Abstract
AIM: A novel series of Pyridine-Quinazoline-Oxadiazole hybrid analogs was synthesized as potential inhibitors of maternal embryonic leucine zipper kinase (MELK) with anticancer activity. METHOD: The synthesized compounds were confirmed structurally using (1)H, (13)C NMR, and mass spectrometry. Anticancer activity was evaluated in SK-OV3 ovarian cancer cells with the MTT assay. The effects on cell cycle and apoptosis were examined using flow cytometry. MELK inhibition was assessed through an enzyme assay. RESULT: Compound 14j exhibited strong anticancer effects, with an IC(50) of 1.53 ± 0.04 µM, compared to doxorubicin, which had an IC(50) of 14.38 ± 0.10 µM in a concentration-dependent manner. Additionally, the MELK enzyme assay for 14j exhibited the strongest inhibition (IC(50) = 78 ± 0.47 nM), versus doxorubicin (IC(50) = 178 ± 0.66 nM). Furthermore, mechanistic studies on 14j revealed cell cycle at the G1/G2 phase, induction of apoptosis, and only 3.5% cell viability. The molecules also showed notable antioxidant potency. Moreover, molecular docking and dynamics simulations revealed a stable binding conformation within the MELK active site. In-silico ADMET profiling yielded better results regarding pharmacokinetic behavior and stability. CONCLUSION: The synthesized Pyridine-based hybrids exhibit potent MELK inhibition, promising anticancer activity, and favorable in-silico drug profiles. 14j emerged as strong lead candidate for further anticancer drug development.