Synthesis and antiproliferative activity of 3-aryl-5-{[(1-aryl-1h-tetrazol-5-yl)thio]methyl}-1,2,4-oxadiazoles

Abstract

Derivatives of 5-mercapto- 1H -tetrazole have long attracted the attention of researchers as promising groups for introduction into drug-like molecules within the concept of fragment-oriented drug design. One of the first drugs to contain this fragment was the beta-lactam antibiotic Cefamandole, which has been used for over 40 years to treat various infections caused by susceptible strains of bacteria, including lower respiratory tract infections, urinary tract infections, skin infections, bones and joints. Subsequently, a number of antibiotics containing the 5-mercapto-1H-tetrazole fragment were obtained. Recently, a series of new derivatives of 5-(1,2,3-triazolylmethylsulfanyl)tetrazole was synthesized by the CuAAC reaction, their antimicrobial activity showed moderate or good results compared to standard drugs. Moreover, 2-[(1-(naphthalen-1-yl)- 1H -tetrazol-5-yl)thio]- N -(2-nitrophenyl)acetamide is discovered for HIV treatment as a potent non-nucleoside nanomolar inhibitor of reverse transcriptase activity. A convenient route for the synthesis of such compounds is the preparation of 5-mercapto- 1H -tetrazole from various isothiocyanates by the reaction of 1,3-dipolar cycloaddition with sodium azide, trimethylsilyl azide or their synthetic equivalent, and subsequent alkylation of the thiol group. Given the availability of methods for the synthesis of these compounds and their valuable properties, the study aims to obtain a number of compounds and evaluate their antiproliferative properties. The starting 5-mercapto- 1H -tetrazoles were obtained from commercially available anilines. First, the anilines were converted to the corresponding isothiocyanates by the Kaluza method. The next reaction of isothiocyanates 2 with sodium azide in water synthesized the target 5-mercapto- 1H -tetrazoles 3 with approximately quantitative yield. At the same time, 5-(chloromethyl)-3-aryl-1,2,4-oxadiazoles were obtained by us earlier. The reaction of 5-mercapto- 1H -tetrazoles 3 with 5-(chloromethyl)-3-aryl-1,2,4-oxadiazoles 4 synthesized the target compounds, which were tested for antiproliferative activity. The synthesized compounds 5a-d were submitted and evaluated at a concentration of 10 -5 M on a panel of approximately 60 cancer cell lines. Human tumor cell lines have been derived from nine different types of cancer: leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, kidney, prostate, and breast cancer. Primary anti-cancer assays were performed according to the US NCI protocol (http://dtp.nci.nih.gov). The results for each compound are presented as the percentage of cell growth (GP, %). Unfortunately, the selected representatives of this molecular scaffold did not show high activity. Compound 5d showed the highest activity. In particular, this compound inhibited the growth of 44 % (GP = 66.01 %) of UO-31 kidney cancer cells. It should be noted that compounds 5b and 5c were also active against UO-31 cells, inhibiting their growth by almost 30 % (GP = 73.35 and 72.53 %), respectively. In addition, compound 5d was most active against T-47D breast cancer cells (GP = 75.69 %) and a number of leukemia cell lines (CCRF-CEM, K-562, MOLT-4, RPMI-8226, SR). In general, leukemia cells were the most sensitive to compounds 5 , while ovarian and prostate cancer panels were resistant. By convenient synthetic transformations we obtained representatives of the new molecular framework, which were investigated for antitumor activity. The compounds were found to have low activity, but have some selective effect on UO-31 kidney cancer cells. The obtained results indicate the need for significant modification of the molecular scaffold to discover more active compounds. Keywords: tetrazoles, 1,2,4-oxadiazoles, antiproliferative activity, cancer.