Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid-ß (Aß) oligomers.

BACKGROUND AND PURPOSE: Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio-1911 in Aß oligomer (AßO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). EXPERIMENTAL APPROACH: Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AßO. KEY RESULTS: LASSBio-1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AßO-triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio-1911 improves behavioural performance and rescues synaptic and memory function in AßO-infused mice. CONCLUSION AND IMPLICATIONS: These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD.

Evaluation of multitarget drugs on the expression of cocaine-induced locomotor sensitization in male rats: A comparative study.

Purpose: - Cocaine use disorder (CUD) is a complex disease. Several studies have shown the efficacy of multitarget drugs used to treat CUD. Here we compare the efficacy of mirtazapine (MIR), pindolol (PIN), fluoxetine (FLX), risperidone (RIS), trazodone (TRZ), ziprasidone (ZPR), ondansetron (OND), yohimbine (YOH), or prazosin (PRZ), to reduce long-term cocaine-induced locomotor activity and the expression of cocaine-induced locomotor sensitization in rats. Methods: - The study consists of four experiments, which were divided into four experimental phases. Induction (10 days), cocaine withdrawal (30 days), expression (10 days), and post-expression phase (10 days). Male Wistar rats were daily dosed with cocaine (10 mg/kg; i.p.) during the induction and post-expression phases. During drug withdrawal, the MIR, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ were administered 30 min before saline. In the expression, the multitarget drugs were administered 30 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min.During the agonism phase, in experiment four, 8-OH-DPAT, DOI, CP-809-101, SR-57227A, or clonidine (CLO) was administered 30 min before MIR and 60 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min. Results: -MIR, FLX, RIS, ZPR, OND, or PRZ attenuated the cocaine-induced locomotor activity and cocaine locomotor sensitization. PIN, TRZ, and YOH failed to decrease cocaine locomotor sensitization. At the optimal doses used, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ failed to attenuate long-term cocaine locomotor activation. MIR generated a decrease in cocaine-induced locomotor activity of greater magnitude and duration than the other multitarget drugs evaluated. Conclusion: - At the optimal doses of multitarget drugs evaluated, MIR was the multitarget drug that showed the greatest long-term cocaine-induced behavior effects compared to other multitarget drugs.

Molecular hybridization: a powerful tool for multitarget drug discovery.

INTRODUCTION: The current drug discovery paradigm of 'one drug, multiple targets' has gained attention from both the academic medicinal chemistry community and the pharmaceutical industry. This is in response to the urgent need for effective agents to treat multifactorial chronic diseases. The molecular hybridization strategy is a useful tool that has been widely explored, particularly in the last two decades, for the design of multi-target drugs. AREAS COVERED: This review examines the current state of molecular hybridization in guiding the discovery of multitarget small molecules. The article discusses the design strategies and target selection for a multitarget polypharmacology approach to treat various diseases, including cancer, Alzheimer's disease, cardiac arrhythmia, endometriosis, and inflammatory diseases. EXPERT OPINION: Although the examples discussed highlight the importance of molecular hybridization for the discovery of multitarget bioactive compounds, it is notorious that the literature has focused on specific classes of targets. This may be due to a deep understanding of the pharmacophore features required for target binding, making targets such as histone deacetylases and cholinesterases frequent starting points. However, it is important to encourage the scientific community to explore diverse combinations of targets using the molecular hybridization strategy.

Synthesis and biological evaluation of new antiseizure compounds derived from valproic acid.

Background: New hybrid compounds were synthesized by linking the valproic acid (VPA) structure with other anticonvulsant/anti-inflammatory scaffolds. Materials & methods: The chemistry involved the incorporation of the linker oxymethyl ester into VPA, followed by reaction with the second scaffold. The antiseizure effects were investigated by the maximal electroshock seizure test, and the most active compound was additionally evaluated in the 6 Hz test and pentylenetetrazol test in mice. Results: The compounds showed protection against seizures. The hybrid structure with the butylparaben scaffold exhibited an ED50 of 8.265 mg/kg (0.0236 mmol/Kg) in the maximal electroshock seizure test and 50.00 mg/kg (0.147 mmol/kg) in the 6 Hz test. Conclusion: The antiseizure activity of the synthesized compounds highlighted the potential of hybrid structures to treat multifactorial diseases such as epilepsy.

This article focuses on the design of new anticonvulsant compounds that combine the chemical structure of valproic acid with other interesting scaffolds with anticonvulsant or anti-inflammatory properties. These compounds protected against in vivo acute seizure models (mice). The results revealed the capacity of combining known scaffolds into a single structure to generate new active compounds with multitarget purposes.

In Combo Studies for the Optimization of 5-Aminoanthranilic Acid Derivatives as Potential Multitarget Drugs for the Management of Metabolic Syndrome.

Metabolic syndrome is a set of risk factors that consist of abdominal obesity, arterial hypertension, alterations in the lipid profile, and hyperglycemia. The current therapeutic strategy includes polypharmacy, using three or more drugs to control each syndrome component. However, this approach has drawbacks that could lead to therapeutic failure. Multitarget drugs are molecules with the ability to act on different targets simultaneously and are an attractive alternative for treating complex diseases such as metabolic syndrome. Previously, we identified a triamide derivative of 5-aminoanthranilic acid that exhibited hypoglycemic, hypolipemic, and antihypertensive activities simultaneously. In the present study, we report the synthesis and in combo evaluation of new derivatives of anthranilic acid, intending to identify the primary structural factors that improve the activity over metabolic syndrome-related parameters. We found that substitution on position 5, incorporation of 3,4-dimethoxyphenyl substituents, and having a free carboxylic acid group lead to the in vitro inhibition of HMG-CoA reductase, and simultaneously the diminution of the serum levels of glucose, triglycerides, and cholesterol in a diet-induced in vivo model.

In silico Study of Acetylcholinesterase and Beta-secretase Inhibitors: Potential Multitarget Anti-Alzheimer's Agents.

BACKGROUND: Alzheimer's disease is a progressive neurodegenerative process with multifactorial characteristics. This disease follows the natural aging process, affecting mainly people over 65 years. Pharmacotherapeutic treatment currently combats symptoms related to cognitive function. Several targets have begun to attract the interest of the scientific community to develop new drug candidates which have better pharmacokinetic and lower toxicity parameters. OBJECTIVE: The present study aims to design new candidates for acetylcholinesterase/ß-secretase (AChE/BACE1) multitarget inhibitor drugs. METHODS: 17 natural products were selected from the literature with anticholinesterase activity and 1 synthetic molecule with inhibitory activity for BACE1. Subsequently, the molecular docking study was performed, followed by the derivation of the pharmacophoric pattern and prediction of pharmacokinetic and toxicological properties. Finally, the hybrid prototype was designed. RESULTS: All selected molecules showed interactions with their respective target enzymes. Derivation of the pharmacophoric pattern from molecules that interacted with the AChE enzyme resulted in 3 pharmacophoric regions: an aromatic ring, an electron-acceptor region and a hydrophobic region. The molecules showed good pharmacokinetic and toxicological results, showing no warnings of mutagenicity and/or carcinogenicity. After the hybridization process, three hybrid molecules were obtained, which showed inhibitory activity for both targets. CONCLUSION: It is concluded that research in the field of medicinal chemistry is advancing towards the discovery of new drug candidates that bring a better quality of life to patients with AD.

Computational and Synthetic Target-based Approaches to the Discovery of Novel Anticonvulsant Compounds.

BACKGROUND: During the past decades, an important number of anticonvulsant drugs have been incorporated into the collection of drugs to treat epilepsy. However, two main difficulties remain unsolved in therapy: the development of drug-resistant epilepsy and the occurrence of severe toxic effects caused by the medication in responsive patients. The retrospective analysis of the strategies for discovering known anticonvulsant drugs showed that screening campaigns on animal models of epilepsy have been almost the exclusive strategy for identifying the marketed compounds. However, the actual structural and functional information about the molecular targets of the anticonvulsant drugs and the increasing knowledge of the molecular alterations that generate epileptic seizures allow a more rational identification of active compounds. OBJECTIVE: This review compiles target-based strategies used for the discovery of new anticonvulsant candidates and is divided in two main topics. The first one provides an overview of the computational approaches (docking-based virtual screening and molecular dynamics) to find anticonvulsant structures that interact with the voltage-gated ion channels and the enzyme carbonic anhydrase. The second one includes the analysis of active compounds synthesized to act simultaneously on different molecular targets by the combination of pharmacophores of anticonvulsant drugs. CONCLUSION: Current knowledge of the architectures of anticonvulsant targets makes computational simulations attractive methods for the discovery and optimization of active compounds. Combining the results achieved by virtual screening of different targets could lead to multitarget compounds, as an alternative to the design of structures that merge scaffolds of known drugs.

A Definition of "Multitargeticity": Identifying Potential Multitarget and Selective Ligands Through a Vector Analysis.

The design of multitarget drugs is an essential area of research in Medicinal Chemistry since they have been proposed as potential therapeutics for the management of complex diseases. However, defining a multitarget drug is not an easy task. In this work, we propose a vector analysis for measuring and defining "multitargeticity." We developed terms, such as order and force of a ligand, to finally reach two parameters: multitarget indexes 1 and 2. The combination of these two indexes allows discrimination of multitarget drugs. Several training sets were constructed to test the usefulness of the indexes: an experimental training set, with real affinities, a docking training set, within theoretical values, and an extensive database training set. The indexes proved to be useful, as they were used independently in silico and experimental data, identifying actual multitarget compounds and even selective ligands in most of the training sets. We then applied these indexes to evaluate a virtual library of potential ligands for targets related to multiple sclerosis, identifying 10 compounds that are likely leads for the development of multitarget drugs based on their in silico behavior. With this work, a new milestone is made in the way of defining multitargeticity and in drug design.

Multi-Target Directed Drugs as a Modern Approach for Drug Design Towards Alzheimer's Disease: An Update.

Alzheimer's disease (AD) is a progressive multifactorial neurodegenerative disorder. Currently, no effective treatment is available and this is due to multiple factors involved in pathophysiology and severity of AD. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDL) strategy, has been used to develop a variety of hybrid compounds capable to act simultaneously in diverse biological targets. The discovery of drug candidates capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. This review is a complement to another review article, recently published by our group, which covered the previous period of 2005-2012, and highlights recent advances and examples of the exploitation of MTDLs approach in the rational design of novel drug candidate prototypes for the treatment of AD.

Potent and Selective Inhibitors of Trypanosoma cruzi Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity.

Triosephosphate isomerase (TIM) is an essential Trypanosoma cruzi enzyme and one of the few validated drug targets for Chagas disease. The known inhibitors of this enzyme behave poorly or have low activity in the parasite. In this work, we used symmetrical diarylideneketones derived from structures with trypanosomicidal activity. We obtained an enzymatic inhibitor with an IC50 value of 86 nm without inhibition effects on the mammalian enzyme. These molecules also affected cruzipain, another essential proteolytic enzyme of the parasite. This dual activity is important to avoid resistance problems. The compounds were studied in vitro against the epimastigote form of the parasite, and nonspecific toxicity to mammalian cells was also evaluated. As a proof of concept, three of the best derivatives were also assayed in vivo. Some of these derivatives showed higher in vitro trypanosomicidal activity than the reference drugs and were effective in protecting infected mice. In addition, these molecules could be obtained by a simple and economic green synthetic route, which is an important feature in the research and development of future drugs for neglected diseases.