Trypanosoma cruzi (T. cruzi) is a parasite that affects humans and other mammals. T. cruzi depends on glycolysis as a source of adenosine triphosphate (ATP) supply, and triosephosphate isomerase (TIM) plays a key role in this metabolic pathway. This enzyme is an attractive target for the design of new trypanocidal drugs. In this study, a ligand-based virtual screening (LBVS) from the ZINC15 database using benzimidazole as a scaffold was accomplished. Later, a molecular docking on the interface of T. cruzi TIM (TcTIM) was performed and the compounds were grouped by interaction profiles. Subsequently, a selection of compounds was made based on cost and availability for in vitro evaluation against blood trypomastigotes. Finally, the compounds were analyzed by molecular dynamics simulation, and physicochemical and pharmacokinetic properties were determined using SwissADME software. A total of 1604 molecules were obtained as potential TcTIM inhibitors. BP2 and BP5 showed trypanocidal activity with half-maximal lytic concentration (LC₅₀) values of 155.86 and 226.30 µM, respectively. Molecular docking and molecular dynamics simulation analyzes showed a favorable docking score of BP5 compound on TcTIM. Additionally, BP5 showed a low docking score (−5.9 Kcal/mol) on human TIM compared to the control ligand (−7.2 Kcal/mol). Both compounds BP2 and BP5 showed good physicochemical and pharmacokinetic properties as new anti-T. cruzi agents.

Currently, antimicrobial resistance (AMR) is a serious health problem in the world, mainly because of the rapid spread of multidrug-resistant (MDR) bacteria. These include bacteria that produce β-lactamases, which confer resistance to β-lactams, the antibiotics with the most prescriptions in the world. Carbapenems are particularly noteworthy because they are considered the ultimate therapeutic option for MDR bacteria. However, this group of antibiotics can also be hydrolyzed by β-lactamases, including metallo-β-lactamases (MBLs), which have one or two zinc ions (Zn²⁺) on the active site and are resistant to common inhibitors of serine β-lactamases, such as clavulanic acid, sulbactam, tazobactam, and avibactam. Therefore, the design of inhibitors against MBLs has been directed toward various compounds, with groups such as nitrogen, thiols, and metal-binding carboxylates, or compounds such as bicyclic boronates that mimic hydrolysis intermediates. Other compounds, such as dipicolinic acid and aspergillomarasmin A, have also been shown to inhibit MBLs by chelating Zn^2+. In fact, recent inhibitors are based on Zn²⁺ chelation, which is an important factor in the mechanism of action of most MBL inhibitors. Therefore, in this review, we analyzed the current strategies for the design and mechanism of action of metal-ion-binding inhibitors that combat MDR bacteria.

Cutaneous leishmaniasis (CL) is a public health problem affecting more than 98 countries worldwide. No vaccine is available to prevent the disease, and available medical treatments cause serious side effects. Additionally, treatment failure and parasite resistance have made the development of new drugs against CL necessary. In this work, a virtual screening of natural products from the BIOFACQUIM and Selleckchem databases was performed using the method of molecular docking at the triosephosphate isomerase (TIM) enzyme interface of Leishmania mexicana (L. mexicana). Finally, the in vitro leishmanicidal activity of selected compounds against two strains of L. mexicana, their cytotoxicity, and selectivity index were determined. The top ten compounds were obtained based on the docking results. Four were selected for further in silico analysis. The ADME-Tox analysis of the selected compounds predicted favorable physicochemical and toxicological properties. Among these four compounds, S-8 (IC₅₀ = 55 µM) demonstrated a two-fold higher activity against the promastigote of both L. mexicana strains than the reference drug glucantime (IC₅₀ = 133 µM). This finding encourages the screening of natural products as new anti-leishmania agents.

Leishmania mexicana (L. mexicana) is a causal agent of cutaneous leishmaniasis (CL), a “Neglected disease”, for which the search for new drugs is a priority. Benzimidazole is a scaffold used to develop antiparasitic drugs; therefore, it is interesting molecule against L. mexicana. In this work, a ligand-based virtual screening (LBVS) of the ZINC15 database was performed. Subsequently, molecular docking was used to predict the compounds with potential binding at the dimer interface of triosephosphate isomerase (TIM) of L. mexicana (LmTIM). Compounds were selected on binding patterns, cost, and commercial availability for in vitro assays against L. mexicana blood promastigotes. The compounds were analyzed by molecular dynamics simulation on LmTIM and its homologous human TIM. Finally, the physicochemical and pharmacokinetic properties were determined in silico. A total of 175 molecules with docking scores between −10.8 and −9.0 Kcal/mol were obtained. Compound E2 showed the best leishmanicidal activity (IC₅₀ = 4.04 µM) with a value similar to the reference drug pentamidine (IC₅₀ = 2.23 µM). Molecular dynamics analysis predicted low affinity for human TIM. Furthermore, the pharmacokinetic and toxicological properties of the compounds were suitable for developing new leishmanicidal agents.

Background: Worldwide, the number of cases of parasitic diseases has been increasing; however, available treatments have variable adverse effects and low efficacy, mainly in Neglected Tropical Diseases such as Chagas disease and Leishmaniasis. Therefore, the development of new and more effective antiparasitic drugs is important. Natural products are the source of secondary metabolites with different biological activities, such as antibacterial, anticancer, anti-inflammatory, and antiparasitic. Objectives: In this work, secondary metabolites (phenols and terpenes) from natural products were selected to be evaluated against the epimastigotes of NINOA and A1 strains of Trypanosoma cruzi and the promastigotes of M379 strain and FCQEPS native isolate of Leishmania mexicana. Additionally, their cytotoxicity and selectivity index were determined. Methods: Eighteen secondary metabolites were evaluated in vitro against T. cruzi epimastigotes and L. mexicana promastigotes; additionally, their cytotoxicity on the J774.2 macrophage cell line was determined. Results: The compounds l-(-)-menthol (14, IC₅₀ = 24.52 µM) and β-citronellol (11, IC₅₀ = 21.54 µM) had higher trypanocidal activity than the reference drug (benznidazole) against NINOA and A1 strains of T. cruzi, respectively. On the other hand, para-anisyl alcohol (4, IC₅₀ = 34.89 µM) had higher leishmanicidal activity than the reference drug (glucantime^®) against M379 and the FCQEPS native isolate of L. mexicana. Finally, in silico, the determination of their pharmacokinetic and toxicological properties showed that they are promising candidates for oral and topical uses. Conclusions: This study opens the possibility of using secondary metabolites as scaffolds for access to the development of new molecules for the treatment of parasite diseases.

Protozoan parasite diseases cause significant mortality and morbidity worldwide. Factors such as climate change, extreme poverty, migration, and a lack of life opportunities lead to the propagation of diseases classified as tropical or non-endemic. Although there are several drugs to combat parasitic diseases, strains resistant to routinely used drugs have been reported. In addition, many first-line drugs have adverse effects ranging from mild to severe, including potential carcinogenic effects. Therefore, new lead compounds are needed to combat these parasites. Although little has been studied regarding the epigenetic mechanisms in lower eukaryotes, it is believed that epigenetics plays an essential role in vital aspects of the organism, from controlling the life cycle to the expression of genes involved in pathogenicity. Therefore, using epigenetic targets to combat these parasites is foreseen as an area with great potential for development. This review summarizes the main known epigenetic mechanisms and their potential as therapeutics for a group of medically important protozoal parasites. Different epigenetic mechanisms are discussed, highlighting those that can be used for drug repositioning, such as histone post-translational modifications (HPTMs). Exclusive parasite targets are also emphasized, including the base J and DNA 6 mA. These two categories have the greatest potential for developing drugs to treat or eradicate these diseases.