Synthesis and SAR Studies of Novel Oxazolyl- and Thiazolyl-indoles and Their Intermediates as Selective Antiproliferative Agents Against HL-60 Leukemia and C6 Glioma Cell Lines.

Abstract

1,3-Oxazole-2-carboxamides, -carbothioamides and their 1,3-thiazole analogues coupled with indoles were synthesized with promising selective antitumor effects. All compounds were prepared from tryptamine derivatives in 3-5 reaction steps including a Robinson-Gabriel cyclization to construct the oxazole or thiazole ring. The pharmacological activities of the intermediates and target compounds were assessed. Our findings revealed several novel small molecules with cancer cell-specific antiproliferative and/or cytotoxic properties, tested on HL-60 leukemia and C6 glioma cell lines. The 3-heteroarylindole target compounds demonstrated greater effectiveness compared to their acyclic intermediates. Notably, only the sulfur-containing compounds, such as thiazoles and the intermediates containing an acyclic side chain with a carbothioamide group showed significant antiproliferative properties. This activity was further enhanced by adding an extra sulfur atom, either by replacing oxazole heterocycles with thiazoles or by modifying carboxamides into carbothioamides. Additionally, the presence of a chlorine substituent at position 5 of the indole ring improved both the potency and cancer selectivity of the compounds. The synthesized novel compounds and the reported synthetic methodologies present valuable tools for drug discovery aiming at emerging pharmacological targets in the field of oncology.