhydrous MgSO 4 . The solvent was removed in vacuo, and the crude product was purified by column chromatography with ethyl acetate/hexane ( The other derivatives are also prepared according to the same procedure and described in Additional file 1.

Biological evaluation In vitro cytotoxicity assay
The synthesized compounds 8a-i were evaluated for their anticancer activity in selected human cancer cell lines of A375, B-16, colon-205, MCF-7, and A-549 by using MTT assay. All the compounds (8a-i) exhibited significant anticancer activity with IC 50 values ranging from 0.1 to 43 μM, while the positive control, adriamycin, demonstrated the IC 50 in the range of 0.03 to 3.5 μM respectively, in the cell lines employed as shown in Table 1.

Procedure for MTT assay
Toxicity of test compound in cells was determined by MTT assay based on mitochondrial reduction of yellow MTT tetrazolium dye to a highly colored blue formazan product. Cells (1 × 10 4 ) (counted by Trypan blue exclusion dye method) in 96-well plates were incubated with compounds with series of concentrations tested for 48 h at 37°C in RPMI/DMEM/MEM with 10% FBS medium. Then, the above media was replaced with 90 μl of fresh serum free media and 10 μl of MTT reagent (5 mg/ml),

Additional file
Additional file 1: Experimental procedure and characterization data of all new compounds.