Design and synthesis of novel furan, furo[2,3-d]pyrimidine and furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives as potential VEGFR-2 inhibitors.

Novel furan 6a-c, furo[2,3-d]pyrimidine 7a-f, 9, 10a-f, 12a,b, 14a-d and furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine 8a-f derivatives were designed based on their structural similarity to a previously described oxazole VEGFR-2 back pocket binding fragment. The 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. 8b and 10c (IC50 = 38.72 ± 1.7 and 41.40 ± 1.8 nM, respectively) were equipotent to sorafenib and 6a, 6c, 7f, 8a, 8c, 10b, 10f, 12b, 14c and 14d showed good activity (IC50 = 43.31-98.31 nM). The furotriazolopyrimidines 8a-c and furopyrimidine derivative 10c were further evaluated for their in vitro antiproliferative activity against human umbilical vein endothelial cells (HUVECs) where 8b showed higher potency than sorafenib and resulted in cell cycle arrest at G2/M phase whereas 8c revealed good antiproliferative activity with cell cycle arrest at G1 phase. Moreover, 8a-c and 10c 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 8b and 8c represent interesting starting point for antiangiogenic compounds based on their activity and favorable drug likeness profiles.

Design, synthesis, in vitro and in vivo evaluation of novel pyrrolizine-based compounds with potential activity as cholinesterase inhibitors and anti-Alzheimer's agents.

Novel series of pyrrolizine based compounds (4-6 and 9-11) were designed, synthesized and evaluated as potential anti-Alzheimer agents. Most of the tested compounds showed selectivity to hAChE over hBChE and effectively inhibited self-induced amyloid beta aggregation in vitro. Among these derivatives, compound 10 displayed high selectivity towards hAChE (Ki = 1.47 ±â€¯0.63 µM for hAChE and Ki = 40.15 ±â€¯3.31 µM for hBChE). However, compound 11 displayed dual inhibitory effect against hAChE and hBChE at submicromolar range (Ki = 0.40 ±â€¯0.03 and 0.129 ±â€¯0.009 µM, respectively). Kinetic studies of the new ligands showed competitive type inhibition for both hAChE and hBChE. Moreover, compounds 10 and 11 showed lower or comparable cytotoxicity to donepezil against human neuroblastoma (SH-SY5Y) and normal human hepatic (THLE2) cell lines. In vivo studies confirmed that both compounds were able to improve cognitive dysfunction of scopolamine-induced AD mice. Finally, molecular docking simulation of compounds 10 and 11 in hAChE active site showed good agreement with the obtained pharmaco-biological results.