Multi-Targeting Tacrine Conjugates with Cholinesterase and Amyloid-Beta Inhibitory Activities: New Anti-Alzheimer's Agents.

Alzheimer's disease (AD) is a severe age dependent and chronic problem with no cure so far. The available treatments are temporary, acting over short period of time. The main pathological hallmark of the disease includes cholinergic dysfunction, oxidative stress, accumulation of Aß fibrils and tau tangles. In context with the multi-factorial nature of this disease, two different series of molecules were developed to hit the multifactorial disease targets. Mainly, the molecules were designed to inhibit the AChE and aggregation of Aß, and also oxidative damage. Two novel series of TAC-fenbufen/menbutone conjugated molecules were designed, synthesized and bio-assayed. All compounds showed inhibition capacity towards AChE, Aß aggregation and moderate to good radical scavenging capacity. Particularly, five TAC-menbutone molecules showed improved AChE and Aß aggregation inhibition capacity compared to TAC-fenbufen conjugated molecules. Overall, these novel series of molecules may be potential drug lead molecules in the treatment of AD.

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 (Aß) 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 Aß1-42 self-mediated aggregation. The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aß42 aggregation and the antioxidant capacity. Moreover, neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aß1-42 induced toxicity. Structure-activity relationship allowed the identification of some promising compounds and the main determinant structural features for the targeted properties.

Development of coumarin-benzofuran hybrids as versatile multitargeted compounds for the treatment of Alzheimer's Disease.

Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disorder characterized by progressive deterioration of memory and cognition. The evidenced multifactorial nature of AD has been considered the main reason for the absence of cure so far. Therefore, the development of novel hybrids to treat the disease is very much essential. Focusing on this, a novel series of coumarin-benzofuran hybrids have been designed and screened as anti-Alzheimer's disease agents. The strategy is to obtain an effective mimetic of donepezil, which is acetylcholinesterase inhibitor. Herein, the two main scaffolds namely coumarin and benzofuran are known pharmacophore moieties and we have performed their molecular design, pharmacokinetic descriptor studies for drug-likeliness. Further, in vitro studies such as antioxidant capacity, acetylcholinesterase (AChE) inhibition and amyloid-ß (Aß) self-aggregation inhibition have also been performed. Most importantly, these studies revealed that the newly synthesized hybrids can be versatile and promising drug-like moieties as efficient anti-AD agents.

Novel Tacrine-Hydroxyphenylbenzimidazole hybrids as potential multitarget drug candidates for Alzheimer's disease.

Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting millions of people, with no cure so far. The current treatments only achieve some temporary amelioration of the cognition symptoms. The main characteristics of the patient brains include the accumulation of amyloid plaques and neurofibrillary tangles (outside and inside the neurons) but also cholinergic deficit, increased oxidative stress and dyshomeostasis of transition metal ions. Considering the multi-factorial nature of AD, we report herein the development of a novel series of potential multi-target directed drugs which, besides the capacity to recover the cholinergic neurons, can also target other AD hallmarks. The novel series of tacrine-hydroxyphenylbenzimidazole (TAC-BIM) hybrid molecules has been designed, synthesized and studied for their multiple biological activities. These agents showed improved AChE inhibitory activity (IC50 in nanomolar range), as compared with the single drug tacrine (TAC), and also a high inhibition of self-induced- and Cu-induced-Aß aggregation (up to 75%). They also present moderate radical scavenging activity and metal chelating ability. In addition, neuroprotective studies revealed that all these tested compounds are able to inhibit the neurotoxicity induced by Aß and Fe/AscH(-) in neuronal cells. Hence, for this set of hybrids, structure-activity relationships are discussed and finally it is highlighted their real promising interest as potential anti-AD drugs.

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 their 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.

Hydroxypyridinone-benzofuran hybrids with potential protective roles for Alzheimer´s disease therapy.

A series of (3-hydroxy-4-pyridinone)-benzofuran hybrids have been developed and studied as potential multitargeting drugs for Alzheimer's disease (AD). Their design envisaged mainly to mimic the donepezil drug, a marketed inhibitor of acetylcholinesterase (AChE), and to endow the conjugate molecules with extra-properties such as metal chelation, radical scavenging and inhibition of amyloid peptide (Aß) aggregation. Thus, a set of eleven new hybrid compounds was developed and evaluated for chemical and biological properties, in solution and in neuronal cell environment. The results are discussed in terms of the type of substituents on both main moieties and the linker size. The closest similarity with donepezil, in terms of AChE inhibitory activity, was obtained for the O-benzyl-hydroxypyridinone hybrids containing a 2-methylene linker, although still less active than the drug. However, the free-hydroxypyridinone hybrids present higher activity for the Aß aggregation inhibition, metal chelating capacity and radical scavenging activity. Overall, some compounds demonstrated capacity to exert a multiple action by hitting three- (7d) or four- (8d, 8f) pathophysiological targets of AD. Furthermore, the compounds showed neuroprotective effects in neuronal cells subjected to model stressors of AD, but not significant dependence on the substituent groups. Importantly, the compounds evidenced drug-likeness properties, including good membrane permeability.

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).

A review on antioxidant potential of bioactive heterocycle benzofuran: Natural and synthetic derivatives.

The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. In this context, oxygen heterocycles exhibit diverse biological and pharmacological activities due in part to the similarities with many natural and synthetic molecules with known biological activity. Among oxygen containing heterocycles, benzofuran (synthetic and natural isolated) and its derivatives have attracted medicinal chemists and pharmacologists due to their pronounced biological activities and their potential applications as pharmacological agents such as antioxidant, antitumor, antiplatelet, antimalarial, antiinflammatory, antidepressant and anticonvulsant properties. There are also an amazing number of approved benzofuran-containing drugs in the market as well as compounds currently going through different clinical phases or registration statuses. Due to the wide range of biological activities of benzofurans, their structure activity relationships have generated interest among medicinal chemists, and this has culminated in the discovery of several lead molecules in numerous disease conditions. Recently, this scaffold has emerged as a pharmacophore of choice for designing antioxidant drug development as their derivatives have shown excellent results through different mechanism of action. This review focused on the recent development of benzofuran derivatives as antioxidant agents (including natural products) and their antioxidant activities; summarize the structure property, hoping to inspire new and even more creative approaches. Also, this study systematically provides a comprehensive report on current developments in benzofuran-based compounds as antioxidant agents and is also helpful for the researchers working on a substitution pattern around the nucleus, with an aim to help medicinal chemists to develop structure activity relationships (SAR) on these derivatives as antioxidant drugs.

Comprehensive Review in Current Developments of Benzimidazole-Based Medicinal Chemistry.

The properties of benzimidazole and its derivatives have been studied over more than one hundred years. Benzimidazole derivatives are useful intermediates/subunits for the development of molecules of pharmaceutical or biological interest. Substituted benzimidazole derivatives have found applications in diverse therapeutic areas such as antiulcer, anticancer agents, and anthelmintic species to name just a few. This work systematically gives a comprehensive review in current developments of benzimidazole-based compounds in the whole range of medicinal chemistry as anticancer, antibacterial, antifungal, anti-inflammatory, analgesic agents, anti-HIV, antioxidant, anticonvulsant, antitubercular, antidiabetic, antileishmanial, antihistaminic, antimalarial agents, and other medicinal agents. This review will further be helpful for the researcher on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for developing an SAR on benzimidazole drugs/compounds.