[1,2,4]triazolo[4,3- a]quinoxaline as Novel Scaffold in the Imiqualines Family: Candidates with Cytotoxic Activities on Melanoma Cell Lines
Cutaneous melanoma is one of the most aggressive forms of cancer and the deadliest type of skin cancer, primarily due to its high metastatic potential. The development of resistance to oncogenic pathway inhibitors underscores the need for novel therapeutic approaches. The Imiqualine family consists of heterocyclic compounds featuring diverse substitutions on scaffolds such as imidazo[1,2-a]quinoxaline, imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline. These compounds have demonstrated promising activity against a range of cancer cell lines, particularly melanoma.
In this study, we designed and synthesized new compounds based on the [1,2,4]triazolo[4,3-a]quinoxaline scaffold using a unified synthetic strategy. The synthesis involved the reaction of 1-chloro-2-hydrazinoquinoxaline with appropriate aldehydes, followed by cyclization through an oxidation-reduction mechanism employing chloranil. Substituents at positions 1 and 8 were selected based on prior structure-activity relationship (SAR) studies of the Imiqualine family. Additionally, the physicochemical properties of all compounds were predicted.
The cytotoxicity of 16 synthesized compounds was evaluated using the A375 melanoma cell line. Among these, three novel [1,2,4]triazolo[4,3-a]quinoxalines exhibited cytotoxic activity. Compounds 16a and 16b showed moderate activity, with EC50 values of 3158 nM and 3527 nM, respectively. Compound 17a demonstrated the most potent activity in this series, with an EC50 of 365 nM, although EAPB02303 remains the most effective compound in the Imiqualine family, with an EC50 of 3 nM.