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

Abstract

Abstract A series of C(2)‐N(4)‐disubstituted 1,3,4‐thiadiazoles bearing dichlorocyclopropane, have been prepared from (R)‐carvone 1 in a three‐step procedure. First, (R)‐carvone was treated with dichlorocarbene, generated in‐situ from chloroform using PTC technique. The resulting dichlorocyclopropane 2 was then converted into thiosemicarbazone derivatives 3 a – c before being transformed peri‐selectively and efficiently (up to 80 % yield) into their corresponding 1,3,4‐thiadiazoles ( 6 a – d and 7 a – c ) via 1,3‐dipolar cycloaddition reaction with diarylnitrilimines 4 a – d and N‐aryl‐C‐ethoxycarbonyl‐nitrilimines 5 a – c . The structures of all the newly synthesized cyclopropanic 1,3,4‐thiadiazoles 6 a – d and 7 a – c were fully identified on the basis of their HRMS and NMR (1D & 2D) spectral data. The evaluation of compounds 2 , 3 a – c , 6 a – d and 7 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 compounds 3 a , 6 b and 6 c for which the IC 50 values, against HT‐1080 fibrosarcoma, were respectively 18.92, 16.12 and 15.37 (μM).