Synthesis and Antitumor Activity of Novel Heterocyclic Systems with Monoterpenic Skeleton Combining Dichlorocyclopropane and 1,3,4-Thiadiazole Nucleus

A series of C(2)-N(4)-disubstituted 1,3,4-thiadiazoles bearing dichlorocyclopropane, have been prepared from (R)-carvone1in a three-step procedure. First, (R)-carvone was treated with dichlorocarbene, generated in-situ from chloroform using PTC technique. The resulting dichlorocyclopropane2was then converted into thiosemicarbazone derivatives3 a-cbefore being transformed peri-selectively and efficiently (up to 80 % yield) into their corresponding 1,3,4-thiadiazoles (6 a-dand7 a-c) via 1,3-dipolar cycloaddition reaction with diarylnitrilimines4 a-dand N-aryl-C-ethoxycarbonyl-nitrilimines5 a-c. The structures of all the newly synthesized cyclopropanic 1,3,4-thiadiazoles6 a-dand7 a-cwere fully identified on the basis of their HRMS and NMR (1D & 2D) spectral data. The evaluation of compounds2,3 a-c,6 a-dand7 a-c, against HT-1080 fibrosarcoma, breast adenocarcinoma (MCF-7 and MDA-MB-231), and lung carcinoma A-549 cells, using viability testing (MTT) showed promising antitumor activity, especially for compounds3 a,6 band6 cfor which the IC(50)values, against HT-1080 fibrosarcoma, were respectively 18.92, 16.12 and 15.37 (mu M).