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

A novel series of Pyridine-Quinazoline-Oxadiazole hybrid analogs was synthesized as potential inhibitors of maternal embryonic leucine zipper kinase (MELK) with anticancer activity. 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. 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. 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.