Synthesis, determination of the lipophilicity, anticancer and antimicrobial properties of some fused 1,2,4-triazole derivatives

Abstract

3-Unsubstituted and 3-substituted-7-aryl-5 H-6,7-dihydroimidazo[2,1- c][1,2,4]triazoles ( 1– 14) were designed and obtained from biologically active 1-aryl-2-hydrazonoimidazolidines by cyclocondensation reaction with triethyl orthoformates ( 1– 4), phenoxyacetic acid derivatives ( 5– 13) and carbon disulfide ( 14), respectively. Their chemical structures were confirmed by IR, 1H NMR, 13C NMR, MS spectra and elemental analysis. In the high performance liquid chromatographic series of experiments, fourteen synthesized compounds ( 1– 14) were chromatographed on octadecyl silica adsorbent and their lipophilicity parameter (log k W) was determined using various aqueous systems: mixture of water and organic modifiers (methanol – MeOH, acetonitrile – MeCN or dioxane – DX). Compounds 7 and 12 were evaluated for their cytotoxic activity against three cancer cell lines: human Caucasian colon adenocarcinoma cell line – LS180 (ECACC 87021202), human uterus carcinoma cell line – SiHa (ECACC 85060701) and human breast carcinoma cell line – T47D (ECACC 85102201). Compound 12 was found to be the most effective in vitro against human colon adenocarcinoma cell line (LS180). Moreover, the distinctly marked lower cytotoxicity of compounds 7 and 12 against the normal cell line – human skin fibroblasts (HSF) and almost several-fold higher against the examined cancer cell lines was ascertained. The cytotoxic effect of imidazotriazole 7 was noticed on DNA structure of breast cancer cell line (T47D) by using the comet assay. Compound 7 in concentration of 29.3 μM was found to possess efficiency for DNA strand breakage. In particular, this led to cutting of the DNA strands and formation of small fragments of DNA – two higher and one lighter in comparison with control DNA. Moreover, significant viability decreases in the human leukaemic RPMI 8226 cells treated with different concentrations of imidazotriazoles 8– 12 were observed, suggesting their antiproliferative properties. Besides, three tested compounds ( 9, 13, 14) revealed significant antimicrobial activities with MIC values in the range of 30.9–44.0 μM. Compound 13 showed superior antibacterial activity to ampicillin and chloramphenicol in vitro, whereas 14 displayed superior antifungal activity to miconazole.