Design, synthesis, and biological evaluation of pyridine-quinazoline-oxadiazole hybrids as novel MELK inhibitors: in-silico analysis, anti-ovarian cancer activity, antioxidant potential, and assessment of cell cycle arrest and apoptosis.

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 1H, 13C 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 IC50 of 1.53 ± 0.04 µM, compared to doxorubicin, which had an IC50 of 14.38 ± 0.10 µM in a concentration-dependent manner. Additionally, the MELK enzyme assay for 14j exhibited the strongest inhibition (IC50 = 78 ± 0.47 nM), versus doxorubicin (IC50 = 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.