New thiadiazolopyrimidine-ornamented pyrazolones as prospective anticancer candidates via suppressing VEGFR-2/PI3K/Akt signaling pathway: Synthesis, characterization, in-silico, and in-vitro studies

New thiadiazolopyrimidine-ornamented pyrazolones (4a-8b) have been synthesized by a cyclocondensation reaction of 3a, b with different active methylene compounds. The structure of our products was confirmed via different physical and spectroscopic data. We assessed all newly thiadiazolopyrimidine-ornamented pyrazolones' potential to inhibit angiogenesis, metastasis, and cancer growth by utilizing in-silico investigations focused on the VEGFR-2 signaling pathway and elucidate their pharmacokinetic features using ADMET. Based on our results, compound 8b was chosen for in vitro evaluation since it had the highest binding energy of -10.252 kcal/mol using molecular docking. Compound 8b significantly damaged the T47D (IC₅₀ = 33.01 ± 2.2 μM) cells, without any toxic effect on normal cells in comparison to chemotheraputic FDA approved drug cisplatin (Cis) (IC₅₀ = 3.163 ± 1.7 μM). Additionally, compound 8b significantly suppressed the VEGFR-2 receptor protein that triggers the inhibition of PI3K/Akt genes which causes mitochondrial membrane malfunction resulting in Bax overexpression and Bcl-2 downregulation levels. Besides, compound 8b showed a notable decrease in the levels of nitric oxide (NO) production levels and arrested the cell cycle in the G0/G1 stage. These outcomes demonstrated that compound 8b adhered to Lipinski's rules and may serve as a potential candidate for future breast cancer treatments via obstructing the VEGFR-2/PI3K/Akt signaling pathway, which in turn prevents metastasis, angiogenesis, and proliferation.