Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitors.

Novel series of nitric oxide-releasing thiazolidine-2,4-diones () and 3,4,5-trimethoxychalcone-based multifunctional 1,4-dihydropyrimidines () have been designed and synthesised as potent broad-spectrum anticancer agents with potential VEGFR-2 inhibition. The designed analogs were evaluated for their anticancer activities towards a full panel of NCI-60 tumour cell lines and emerged mean %inhibitions ranging from 76.40 to 147.69%. Among them, and demonstrated the highest MGI% of 147.69 and 140.24%, respectively. Compounds showed higher mean %inhibitory activity than the reference drug sorafenib (MGI% = 105.46%). Superiorly, the hybrid displayed the highest potencies towards all the herein tested subpanels of nine types of cancer with MGI of 1.83 µM. Also, it revealed potent cytostatic single-digit micromolar activity towards the herein examined cancer cell lines. The designed compounds were exposed as potent non-selective broad-spectrum anticancer agents over all NCI subpanels with an SI range of 0.66-1.97. In addition, the target analog revealed potency towards VEGFR-2 kinase comparable to that of sorafenib with a sub-micromolar IC value of 0.11 µM. Also, could effectively induce Sub-G1-phase arrest and prompt apoptosis caspase and p53-dependent mechanisms. Furthermore, revealed significant anti-metastatic activity as detected by wound healing assay. The modelling study implies that overlaid well with sorafenib and formed a strong H-bond in the DFG binding domain. The ADMET studies hinted out that met Pfizer's drug-likeness criteria. The presented novel potent anticancer agent merits further devotion as a new lead product in developing more chalcone-based VEGFR-2 inhibitors.