Design, synthesis, and structure-activity relationships of five-membered heterocyclic incorporated aryl(alkyl)azoles: From antiproliferative thiazoles to safer anticonvulsant oxadiazoles.

In the current study, a novel series of 1,2,4-oxadiazoles were designed, synthesized, and evaluated for their biological activities. A cell-based antiproliferative screening was accomplished on the newly synthesized 1,2,4-oxadiazoles along with our previously reported aryl(alkyl)azoles (AAAs) containing middle heterocyclic cores thiazole and oxazole. Among the tested compounds, naphthyl- thiazoles demonstrated higher antiproliferative activity and B3 was identified as the most potent compound with IC values in the range of 2.03-3.6 µM against SH-SY5Y neuroblastoma, HT-29 colorectal adenocarcinoma, and fibroblast cells (ten folds more potent than 5-FU and irinotecan). Further investigation revealed that B3 strongly inhibits tubulin polymerization with an IC of 0.79 µM, outperforming the reference drug colchicine (IC = 1.46 µM). In addition, evaluation of B3 on the expression level of BAX, BCL2, and CYCLIN D1 genes indicated the suppression of the cell cycle in the genome level. Interestingly, the 1,2,4-oxadiazole congeners displayed optimal anticonvulsant activity with significantly reduced cytotoxicity. Among the oxadiazole series, compound D4 featuring a 1,2,4-triazole head group demonstrated the highest activity in the maximal electroshock (MES) and pentylenetetrazol (PTZ) tests, with ED values of 2.23 and 24.60 mg/kg, respectively. In vivo evaluations suggested that D4 exerts its anticonvulsant effects by enhancing GABA currents. In conclusion, our findings indicated that B3 in the thiazole congeners is a promising drug candidate for cancer treatment with a well-defined mechanism of action. Moreover, D4 and its congeners containing oxadiazole core are much safer anti-seizures which have potential for preclinical considerations as novel anticonvulsants.