Work

Therapeutic evaluation of thiadiazole–piperidinone hybrids as selective anticancer agents for advanced melanoma: Role of PI3K/AKT/mTOR inhibition and induction of cell cycle arrest, apoptosis, and autophagy

Year: 2026

Type: article

Abstract: ABSTRACT Melanoma remains difficult to treat because of therapy resistance, highlighting the need for new targeted therapeutic agents. A series of 4-methyl-N′-[(2r,6c)-3,3-dimethyl-2,6-diarylpiperidin-4-ylidene]-1,2,3-thiadiazole-5-carbohydrazides (5a–g) was synthesized and characterized by IR, 1 H NMR, 13 C NMR, and CHN analysis. The antiproliferative activity of the synthesized compounds was evaluated in melanoma, non-melanoma, and normal cell lines. Among the tested compounds, 5a exhibited potent and selective activity against melanoma cells, with IC 50 values of 0.58 μM in WM-266-4 cells and 2.88 μM in M14 cells, while showing minimal toxicity toward normal HEK293 cells (IC 50 >100 μM). Compound 5a also showed strong activity against A375, SKMEL-28, and B16F10 melanoma cells but exhibited limited activity in A549 and BT474 cells. Mechanistic studies in WM-266-4 cells demonstrated that compound 5a induced G2/M cell cycle arrest, reduced cyclin B1 and phosphorylated Cdc2 expression, and triggered caspase-dependent apoptosis, as indicated by increased levels of cleaved caspase-3 and PARP. In addition, compound 5a induced autophagy, as evidenced by increased LC3-II and Beclin 1 expression, and suppressed PI3K/AKT/mTOR/ULK1 signaling. In vivo, compound 5a significantly inhibited tumor growth in a B16F10 melanoma mouse model without observable toxicity, as supported by normal liver and spleen histology. Analysis of tumor tissues further confirmed reduced cell cycle progression, increased apoptosis, enhanced autophagy, and suppression of PI3K/AKT/mTOR signaling. Collectively, these findings identify compound 5a as a promising selective anti-melanoma agent for further therapeutic development.

Source: European Journal of Medicinal Chemistry Reports

DOI: 10.1016/j.ejmcr.2026.100368