Fernando Cagide

Abstract The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure-activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood-brain barrier permeability, thus being a valid candidate for subsequent animal studies. © 2016 American Chemical Society.

Abstract In this work, we report for the first time the accumulation activity by energized rat heart mitochondria and the ionic transfer process at a liquid liquid interface of a novel mitochondria-targeted antioxidant, named as AntiOxCIN(4), which is structurally based on a hydroxycinnamic acid. Lipophilicity studies conducted at the water/1,6-dichlorohexane (DCH) interface allowed the building up of an ionic partition diagram of AntiOxCIN(4) in accordance with the electrochemical data obtained. The partition coefficients of both positively charged (-2.3) and zwitterionic (0.2) forms of the antioxidant were determined. This study contributed to gaining an insight about the ability of the synthesized antioxidants to cross biomembrane barriers by using an interface between two immiscible electrolyte solutions (ITIES) as a model system.

Abstract Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with twomitochondriotropic antioxidants AntiOxBEN(1) (catechol derivative), and AntiOxBEN(2) (pyrogallol derivative) and compounds 15-18, which have longer spacers. Compounds AntiOxBEN(1) and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 +/- 5 and 106 +/- 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain weremore effective AChE inhibitors (IC50 = 7.7 +/- 0.4 and 7.2 +/- 0.5 mu M, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while A beta-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, themitochondriotropic antioxidant AntiOxBEN(1) is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.