Background: 8-Hydroxyquinoline and phthalimide are two significant heterocyclic scaffolds
in medicinal chemistry due to their pharmacological profiles. Hybridizing these pharmacophores
and further modifying them via modified Mannich reactions provides a strategy to improve
their physicochemical parameters and selectivity toward multidrug-resistant (MDR)
cancer cells. Objectives: To synthesize a series of 8-hydroxyquinoline–phthalimide
hybrids and their Mannich base derivatives and evaluate their cytotoxic activity and
resistance-selective properties against sensitive Colo205 and resistant Colo320 cancer
cell lines. Methods: Four hybrid compounds were synthesized by reacting 5-amino-8-hydroxyquinoline
with different phthalic anhydride derivatives. Twelve fine-tuned derivatives were
prepared by using the modified Mannich reaction. Cytotoxic activity was measured using
the MTT assay, and relative resistance (RR) was calculated to determine selectivity
toward the resistant cell line. P-glycoprotein (Pgp) ATPase activity was evaluated
for the most active compounds. Results: All derivatives displayed cytotoxic activity,
with higher potency toward the resistant Colo320 cell line. Compounds 2 and 4 showed
the strongest activity against both cell lines (IC50 down to 4.88 µM). Compounds 5,
8a, 9a, and 9c retained potent activity against Colo320 (IC50 = 9.89–22.79 µM). Incorporating
a CH2–N group at position C7 substantially enhanced the selectivity for MDR cells.
Compounds 9c, 9a, and 8a exhibited the highest selectivity, with RR values of 0.29,
0.33, and 0.35, respectively. Compounds 2, 4, 5, 8a, and 9a showed inhibitory effects
on Pgp ATPase activity. Conclusion: The newly synthesized HQ–phthalimide hybrids represent
promising candidates for targeting MDR in colorectal cancer, with Mannich modification
enhancing the selectivity toward resistant cells.
