Molecular informatics guided assessment of triazole-thiadiazole conjugates as anti-leukemia entities: Computational fingerprinting, pharmacokinetic behavior and biological outcomes.

Leukemia is a heterogeneous hematological malignancy that remains a major challenge in cancer therapy, highlighting the need for the development of structurally diverse and potent anticancer agents. In this study, a novel series of triazole-thiadiazole-based sulfonamide derivatives was designed and synthesized through a facile synthetic approach and characterized using 1H NMR, 13C NMR, and HRMS techniques. The synthesized compounds were evaluated for their antiproliferative activity against HL-60, PLB-985, and K-562 leukemia cell lines. Among the investigated derivatives, the trifluoromethyl-substituted compound 6 emerged as the most promising candidate, exhibiting IC₅₀ values of 5.20 ± 0.10, 6.10 ± 0.20, and 8.30 ± 0.60 μM against HL-60, PLB-985, and K-562 cells, respectively, and showing greater potency than etoposide. Concentration-dependent cell viability studies further supported the antiproliferative potential of the lead compound. Molecular docking studies provided structural insights into the interactions of the active derivatives with leukemia-associated molecular targets, while ADMET profiling indicated generally favorable drug-like and pharmacokinetic properties. DFT calculations further elucidated the electronic characteristics and reactivity-related properties of the promising compounds. Collectively, the integrated in-vitro and in-silico findings identify the triazole-thiadiazole sulfonamide scaffold as a promising framework for leukemia drug discovery and highlight compound 6 as a lead candidate. Further target-specific biochemical validation, molecular dynamics simulations, selectivity studies, and in-vivo efficacy and safety investigations are warranted to establish its mechanism of action and therapeutic potential.