There is an urgent have to propose effective remedies for Alzheimers disease (AD). development of tau-associated neurofibrillary tangles (NFTs) that constitute the next histopathological hallmarks of Advertisement. Cu2+ and Fe3+ promote tau phosphorylation disturbing tau-microtubule set up and stabilization. Interaction of changeover metals with free of charge tau protein leads to its aggregation (S)-Tedizolid and their deposition in NFTs works as another way to obtain oxidative tension [1,4]. The biometal-catalyzed overproduction from the hydroxyl radical (OH?) from hydrogen peroxide (H2O2) and reductants also induces a carbonyl tension exacerbation. nFTs and plaques, especially with a cross-linking advertising and the excitement of Age group/Trend (Age group receptors) apoptotic axis [5,6]. Furthermore, oxidative problems on polyunsaturated essential fatty acids (PUFAs) bring about the creation of (S)-Tedizolid another neurotoxic RCS such as for example 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Michael addition of nucleophilic sets of biomolecules to these and tau proteins was reported to be a part of the biometal-mediated vicious downward redox (S)-Tedizolid spiral involved with Advertisement pathogenesis [3,7]. In addition, the ALE neurodegenerative pathway was explained recently as a new iron-dependent process of programmed cell death, termed ferroptosis, that appears morphologically and biochemically different from apoptosis. Indeed, iron not only stimulates lipid peroxidation as the ROS promoter but also as the lipoxygenase catalyst. In AD, 4-HNE-associated modifications of proteins that are implicated in neuronal communication, neurite outgrowth, antioxidant and dynamic metabolism induce considerable ferroptotic cell death [1,2]. With this AD-triggering biometal dyshomeostasis hypothesis in mind, we have previously reported the development of efficient AGE/ALE inhibitors as multitarget-directed ligands (MTDLs) [8,9]. These hydroxypyridinone-diamine hydrid molecules appear to be able to trap RCS (vicinal diamine function) as well as ROS and transition metals (hydroxypyridinone moiety) simultaneously. As a continuation of our efforts, extended pharmacomodulations Rabbit Polyclonal to KLF11 have been recognized to expand an efficacy screening and, in particular, to improve absorption, distribution, metabolism and excretion (ADME) profile of the lead compound 1, and its capacity to cross the blood brain barrier. In this paper, we statement the synthesis of two novel series of derivatives bearing numerous suitable linkers between the two pharmacophores: i) the series I presenting an amide (Ia) or piperazine-1,4-diamide (Ib) spacer, and ii) the series II possessing an alkyl (IIa) or piperazine-1,4-dialkyl (IIb) spacer (Physique 1). We also describe their preserved scavenging capacities (S)-Tedizolid and a QikProp-prediction of their ADME properties. In addition, the evaluations of their cytotoxicity and their protective effect against MGO-induced apoptosis in the model AD cell-line PC12 are offered. Open in a separate window Physique 1 New pharmacomodulations around the linker of multifunctional advanced glycation endproducts (AGE)/advanced lipid peroxidation endproducts (ALE) inhibitor lead compound 1. 2. Results and Discussion 2.1. Chemical Synthesis As shown in Table 1 and Physique 1, our previously explained synthetic strategy based on a key pseudopeptidic coupling step between diamine building blocks 2C6 and hydroxypyridinone (HOPO) ligands 9C10 was first extended to allow a decrease in size of the amide or piperazine-1,4-diamide linker and afforded the derivatives Ia-1 to Ia-4 or Ib-1 to Ib-3 respectively [8]. Moreover, simple alkyl chains could be introduced between the two functional moieties of 2-methyl-3,4-HOPO-diamine hybrids IIa-1 and IIa-2 carrying out a condensation of amino precursors 4 and 5 with maltol benzyl ether respectively. A nucleophilic substitution reaction between new diamine scaffolds 7C8 bearing an iodo group in their side chain and 3,2-HOPO benzyl ether gave the analogs IIa-3 and IIa-4. (S)-Tedizolid A new compound IIb-1 bearing a piperazine-1,4-dialkyl spacer was also obtained by the reduction of.