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

3-Unsubstituted and 3-substituted-7-aryl-5H-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, H-1 NMR, 13 C 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, acetorritrile - 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 (LS 180). 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 mu M 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 mu M. Compound 13 showed superior antibacterial activity to ampicillin and chloramphenicol in vitro, whereas 14 displayed superior antifungal activity to miconazole. (c) 2007 Elsevier Masson SAS. All rights reserved.