Design, synthesis, and evaluation of formylpiperazine analogs of Ferrostatin-1 as novel improved ferroptosis inhibitors.

In this study, a series of new formylpiperazine-derived ferroptosis inhibitors were designed and synthesized based on the structure of a known ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge reactive oxygen species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new ferroptosis inhibitors for the treatment of vascular diseases.

Design, synthesis, and evaluation of novel ferrostatin derivatives for the prevention of HG-induced VEC ferroptosis.

Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated cell death. It has been shown that high glucose (HG) could induce ferroptosis in vascular endothelial cells (VECs), consequently contributing to the development of various diseases. This study synthesized and evaluated a series of novel ferrostatin-1 (Fer-1) derivatives fused with a benzohydrazide moiety to prevent HG-induced VEC ferroptosis. Several promising compounds showed similar or improved inhibitory effects compared to positive control Fer-1. The most effective candidate 12 exhibited better protection against erastin-induced ferroptosis and high glucose-induced ferroptosis in VECs. Mechanistic studies revealed that compound 12 prevented mitochondrial damage, reduced intracellular ROS accumulation, upregulated the expression of GPX4, and decreased the amounts of ferrous ion, LPO and MDA in VECs. However, compound 12 still exhibited undesirable microsomal stability like Fer-1, suggesting the need for further optimization. Overall, the present findings highlight ferroptosis inhibitor 12 as a potential lead compound for treating ferroptosis-associated vascular diseases.

New cycloalkyl[b]thiophenylnicotinamide-based α-glucosidase inhibitors as promising anti-diabetic agents: Synthesis, in silico study, in vitro and in vivo evaluations.

In the present study, a series of cycloalkyl[b]thiophenylnicotinamide derivatives against α-glucosidase were synthesized, and evaluated for their in vitro and in vivo anti-diabetic potential. Most of the synthetic analogues exhibited superior α-glucosidase inhibitory effects than the standard drug acarbose (IC50 = 258.5 µM), in which compound 11b with cyclohexyl[b]thiophene core demonstrated the highest activity with an IC50 value of 9.9 µM and showed higher selectivity towards α-glucosidase over α-amylase by 7.4-fold. Fluorescence quenching experiment confirmed the direct binding of 11b with α-glucosidase, kinetics study revealed that 11b was a mixed-type inhibitor, and its binding mode was analyzed using molecular docking. Moreover, analogs compounds 6a-9b, 11b, 12b did not show in vitro cytotoxicity against LO2 and HepG2 cells. Finally, compound 11b exhibited in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-loaded rats.