Current Medicinal Chemistry - Volume 29, Issue 19, 2022

Malaria is a tropical threatening disease caused by Plasmodium parasites, resulting in 409,000 deaths in 2019. The delay of mortality and morbidity has been compounded by the widespread of drug resistant parasites from Southeast Asia since two decades. The emergence of artemisinin-resistant Plasmodium in Africa, where most cases are accounted, highlights the urgent need for new medicines. In this effort, the World Health Organization and Medicines for Malaria Venture joined to define clear goals for novel therapies and characterized the target candidate profile. This ongoing search for new treatments is based on imperative labor in medicinal chemistry which is summarized here with particular attention to hit-to-lead optimizations, key properties, and modes of action of these novel antimalarial drugs. This review, after presenting the current antimalarial chemotherapy, from quinine to the latest marketed drugs, focuses in particular on recent advances of the most promising antimalarial candidates in clinical and preclinical phases.

Epilepsy is a chronic brain disorder caused by the abnormal firing of neurons. Up to now, the use of antiepileptic drugs is the main method of epilepsy treatment. The development of antiepileptic drugs lasted for centuries. In general, most agents entering clinical practice act on the balance mechanisms of brain “excitability-inhibition”. More specifically, they target voltage-gated ion channels, GABAergic transmission and glutamatergic transmission. In recent years, some novel drugs representing new mechanisms of action have been discovered. Although there are about 30 available drugs in the market, it is still in urgent need of discovering more effective and safer drugs. The development of new antiepileptic drugs is into a new era: from serendipitous discovery to evolutionary mechanism-based design. This article presents an overview of drug treatment of epilepsy, including a series of traditional and novel drugs.

Traumatic brain injury (TBI) is a serious cause of disability and death among young and adult individuals, displaying complex pathophysiology including cellular and molecular mechanisms that are not fully elucidated. Many experimental and clinical studies investigated the potential relationship between TBI and the process by which neurons are formed in the brain, known as neurogenesis. Currently, there are no available treatments for TBI’s long-term consequences being the search for novel therapeutic targets, a goal of highest scientific and clinical priority. Some studies evaluated the benefits of treatments aimed at improving neurogenesis in TBI. In this scenario, herein, we reviewed current pre-clinical studies that evaluated different approaches to improving neurogenesis after TBI while achieving better cognitive outcomes, which may consist in interesting approaches for future treatments.

Cardiovascular diseases (CVD) are the major cause of death in the world. Numerous genetic studies involving transcriptomic approaches aimed at the detailed understanding of the disease and the development of new therapeutic strategies have been conducted over recent years. There has been an increase in research on platelets, which are implicated in CVD due to their capacity to release regulatory molecules that affect various pathways. Platelets secrete over 500 various kinds of molecules to plasma including large amounts of non-coding (nc) RNA (miRNA, lncRNA or circRNA). These ncRNA correspond to 98% of transcripts that are not translated into proteins as they are important regulators in physiology and disease. Thus, miRNAs can direct protein complexes to mRNAs through base-pairing interactions, thus causing translation blockage or/and transcript degradation. The lncRNAs act via different mechanisms by binding to transcription factors. Finally, circRNAs act as regulators of miRNAs, interfering with their action. Alteration in the repertoire and/or the amount of the platelet-secreted ncRNA can trigger CVD as well as other diseases. NcRNAs can serve as effective biomarkers for the disease or as therapeutic targets due to their disease involvement. In this review, we will focus on the most important ncRNAs that are secreted by platelets (9 miRNA, 9 lncRNA and 5 circRNA), their association with CVD, and the contribution of these ncRNA to CVD risk to better understand the relation between ncRNA of human platelet and CVD.

Drug delivery systems are designed for the targeted delivery and controlled release of medicinal agents. Among the materials employed as drug delivery systems, dendrimers have gained increasing interest in recent years because of their properties and structural characteristics. The use of dendrimer-nanocarrier formulations enhances the safety and bioavailability, increases the solubility in water, improves stability and pharmacokinetic profile, and enables efficient delivery of the target drug to a specific site. However, the synthesis of dendritic architectures through convergent or divergent methods has drawbacks and limitations that disrupt aspects related to design and construction, and consequently, slow down the transfer from academia to industry. In that sense, the implementation of click chemistry has received increasing attention in the last years, as it offers new efficient approaches to obtain dendritic species in good yields and higher monodispersity. This review focuses on recent strategies for building dendrimer drug delivery systems using click reactions from 2015 to early 2021. The dendritic structures showed in this review are based on β -cyclodextrins (β-CD), poly(amidoamine) (PAMAM), dendritic poly (lysine) (PLLD), dimethylolpropionic acid (bis-MPA), phosphoramidate (PAD), and poly(propargyl alcohol-4-mercaptobutyric (PPMA).

As a novel group of non-coding RNAs, long non-coding RNA (lncRNAs) can substantially regulate various biological processes. Downregulated tumor-suppressive lncRNAs and upregulated oncogenic lncRNAs (onco-lncRNAs) have been implicated in gastric cancer (GC) development. These dysregulations have been associated with decreased chemosensitivity, inhibited apoptosis, and increased tumor migration in GC. Besides, growing evidence indicates that lncRNAs can be a valuable diagnostic and prognostic biomarker, and their expression levels are substantially associated with the clinicopathological features of affected patients. The current study aims to review the recent findings of the tumor-suppressive lncRNAs and onco-lncRNAs in GC development and highlight their therapeutic, diagnostic, and prognostic values in treating GC cells. Besides, it intends to highlight the future direction of lncRNAs in treating GC.

Background and Objective: Stroke, a leading cause of mortality and disability, characterized by neuronal death, can be induced by a reduction or interruption of blood flow. In this study, the role of Alamandine, a new peptide of the renin-angiotensin system, was evaluated in in-vitro and in-vivo brain ischemia models. Methods: In the in-vitro model, hippocampal slices from male C57/Bl6 mice were placed in a glucose-free aCSF solution and bubbled with 95% N2 and 5% CO2 to mimic brain ischemia. An Alamandine concentration-response curve was generated to evaluate cell damage, glutamatergic excitotoxicity, and cell death. In the in-vivo model, cerebral ischemia/ reperfusion was induced by bilateral occlusion of common carotid arteries (BCCAo-untreated) in SD rats. An intracerebroventricular injection of Alamandine was given 20–30 min before BCCAo. Animals were subjected to neurological tests 24 h and 72 h after BCCAo. Cytokine levels, oxidative stress markers, and immunofluorescence were assessed in the brain 72 h after BCCAo. Results: Alamandine was able to protect brain slices from cellular damage, excitotoxicity and cell death. When the Alamandine receptor was blocked, protective effects were lost. ICV injection of Alamandine attenuated neurological deficits of animals subjected to BCCAo and reduced the number of apoptotic neurons/cells. Furthermore, Alamandine induced anti-inflammatory effects in BCCAo animals as shown by reductions in TNFα, IL- 1β, IL-6, and antioxidant effects through attenuation of the decreased SOD, catalase, and GSH activities in the brain. Conclusion: This study showed, for the first time, a neuroprotective role for Alamandine in different ischemic stroke models.