Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmaceutical Chemistry

Novel furan VIa-c, furo[2,3-d]pyrimidine VIIa-f, IX, Xa-f, XIIa,c, XIVa-d and furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine VIIIa-f derivatives were designed based on their structural similarity to a previously described oxazole VEGFR-2 back pocket binding fragment.The twenty-eight designed compounds were synthesized and screened for their in vitro VEGFR-2 inhibitory activity where they exhibited good to moderate nanomolar inhibition with improved ligand efficiencies. VIIIb and Xc (IC₅₀ = 38.72 ± 1.7 and 41.40 ± 1.8 nM, respectively) were equipotent to sorafenib and VIa, VIc, VIIf, VIIIa, VIIIc, Xb, Xf, XIIc, XIVc and XIVd showed good activity (IC₅₀ = 43.31-98.31 nM). Additionally, all the novel compounds were evaluated for their antiproliferative activity at the National Cancer Institute (NCI), USA using sulforhodamine B assay (SRB) at a single dose of 10 oM and compounds XIVa,b were selected for NCI-60 five-dose screen to determine their Growth inhibition 50% (GI50), total growth inhibition (TGI) and lethal concentration 50% (LC50).The furotriazolopyrimidines VIIIa-c and furopyrimidine derivative Xc were further evaluated for their in vitro antiproliferative activity against human umbilical vein endothelial cells (HUVECs) where VIIIb showed higher potency than sorafenib and resulted in cell cycle arrest at G2/M phase whereas VIIIc revealed good antiproliferative activity with cell cycle arrest at G1 phase. Moreover, VIIIa-c and Xc showed significant inhibitory effects on the invasion and migration of HUVECs. Molecular docking study was conducted to gain insight about the potential binding mode. The furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives VIIIb and VIIIc among the synthesized compounds represent interesting starting point for antiangiogenic compounds based on their activity and favorable drug likeness profiles

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