Synthesis of N-substituted-N-acylthioureas of 4-substituted piperazines endowed with local anaesthetic, antihyperlipidemic, antiproliferative activities and antiarrythmic, analgesic, antiaggregating actions

Three series of N-acyl and N-cyclohexyl- or N-Me or N-phenyl-thioureas of 4-substituted (Me, Ph, 2-pyridyl)piperazines (4-12) were synthesized according to a highly convergent one-pot procedure and tested in vivo (local anesthetic, anti-hyperlipoproteinemic, analgesic, anti-inflammatory, antiarrythmic activities) and in vitro (antiaggregating and, for some selected derivs., antiproliferative activities) expts. All the test compds. showed local anesthesia in particular 4Ar4, 5Ar4, 12Ar3 (after 5 min) and 5Ar2, 5Ar3, 9Ar4 (after 30 min) were equipotent to lidocaine. In lowering triglyceride levels, compds. 6Ar4 and 7Ar3 were more active than nicotinic acid, whereas 7Ar4 and 11Ar4 were approx. equipotent. As concerns analgesic activity, 5Ar2 and 5Ar4 were as active as indomethacin. Appreciable anti-inflammatory activity was found in 8Ar1, 5Ar2 and 11Ar2, but inferior to that of indomethacin. High levels of antiarrythmic activity, comparable with that of quinidine, were found in derivs. 4Ar2 and 10Ar1. Compds. 4Ar2 and 8Ar2, assayed in antitumor in vitro screening system at National Cancer Institute (NCI), showed significant antiproliferative activity against ACHN cell line (GI50: 0.13 μM) and NCI-H226 cell line (GI50: 1.03 μM), resp.