N-Substituted-2-(9H-Xanthen-9-yl)acetamide Derivatives Induce In Vitro Colon Cancer Cell Death via TASK-1 Inhibition: Lead Compounds for Further Optimization as TASK-1-Targeted Therapeutics in Colorectal Cancer

Colorectal cancer (CRC) is the third most prevalent cancer globally. TASK-1, encoded by the KCNK3 gene, is emerging as a putative target in cancer; it regulates resting membrane potential, cell proliferation, and apoptosis. A series of 27 novel xanthene derivatives, modified at position 9, were synthesized via azide coupling of 2-(9H-xanthen-9-yl)acetohydrazide with selected amines and amino acids, followed by hydrazine-mediated conversion to the corresponding hydrazides. The cytotoxic activity of selected compounds (5a–5g, 6a–6h, 7b, 7f–7h) was evaluated against the HCT-116 cell line in vitro. In addition, molecular docking and molecular dynamics simulations were performed to investigate binding interactions and assess the stability of the protein–ligand complexes. Several compounds (5f, 5g, 6c, 6d, 6f, 6g, 7b, 7f, and 7h) exhibited moderate cytotoxic activity against HCT-116 cells (IC₅₀: 66.97–99.62 µM), compared to cisplatin (IC₅₀: 18.25 µM). Compound 7h demonstrated pronounced antiproliferative effects, evidenced by DAPI staining showing chromatin condensation and apoptotic body formation, along with a marked reduction in cell count and coverage. Molecular docking indicated favorable binding within the TASK-1 potassium channel, and molecular dynamics simulations confirmed the stability of the protein–ligand complex, with consistent interactions, including a key hydrogen bond with Asn240. These findings support 7h as a promising lead candidate. These findings identify xanthene-based derivatives as promising lead compounds for further optimization as TASK-1-targeted therapeutic candidates in colorectal cancer.