Cytotoxic activities and in silico study of carbazole alkaloids isolated from Murraya koenigii against HL-60 and HeLa cancer cell lines

Carbazole alkaloids from Murraya koenigii exhibit diverse structural features and promising anticancer potential. This study evaluated the cytotoxic activity and structure–activity relationship (SAR) of 24 carbazole alkaloids against HL-60 and HeLa cancer celllines, alongside molecular docking studies against the anti-apoptotic protein Bcl-2 (PDB ID: 2W3L).The SAR analysis revealed that electron-donating and redox-active substituents, particularly formyl groups, significantly enhanced cytotoxicity, while dimerization generally reduced potency. Docking results showed binding energies ranging from −5.49 to −9.37 kcal/mol, with key interactions mainly involving Phe63, Asp70, Phe71, Met74, Val92,Glu95, Leu96, Asp99, Gly104, Phe109, Glu111 and Phe112 residues. Potent compounds such as mahanine (15) and murrayamine-J (18) exhibited both strong cytotoxicity (IC50 = 12.1 and 5.1 μg/mL for HL-60 and 12.8 and 7.7 μg/mL for HeLa, respectively) and favorable binding affinities (−7.66 and −7.25 kcal/mol), suggesting that Bcl-2 inhibition contributes to their activity. Conversely, murrayafolline-A (2) displayed notable cytotoxicity (IC50 = 8.5 μg/mL forHL-60 and 4.6 μg/mL forHeLa) despite only moderate predicted affinity (−5.71 kcal/mol), indicating possible alternative mechanisms of action. Similarly, bisisomahanine (24) showed the strongest predicted binding (−9.37 kcal/mol) with lowest ligand efficiency but negligible cytotoxicity, suggesting that the high binding affinity is attributed to its bulky size. Overall, this study provides supportive computational insights into the cytotoxic potential of carbazole alkaloids and highlights their predictive relevance for future mechanistic and pharmacokinetic studies.