Synthesis and Antitumor Activity of Novel Heterocyclic Systems with Monoterpenic Skeleton Combining Dichlorocyclopropane and 1,3,4‐Thiadiazole Nucleus
Ali Oubella, Mourad Fawzi, Aziz Auhmani, Abdelkhalek Riahi, Hamid Morjani, Anthony Robert, My Youssef Ait Itto
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).