Tacrine-allyl/propargylcysteine-benzothiazole trihybrids as potential anti-Alzheimer's drug candidates

The authors acknowledge the Portuguese Fundação para a Ciência e Tecnologia (FCT) for the project UID/QUI/00100/2013, postdoctoral fellowships (RSK and KC). We also thank the doctoral fellowship from Erasmus Namaste program (AH).On continuing our research on new drug candidates for Alzheimer's disease (AD), we have designed, synthesized and evaluated a series of multifunctional trihybrid agents. The design strategy was based on the incorporation of a benzothiazole (BTA) moiety on a series of very recently reported bihybrids, resulting from the conjugation of a tacrine (TAC) with natural based moieties, namely S-allylcysteine (SAC) (garlic constituent) and S-propargylcysteine (SPRC). Thus, in addition to the acetylcholinesterase inhibition (AChEI) and anti-ROS capacity of the bihybrids (TAC-SAC/SPRC), the new trihybrids (TAC-SAC/SPRC-BTA) were endowed with 5-fold capacity for inhibition of the amyloid beta-peptide (Aβ) aggregation. The BTA moiety led also to considerable enhancement of the AChEI on the trihybrids, which molecular modeling suggested to be due to the simultaneous binding to the catalytic active site and peripheral anionic site of AChE. The trihybrids were also assessed for the MAO inhibition, but resulted in lower activity than expected, ascribed to the low accessibility of the propargyl groups to the enzyme active site. Finally, the effects of the compounds on the viability of neuroblastome cells stressedwith Aβ42 and H2O2 showed moderate cell protection. Overall, the performed studies illustrate the importance (and limitations) of enclosing several molecular scaffolds in one molecular entity to allow the modulation of multiple AD targets.PostprintPeer reviewe

Heterocyclic compounds as key structures for the interaction with old and new targets in Alzheimer′s disease therapy

Nowadays, Alzheimer's disease (AD) is widely recognized as a real social problem. In fact, only five drugs are FDA approved for the therapy of this widespread neurodegenerative disease, but with low results so far. Three of them (rivastigmine, donepezil and galantamine) are acetylcholinesterase inhibitors, memantine is a N-methyl-D-aspartate receptor antagonist, whereas the fifth formulation is a combination of donepezil with memantine. The prevention and treatment of AD is the new challenge for pharmaceutical industry, as well as for public institutions, physicians, patients, and their families. The discovery of a new and safe way to cure this neurodegenerative disease is urgent and should not be delayed further. Because of the multiple origin of this pathology, a multi-target strategy is currently strongly pursued by researchers. In this review, we have discussed new structures designed to better the activity on the classical AD targets. We have also examined old and new potential drugs that could prove useful future for the therapy of the pathology by acting on innovative, not usual, and not yet fully explored targets like peroxisome proliferator-activated receptor (PPARs)

Hydroxypyridinone derivatives: a fascinating class of chelators with therapeutic applications - an update

Hydroxypyridinones (HPs) are a family of N-heterocyclic metal chelators, which have been an attractive target in the development of a variety of new pharmaceutical drugs, due to its high metal chelating efficacy/specificity and easy derivatization to tune the desired biological properties. In fact, along the last decades, hydroxypyridinone derivatives, but mostly 3-hydroxy-4-pyridinone (3,4-HP), have been intensively used in drug design, following either a multitarget approach, in which one chelating unity is extrafunctionalized (hybridized) to enable the interaction with other important specific biological sites, or a polydenticity approach, in which more than one chelating moiety is conveniently attached to one scaffold, to increase the metal chelating efficacy. This review represents an update of the most recent publications (2014-2016) in mono-HP hybrids, namely as potential anti-Alzheimer´s drugs, inhibitors of metalloenzymes and anti-microbials, and also polychelating compounds (poly-HP), in view of potential application, such as anti-microbial/biostatic agents, luminescent biosensors or diagnostic agents

Exploiting hydroxyphenylbenzimidazol-based hybrids for metal-modulation in potential anti-Alzheimer´s drugs

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Exploring the chelating capacity of 2-hydroxyphenyl-benzimidazole based hybrids with multi-target ability as anti-Alzheimer's agents

Alzheimer's disease (AD) is the most common (60–70%) form of dementia in the elderly population. Its complex and multifactorial nature requires the development of drugs capable of hitting several disease targets, such as cholinergic dysfunction, oxidative stress, deposits of amyloid-β (Aβ) and metal ion dyshomeostasis. Two series of hybrids, mimetics of donepezil (DNP) and tacrine (TAC), containing a 2-hydroxyphenyl-benzimidazole (BIM) chelating moiety (DNP-BIM and TAC-BIM), were formerly developed and found to exhibit multi-target ability as anti-AD compounds. Due to the recognized role of metal ions as age triggers of AD, namely responsible for oxidative stress and Aβ aggregation, the copper and zinc chelating capacity is herein evaluated for two DNP-BIM hybrids (PP-BIM and PZ-BIM) and one TAC-BIM (TAC-BIM1) hybrid, as well as the role of copper in their Aβ aggregation inhibitory capacity. The compounds exhibit good chelating capacity towards Cu(II) (pCu ∼ 11) and moderate towards Zn(II) (pZn ∼ 6) in a 50% w/w DMSO/water medium, with the formation of 1 : 1 (MHL) and 1 : 2 (MH2L2, ML2 and MH−1L2) complex species involving the phenolic oxygen and the imidazole nitrogen N(3) of the BIM moiety in the coordination shell. All hybrids are able to improve the inhibition of self-induced Aβ aggregation, probably by ligand intercalation between the β-sheets of Aβ fibrils, with markedly higher inhibitory capacity for the tacrine conjugates than for the donepezil conjugates. Nevertheless, the compounds do no’t seem able to retrieve Cu(II) from Aβ peptide and so they may have no relevant role in Cu(II)-induced-Aβ aggregation

Donepezil structure-based hybrids as potential multifunctional anti-Alzheimer’s drug candidates

A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer’s disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation. Overall, they showed good activity for AChE inhibition (IC50=4.0–30.0 μΜ) and moderate ability for inhibition of Aβ1–42 self-mediated aggregation. The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aβ42 aggregation and the antioxidant capacity. Moreover, neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aβ1–42 induced toxicity. Structure–activity relationship allowed the identification of some promising compounds and the main determinant structural features for the targeted properties

Metal chelators for the multi-target therapy of Alzheimer's Disease: isolation/synthesis and preliminary biological evaluation of new natural and synthetic compounds.

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