Synthesis, spectroscopic characterization, computational investigation, and in vitro cytotoxic evaluation of a novel Propargylated climbazole derivative

This study involved the synthesis, spectroscopic characterization, computational investigation, and in vitro cytotoxic evaluation of a novel propargylated derivative of climbazole. The compound was synthesized via nucleophilic substitution of climbazole alcohol with propargyl bromide under mild basic conditions and obtained in good yield. Structural elucidation was confirmed by FT-IR, 1 H/ 13 C NMR, and high-resolution mass spectrometry, verifying successful incorporation of the propargyl ether moiety. Density functional theory calculations at the B3LYP/6-311G(d,p) level employing the SMD solvation model (water) were performed to analyze optimized geometries, frontier molecular orbitals (HOMO–LUMO), global reactivity descriptors, and electrostatic potential surfaces. The results indicated subtle electronic redistribution upon propargyl substitution while preserving overall molecular stability. Molecular docking studies against the antiapoptotic protein BCL-2 (PDB ID: 6O0K ) revealed favorable binding affinities, with the most stable stereoisomer exhibiting a predicted binding energy of −8.4 kcal/mol within the BH3-binding groove. The interaction profile was dominated by π–π, π–alkyl, and hydrophobic contacts. Docking protocol validation through redocking of the cocrystallized ligand confirmed the reliability of the computational setup. In vitro cytotoxic evaluation against HL-60 leukemia cells demonstrated a concentration-dependent antiproliferative effect, with an IC 50 value of 14.46 μg/mL (43.5 μM). In silico ADMET analysis suggested increased lipophilicity, enhanced predicted blood–brain barrier penetration, and reduced hepatotoxicity risk relative to the parent compound. Propargyl modification of the climbazole scaffold resulted in coordinated changes in electronic structure, predicted BCL-2 binding behavior, pharmacokinetic properties, and measurable cytotoxic activity, providing a rational basis for further optimization toward leukemia-targeted therapeutic development. • A novel propargylated climbazole derivative was successfully synthesized. • Structure confirmed by FT-IR, NMR, HRMS, and supported by DFT analysis. • Docking revealed favorable binding to BCL-2 (PDB ID: 6O0K ). • Compound 3 showed cytotoxic activity against HL-60 cells (IC₅₀ = 43.5 μM). • ADMET analysis indicated altered lipophilicity and reduced hepatotoxicity.