Abstract

Twelve novel trihybrids bearing salicylic acid/isoleucine/N-acylhydrazone (SA-Ile-NAH) features were designed, synthetized, and evaluated for anti-colorectal cancer effects against SW480 human colon adenocarcinoma cells. SA-Ile-NAH hybrids 4a-l were obtained in moderated to excellent yields (54-94%). Regarding biological results, trihybrids 4a, 4c, 4f and 4j showed 2 to 8-fold higher cytotoxic activities after 48 h of exposure than the standard chemotherapeutic 5-fluorouracil (174. 30 ± 19.10), with IC50 values of 20.43 ± 1.88 to 78.15 ± 6.73 µM, respectively. Of those, the 2,5-dimethoxy-substituited trihybrid 4j is highlighted for its antiproliferative response with viability below 11% in the low micromolar range after 8 days of treatment, as well as for having no significant toxic effects on non-tumorigenic cells (IC50:102.40 ± 4.64; IS: 1.31) beyond 48h of treatment. Finally, theoretical drug-likeness studies suggest that the promising 4j exhibits optimal biopharmaceutical indices. From a therapeutic perspective, merging key pharmacophoric features from salicylic acid/isoleucine/N-acylhydrazone provide a new medicinal scaffold for developing new chemopreventive agents against colorectal cancer.

Key words: Colorectal cancer, salicylic acid, isoleucine, N-acylhydrazone, cytotoxicity, antiproliferative activity.