Design, synthesis, molecular docking and anticancer activity of novel N-(4-(chlorodifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives.

New N-(4-(chlorodifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives were designed, synthesised, and evaluated as potential anticancer agents. Among the synthesised derivatives, compound 9c showed the highest potency against BCR-ABL1-positive K562 leukemia cells, with an IC50 of 0.26 ± 0.029 µM, followed by 9a (0.50 ± 0.005 µM), 9k (0.64 ± 0.075 µM) and 9l (0.69 ± 0.11 µM). Importantly, compounds 9a, 9c and 9k showed selectivity for leukemia cells and low toxicity to normal fibroblasts (IC50 > 50 µM), with selectivity indices of 100-192. Docking analysis showed that the designed analogues preserved the key pharmacophoric interactions of Asciminib, with compound 9k showing the best docking score (-42.07 kcal mol-1), followed by 9a (-40.44 kcal mol-1), compared with Asciminib (-40.13 kcal mol-1). Taken together, these results suggest that the N-(4-(chlorodifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold is a useful template for designing selective BCR-ABL1-directed anticancer agents, with compound 9c as an encouraging lead for further optimisation and mechanistic studies.