Eco-friendly Synthesis and Molecular Modelling of 2-Phenylimidazo[1,2-b]pyridazine Derivatives: In Vitro and In Vivo Studies for Lead Optimization.

7-methyl-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM1) and 6-methoxy-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM2) have been shown to act as human (h) Cav voltage-gated calcium channel blockers with promising in vivo anti-absence activity, positioning them as potential antiepileptic drugs. The primary aim of this work was to develop cost-effective and environmentally friendly synthetic procedures for preparing 2-phenylimidazo[1,2-b]pyridazine derivatives. After optimizing the synthesis of this compound class using efficient and green techniques such as microwaves and ultrasound irradiation, we further evaluated the antiepileptic effects of DM1 and DM2 in two animal models: CD-1 ICR mice after pentylenetetrazol administration and DBA/2 mice with seizures induced by audiogenic stimuli.

The Insulin-Degrading Enzyme from Structure to Allosteric Modulation: New Perspectives for Drug Design.

The insulin-degrading enzyme (IDE) is a Zn peptidase originally discovered as the main enzyme involved in the degradation of insulin and other amyloidogenic peptides, such as the β-amyloid (Aβ) peptide. Therefore, a role for the IDE in the cure of diabetes and Alzheimer's disease (AD) has been long envisaged. Anyway, its role in degrading amyloidogenic proteins remains not clearly defined and, more recently, novel non-proteolytic functions of the IDE have been proposed.

Tetrasubstituted Pyrrole Derivative Mimetics of Protein-Protein Interaction Hot-Spot Residues: A Promising Class of Anticancer Agents Targeting Melanoma Cells.

A new series of tetrasubstituted pyrrole derivatives (TSPs) was synthesized based on a previously developed hypothesis on their ability to mimic hydrophobic protein motifs. The resulting new TSPs were endowed with a significant toxicity against human epithelial melanoma A375 cells, showing IC values ranging from 10 to 27 μM, consistent with the IC value of the reference compound nutlin-3a (IC = 15 μM). In particular, compound (IC = 10 μM) resulted as both the most soluble and active among the previous and present TSPs.

The role of NOS3 (rs2070744) and GNB3 (rs5443) genes' polymorphisms in endothelial dysfunction pathway and carotid intima-media thickness in hypertensive patients.

The mechanisms orchestrating the balance between nitric oxide and endothelium-derived contracting factors, and genetic predisposition to endothelial dysfunction in hypertensive patients remain to be determined. One-hundred hypertensive patients participated in the case-control study to clarify the risk of endothelial dysfunction and carotid "intima media" thickness (IMT) changes depending on NOS3 (rs2070744) and GNB3 (rs5443) genes' polymorphisms. It is found that presence of NOS3 gene's С-allele significantly elevates the risk of atherosclerotic plaques on carotid arteries (OR95%CI: 1.