Discovery of Novel Inhibitors of Cruzain Cysteine Protease of .

Chagas disease (CD) is a parasitic disease endemic in several developing countries. According to the World Health Organization, approximately 6-8 million people worldwide are inflicted by CD. The scarcity of new drugs, mainly for the chronic phase, is the main reason for treatment limitation in CD.

Exploring the dark side of tertiary and quaternary structure dynamics in FBPaseII.

Tuberculosis (TB) is a major global cause of mortality, primarily stemming from latent tuberculosis infection (LTBI). Failure to fully treat LTBI can result in drug-resistant forms of TB. Therefore, it is essential to develop novel drugs with unique mechanisms of action to combat TB effectively.

Covalent Inhibitors for Neglected Diseases: An Exploration of Novel Therapeutic Options.

Neglected diseases, primarily found in tropical regions of the world, present a significant challenge for impoverished populations. Currently, there are 20 diseases considered neglected, which greatly impact the health of affected populations and result in difficult-to-control social and economic consequences. Unfortunately, for the majority of these diseases, there are few or no drugs available for patient treatment, and the few drugs that do exist often lack adequate safety and efficacy.

Exploring the conformational dynamics of the CRD4: a model for receptor lysosomal activity shifts in search of 'sweet' and 'sour' states.

The macrophage mannose receptor (RMM) is a crucial component of the immune system involved in immune responses, inflammation resolution, and tissue remodeling. When RMM is activated by a specific ligand, it undergoes internalization, forming an endosome that matures into a lysosome. Within the lysosome, structural changes in RMM facilitate the dissociation of ligands for further processing.

The Role of Flavanones as Scaffolds for the Development of New Treatments against Malaria and African and American Trypanosomiases.

Parasitic infections are diseases transmitted by parasites usually found in contaminated food, water, or insect bites. Generally classified as neglected tropical diseases, malaria and trypanosomiases are some of the most prominent parasitic diseases that cause significant loss of life annually. In 2020, an estimated 241 million malaria cases were reported, with 627,000 deaths worldwide.

Neglected tropical diseases and systemic racism especially in Brazil: from socio-economic aspects to the development of new drugs.

Neglected tropical diseases (NTDs) are highly prevalent communicable diseases in tropical and subtropical countries, generally not economically attractive for drug development and related to poverty. In Brazil, more specifically, socioeconomic inequalities and health indicators are strongly influenced by skin color, race, and ethnicity, due to the historical process of slavery. In this context, it is important to understand the concept of systemic racism: a form of indirect racial discrimination present in many institutions, which determines the process of illness and death of the black population, the ethnic group most affected by these diseases.

Resveratrol and Curcumin for Chagas Disease Treatment-A Systematic Review.

Chagas disease (CD) is a neglected protozoan infection caused by , which affects about 7 million people worldwide. There are two available drugs in therapeutics, however, they lack effectiveness for the chronic stage-characterized mainly by cardiac (i.e.

Therapeutic Potential of Flavonoid Derivatives for Certain Neglected Tropical Diseases.

Background: Neglected tropical diseases (NTDs) are infectious diseases that mostly affect people living in tropical and subtropical regions, especially in impoverished areas. Ubiquitously found in plants, flavonoids are a group of compounds that have been reported to exhibit a wide range of biological activities against parasites (Leishmania sp., Trypanosoma cruzi, Trypanosoma brucei, Brugia malayi, etc.

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against .

Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic.

Triazole-containing Heterocycles: Privileged Scaffolds in Anti- Drug Development.

Background: Chagas disease is a potentially life-threatening illness caused by the protozoan parasite Trypanosoma cruzi and is transmitted to humans through the excreta of infected blood-sucking triatomine bugs. According to the World Health Organization, 6 to 7 million people are infected with T. cruzi worldwide, mainly in Latin America, with more than 10000 deaths annually.

Malaria and tuberculosis as diseases of neglected populations: state of the art in chemotherapy and advances in the search for new drugs.

Malaria and tuberculosis are no longer considered to be neglected diseases by the World Health Organization. However, both are huge challenges and public health problems in the world, which affect poor people, today referred to as neglected populations. In addition, malaria and tuberculosis present the same difficulties regarding the treatment, such as toxicity and the microbial resistance.

Perspectives About Self-Immolative Drug Delivery Systems.

Self-immolative drug delivery system is one of the delivery systems, which have drawn attention, in recent research, highlighting the improvement they generate in drug selectivity and efficacy. Self-immolative linkers, or spacers, are covalent groups, which have the role of cleavaging two bonds between a protector group and a drug, in the case of drug delivery systems, after a stimuli.The cascade of reactions allows to control the release of the drug.

Searching for drugs for Chagas disease, leishmaniasis and schistosomiasis: a review.

Chagas disease, leishmaniasis and schistosomiasis are neglected diseases (NDs) and are a considerable global challenge. Despite the huge number of people infected, NDs do not create interest from pharmaceutical companies because the associated revenue is generally low. Most of the research on these diseases has been conducted in academic institutions.

Dendrimers in the context of nanomedicine.

Dendrimers are globular structures, presenting an initiator core, repetitive layers starting radially from the core and terminal groups on the surface, resembling tree architecture. These structures have been studied in many biological applications, as drug, DNA, RNA and proteins delivery, as well as imaging and radiocontrast agents. With reference to that, this review focused in providing examples of dendrimers used in nanomedicine.

Flavonoids as efficient scaffolds: Recent trends for malaria, leishmaniasis, Chagas disease, and dengue.

Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually with over 500,000 deaths. Among the NTDs, some of the most severe consist of leishmaniasis, Chagas disease, and dengue. The impact of the combined NTDs closely rivals that of malaria.

Targeting Groups Employed in Selective Dendrons and Dendrimers.

The design of compounds with directed action to a defined organ or tissue is a very promising approach, since it can decrease considerably the toxicity of the drug/bioactive compound. For this reason, this kind of strategy has been greatly important in the scientific community. Dendrimers, on the other hand, comprise extremely organized macromolecules with many peripheral functionalities, stepwise controlled synthesis, and defined size.

New Advances in General Biomedical Applications of PAMAM Dendrimers.

Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named 'starburst polymers'.

Targeting Leishmania amazonensis amastigotes through macrophage internalisation of a hydroxymethylnitrofurazone nanostructured polymeric system.

Dextran-coated poly (n-butyl cyanoacrylate) nanoparticles (PBCA-NPs) were prepared and were evaluated for enhanced delivery of a promising anti-Leishmania drug candidate, hydroxymethylnitrofurazone (NFOH), to phagocytic cells. Currently available chemotherapy for leishmaniasis, such as pentavalent antimonials, presents low safety and efficacy. Furthermore, widespread drug resistance in leishmaniasis is rapidly emerging.

Dendrimer Prodrugs.

The main objective of this review is to describe the importance of dendrimer prodrugs in the design of new drugs, presenting numerous applications of these nanocomposites in the pharmaceutical field. Therefore, the use of dendrimer prodrugs as carrier for drug delivery, to improve pharmacokinetic properties of prototype, to promote drug sustained-release, to increase selectivity and, consequently, to decrease toxicity, are just some examples of topics that have been extensively reported in the literature, especially in the last decade. The examples discussed here give a panel of the growing interest dendrimer prodrugs have been evoking in the scientific community.

Drug design for neglected disease in Brazil.

Neglected tropical diseases (NTD) are a group of 17 diseases transmitted by virus, protozoa, helminthes and bacteria. These illnesses are responsible for millions of deaths per year, affecting mainly the poorest populations in the world. The therapeutic drugs available are obsolete, toxic, have questionable efficacy and there are reports of resistance.

Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity.

Hybrid bioisoster derivatives from N-acylhydrazones and furoxan groups were designed with the objective of obtaining at least a dual mechanism of action: cruzain inhibition and nitric oxide (NO) releasing activity. Fifteen designed compounds were synthesized varying the substitution in N-acylhydrazone and in furoxan group as well. They had its anti-Trypanosoma cruzi activity in amastigotes forms, NO releasing potential and inhibitory cruzain activity evaluated.

Medicinal Chemistry of New Compounds to Treat Tuberculosis.

Tuberculosis (TB), a 19th century disease, is still present in the beginning of the Third Millennium. It has been considered pandemic, since around two billion people are infected with M. tuberculosis.

Pharmacokinetics of hydroxymethylnitrofurazone, a promising new prodrug for Chagas' disease treatment.

Hydroxymethylnitrofurazone (NFOH) is a trypanocidal prodrug of nitrofurazone (NF), devoid of mutagenic toxicity. The purpose of this work was to study the chemical conversion of NFOH into NF in sodium acetate buffer (pH 1.2 and 7.

Molecular modeling approach to predict a binding mode for the complex methotrexate-carboxypeptidase G2.

Carboxypeptidase G(2) (CPG(2)) is a zinc-metalloenzyme employed in a range of cancer chemotherapy strategies by activating selectively nontoxic prodrugs into cytotoxic drugs in tumor as well as in the treatment of intoxication caused by high-doses of the anticancer drug methotrexate (MTX). CPG(2) catalyzes the hydrolytic cleavage of C-terminal of glutamate moiety from folic acid and analogues. Regardless of its extensive application, its mechanism of catalysis has not yet been determined and, so far, no co-crystallized complex has been published.