In vitro antiviral activity of favipiravir and its 6- and 3-O-substituted derivatives against coronavirus: Acetylation leads to improvement of antiviral activity.

Favipiravir is currently approved for the treatment of the influenza virus and has shown encouraging results in terms of antiviral capacity in clinical studies against severe acute respiratory syndrome coronavirus 2. Favipiravir is a prodrug, where its favipiravir-ribofuranosyl-5B-triphosphate metabolite is capable of blocking RNA replication of the virus. However, the antiviral efficiency of favipiravir is limited by two factors: (i) low accumulation in plasma and rapid excretion/elimination post-administration and (ii) low conversion rate into the active metabolite. To tackle these problems, herein, we have designed new favipiravir analogues focusing on the replacement of the fluorine atom at the 6-position by halogen or hydrogen atoms and 3-O-functionalization with labile groups. The first type of functionalization seeks to increase the antiviral activity because of the better ability of the keto-tautomer as a function of the halogen, and it is hypothesized that the keto-tautomer tends to promote the formation of the ribofuranosyl-5B-triphosphate (RTP) metabolite. Meanwhile, the second type of functionalization seeks to promote lipophilicity and increase accumulation in cells. From the in vitro antiviral activity against two coronavirus models (bovine and human 229E), it was identified that the replacement did not improve the antiviral activity against both the models, which seems to be attributable to the low water solubility of these new 6-functionalized analogues. Meanwhile, with 3-O-functionalization, acetylation provided the most active compounds with higher half-maximal inhibitory concentration and selectivity than favipiravir, whereas benzylation/methanosulfonation yielded the least active compounds. In summary, acetylation is found to be a convenient functionalization to enhance the antiviral profile of favipiravir.

Effect of electron donors on CO2 fixation from a model cement industry flue gas by non-photosynthetic microbial communities in batch and continuous reactors.

The aim of this work was to evaluate the effect of different inorganic compounds as electron donors for the capture of CO2 from a model cement flue gas CO2 /O2 /N2 (4.2:13.5:82.3% v/v) using a non-photosynthetic microbial community. The inoculum obtained from a H2 -producing reactor was acclimated to CO2 consumption achieving 100% of CO2 removal after 45 days. Na2 S, MnCl2 , NaNO2 , NH4 Cl, Na2 S2 O3 , and FeCl2 were used as energy source for CO2 fixation by the acclimated microbial community showing different efficiencies, being Na2 S the best electron donor evaluated (100% of CO2 consumption) and FeCl2 the less effective (28% of CO2 consumption). In all treatments, acetate and propionate were the main endpoint metabolites. Moreover, scaling the process to a continuous laboratory biotrickling filter using Na2 S as energy source showed a CO2 consumption of up to 77%. Analysis of the microbial community showed that Na2 S and FeCl2 exerted a strong selection on the microbial members in the community showing significant differences (PERMANOVA, p = 0.0001) compared to the control and the other treatments. Results suggest that the CO2 fixing pathways used by the microbial community in all treatments were the 3-hydroxypropionate-4-hydroxybutyrate cycle and the Wood-Ljungdahl pathway.

Garbage in, garbage out: how reliable training data improved a virtual screening approach against SARS-CoV-2 MPro.

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence. Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy -performed in a large and diverse chemolibrary- complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening. Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 µM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12-20 µM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7-45 µM). Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known "garbage in, garbage out" machine learning principle.

Tautomerism and Rotamerism of Favipiravir and Halogenated Analogues in Solution and in the Solid State.

Favipiravir is an important selective antiviral against RNA-based viruses, and currently, it is being repurposed as a potential drug for the treatment of COVID-19. This type of chemical system presents different carboxamide-rotameric and hydroxyl-tautomeric states, which could be essential for interpreting its selective antiviral activity. Herein, the tautomeric 3-hydroxypyrazine/3-pyrazinone pair of favipiravir and its 6-substituted analogues, 6-Cl, 6-Br, 6-I, and 6-H, were fully investigated in solution and in the solid state through ultraviolet-visible, 1H nuclear magnetic resonance, infrared spectroscopy, and X-ray diffraction techniques. Also, a study of the gas phase was performed using density functional theory calculations. In general, the keto-enol balance in these 3-hydroxy-2-pyrazinecarboxamides is finely modulated by external and internal electrical variations via changes in solvent polarity or by replacement of substituents at position 6. The enol tautomer was prevalent in an apolar environment, whereas an increase in the level of the keto tautomer was favored by an increase in solvent polarity and, even moreso, with a strong hydrogen-donor solvent. Keto tautomerization was favored either in solution or in the solid state with a decrease in 6-substituent electronegativity as follows: H ≫ I ≈ Br > Cl ≥ F. Specific rotameric states based on carboxamide, "cisoide" and "transoide", were identified for the enol and keto tautomer, respectively; their rotamerism is dependent on the tautomerism and not the aggregation state.

Accuracy between 2D Photography and Dual-Structured Light 3D Facial Scanner for Facial Anthropometry: A Clinical Study.

(1) Background: Facial scanners are used in different fields of dentistry to digitalize the soft tissues of the patient's face. The development of technology has allowed the patient to have a 3-dimensional virtual representation, facilitating facial integration in the diagnosis and treatment plan. However, the accuracy of the facial scanner and the obtaining of better results with respect to the manual or two-dimensional (2D) method are questionable. The objective of this clinical trial was to evaluate the usefulness and accuracy of the 3D method (a dual-structured light facial scanner) and compare it with the 2D method (photography) to obtain facial analysis in the maximum intercuspation position and smile position. (2) Methods: A total of 60 participants were included, and nine facial landmarks and five interlandmarks distances were determined by two independent calibrated operators for each participant. All measurements were made using three methods: the manual method (manual measurement), the 2D method (photography), and the 3D method (facial scanner). All clinical and lighting conditions, as well as the specific parameters of each method, were standardized and controlled. The facial interlandmark distances were made by using a digital caliper, a 2D software program (Adobe Photoshop, version 21.0.2), and a 3D software program (Meshlab, version 2020.12), respectively. The data were analyzed by SPSS statistical software. The Kolmogorov-Smirnov test revealed that trueness and precision values were normally distributed (p > 0.05), so a Student's t-test was employed. (3) Results: Statistically significant differences (p ≤ 0.01) were observed in all interlandmark measurements in the 2D group (photography) to compare with the manual group. The 2D method obtained a mean accuracy value of 2.09 (±3.38) and 2.494 (±3.67) in maximum intercuspation and smile, respectively. On the other hand, the 3D method (facial scanner) obtained a mean accuracy value of 0.61 (±1.65) and 0.28 (±2.03) in maximum intercuspation and smile, respectively. There were no statistically significant differences with the manual method. (4) Conclusions: The employed technique demonstrated that it influences the accuracy of facial records. The 3D method reported acceptable accuracy values, while the 2D method showed discrepancies over the clinically acceptable limits.

One-step synthesis of favipiravir from Selectfluor® and 3-hydroxy-2-pyrazinecarboxamide in an ionic liquid.

Favipiravir is an important selective antiviral that emerged as an alternative against COVID-19 during the pandemic. Its synthesis has gained great interest and the conventional strategies proceed through multiple-step protocols (6-7 reaction steps), which involve, in addition, several drawbacks with global yields, lower than 34%. Herein, a simple, economical, eco-friendly and scalable (1 g) one-step protocol for the synthesis of favipiravir from the direct fluorination of the available 3-hydroxy-2-pyrazinecarboxamide with Selectfluor® is reported. The reaction proceeds easily in BF4-BMIM through a simple operational work-up, affording the favipiravir with a yield of 50% without the need of a special catalyst/additive. The key point of the present strategy was the use of the ionic liquid of BF4-BMIM, which helps to minimize the several chemical limitations derived from 3-hydroxy-2-pyrazinecarboxamide as a substrate for the direct Selectfluor-mediated fluorination. All these chemical reactivity aspects are also discussed in detail.

Surgically induced scleral necrosis associated with concomitant tuberculosis infection: a diagnostic challenge.

Objective: Surgically induced scleral necrosis (SISN) is a potentially blinding sequela that may occur after any ocular procedure. SISN in the context of active tuberculosis is seldom seen. We report a case of a patient with asymptomatic tuberculosis who developed SISN after pterygium surgery. Methods: A 76-year-old Mexican-mestizo woman from Veracruz, Mexico, was referred to our clinic because of severe disabling pain and scleral thinning in her right eye. Results: Tubercular-related SISN was finally diagnosed and managed successfully with antitubercular therapy, topical and systemic corticosteroids. Conclusion: Tuberculosis must be considered as a differential diagnosis of high-risk patients in the context of refractory SISN in endemic countries.

Anti-Trypanosoma cruzi Properties of Sesquiterpene Lactones Isolated from Stevia spp.: In Vitro and In Silico Studies.

Stevia species (Asteraceae) have been a rich source of terpenoid compounds, mainly sesquiterpene lactones, several of which show antiprotozoal activity. In the search for new trypanocidal compounds, S. satureiifolia var. satureiifolia and S. alpina were studied. Two sesquiterpene lactones, santhemoidin C and 2-oxo-8-deoxyligustrin, respectively, were isolated. These compounds were assessed in vitro against Trypanosoma cruzi stages, showing IC50 values of 11.80 and 4.98 on epimastigotes, 56.08 and 26.19 on trypomastigotes and 4.88 and 20.20 µM on amastigotes, respectively. Cytotoxicity was evaluated on Vero cells by the MTT assay. The effect of the compounds on trypanothyone reductase (TcTR), Trans-sialidase (TcTS) and the prolyl oligopeptidase of 80 kDa (Tc80) as potential molecular targets of T. cruzi was investigated. Santhemoidin C inhibited oligopeptidase activity when tested against recombinant Tc80 using a fluorometric assay, reaching an IC50 of 34.9 µM. Molecular docking was performed to study the interaction between santhemoidin C and the Tc80 protein, reaching high docking energy levels. Plasma membrane shedding and cytoplasmic vacuoles, resembling autophagosomes, were detected by transmission microscopy in parasites treated with santhemoidin C. Based on these results, santhemoidin C represents a promising candidate for further studies in the search for new molecules for the development of trypanocidal drugs.

Selective laser trabeculoplasty is safe and effective in patients previously treated with prostaglandin analogs: An evidence-based review.

PURPOSE: Prostaglandin analogs (PGAs) are first-line treatments for ocular hypertension (OHT) and open-angle glaucoma (OAG). However, frequent side effects and high costs hinder patient's compliance resulting in disease progression. Evidence suggests selective laser trabeculoplasty (SLT) may be considered a first-line treatment for OHT and OAG due to its safety profile, minor side effects, and reduced costs. Considering that PGAs and SLT share action mechanisms, it is hypothesized that previous PGA therapy may affect subsequent SLT efficacy. Therefore, we analyzed if PGAs reduce SLT efficacy. METHODS: An evidence-based review was performed to assess the safety and efficacy of SLT in patients previously treated with PGAs. For this purpose, we performed an extensive literature search using the National Library of Medicine's PubMed and Google Scholar database for all English language articles published until May 2021. RESULTS: There is evidence of non-superiority of PGAs therapy versus SLT for OHT and OAG. A multicenter, randomized, observer-masked clinical trial (RCT) of untreated OHT and OAG patients concluded that SLT should be offered as the first-line treatment for these patients. This study was supported by a meta-analysis of RCTs, comparing SLT efficacy versus antiglaucoma drugs only, with the advantage of an SLT lower rate of adverse effects. CONCLUSIONS: Cost-effectiveness, patient compliance, and antiglaucoma drugs' side effects, including higher surgical failure, favor consideration of SLT as first-line therapy for OAG and OHT. Furthermore, SLT efficacy does not seem to be affected by prior PGA administration; however, larger cohort, comparative, multicenter RCTs are necessary to answer this question.

Phenotypic and Target-Directed Screening Yields New Acaricidal Alternatives for the Control of Ticks.

Rhipicephalus microplus, the "common cattle tick", is the most important ectoparasite in livestock worldwide due to the economic and health losses it produces. This tick is a vector for pathogens of several tick-borne diseases. In Latin American countries, damages reach approximately USD 500 million annually due to tick infections, as well as tick-borne diseases. Currently, resistant populations for every chemical group of acaricides have been reported, posing a serious problem for tick control. This study aims to find new alternatives for controlling resistant ticks with compounds derived from small synthetic organic molecules and natural origins. Using BME26 embryonic cells, we performed phenotypic screening of 44 natural extracts from 10 Mexican plants used in traditional medicine, and 33 compounds selected from our chemical collection. We found 10 extracts and 13 compounds that inhibited cell growth by 50% at 50 µg/mL and 100 µM, respectively; the dose-response profile of two of them was characterized, and these compounds were assayed in vitro against different life stages of Rhipicephalus microplus. We also performed a target-directed screening of the activity of triosephosphate isomerase, using 86 compounds selected from our chemical collection. In this collection, we found the most potent and selective inhibitor of tick triosephosphate isomerase reported until now. Two other compounds had a potent acaricidal effect in vitro using adults and larvae when compared with other acaricides such as ivermectin and Amitraz. Those compounds were also selective to the ticks compared with the cytotoxicity in mammalian cells like macrophages or bovine spermatozoids. They also had a good toxicological profile, resulting in promising acaricidal compounds for tick control in cattle raising.

Risk factors for secondary Glaucoma in patients with Vogt-Koyanagi-Harada disease.

BACKGROUND/PURPOSE: Identify the prevalence and risk factors for secondary glaucoma among Mexican-mestizo patients with Vogt-Koyanagi-Harada Disease (VKH). METHODS: Retrospective cohort study analyzing the demographic, clinical, and epidemiological variables. Risk estimates were calculated using a Cox proportional hazards regression model. RESULTS: One hundred eyes of 50 patients, 44 (88%) women and 6 men (12%) with a median age of 35.5 years (IQR 29-46) and a median follow-up time of 72 months (IQR 13.7-126.7) were analyzed. The prevalence of glaucoma was 20%, with angle-closure accounting for 70% of all cases. Significant clinical risk factors for glaucoma development were a chronic recurrent stage at presentation (RR 2.88, 95% CI 1.11-12.63, p = 0.037), ≥ 2 episodes of recurrent anterior uveitis (RR 8.52, 95% CI 2.02-35.92, p < 0.001), angle-closure disease (ACD, RR 7.08, 95% CI 2.44-20.48, p < 0.001), iris bombé (RR 5.0, 95% CI 2.10-11.90, p < 0.001), and peripapillary atrophy (RR 3.56, 95% CI 1.43-8.85, p < 0.001). Exposure to > 24 months of oral (RR 9.33, 95% CI 2.21-39.28, p < 0.001) or > 12 months of topical corticosteroids (RR 3.88, 95% CI 1.31-11.46, p = 0.007) were associated with an increased likelihood for secondary glaucoma development. CONCLUSION: Glaucoma is a frequent complication of VKH, often attributed to mixed pathogenic mechanisms. Chronic disease at presentation, recurrent inflammation, angle-closure mechanisms, iris bombé, and peripapillary atrophy represent clinically significant risk factors for developing secondary glaucoma. Prompt and aggressive steroid-spearing immunosuppressive therapy for adequate inflammation control may lower the risk of glaucoma in VKH.

High prevalence of angle-closure glaucoma in Vogt-Koyanagi-Harada disease.

PURPOSE: To determine the prevalence, clinical characteristics, and mechanisms of secondary glaucoma in Vogt-Koyanagi-Harada (VKH) disease. METHODS: This retrospective, longitudinal observational study analyzed the demographic data, disease stage, glaucoma development, intraocular pressure, best-corrected visual acuity, lens status, optic nerve, gonioscopy, management, and visual outcomes of VKH disease. Clinical features were used to categorize the stage of VKH disease. VKH eyes were divided into two groups, with or without glaucoma, undergoing further analysis, including statistical analysis. RESULTS: 305 eyes of 155 patients with VKH disease with a median follow-up of 22 months were included. Secondary glaucoma developed in 67 (22%) eyes, most of which (64.2%) had chronic recurrent VKH at presentation. Angle-closure was present in 55 (82.1%) of glaucoma eyes. Peripheral anterior and posterior synechiae were present in 58 (86.6%) and 51 (76.1%) eyes, respectively. Pupillary block and posterior synechiae resulted in iris bombé in 17 (25.4%) eyes with glaucoma. At the last visit, visual acuity was worse in eyes with glaucoma (p < 0.001). CONCLUSION: We found that angle-closure disease is a significant cause of secondary glaucoma in VKH. Eyes with glaucoma were more likely to present in the chronic recurrent stage of the disease.

Identification of 2-(4-N,N-Dimethylaminophenyl)-5-methyl-1-phenethyl-1H-benzimidazole targeting HIV-1 CA capsid protein and inhibiting HIV-1 replication in cellulo.

The capsid (CA) subunit of the HIV-1 Gag polyprotein is involved in several steps of the viral cycle, from the assembly of new viral particles to the protection of the viral genome until it enters into the nucleus of newly infected cells. As such, it represents an interesting therapeutic target to tackle HIV infection. In this study, we screened hundreds of compounds with a low cost of synthesis for their ability to interfere with Gag assembly in vitro. Representatives of the most promising families of compounds were then tested for their ability to inhibit HIV-1 replication in cellulo. From these molecules, a hit compound from the benzimidazole family with high metabolic stability and low toxicity, 2-(4-N,N-dimethylaminophenyl)-5-methyl-1-phenethyl-1H-benzimidazole (696), appeared to block HIV-1 replication with an IC50 of 3 µM. Quantitative PCR experiments demonstrated that 696 does not block HIV-1 infection before the end of reverse transcription, and molecular docking confirmed that 696 is likely to bind at the interface between two monomers of CA and interfere with capsid oligomerization. Altogether, 696 represents a promising lead molecule for the development of a new series of HIV-1 inhibitors.

Novel tick glutathione transferase inhibitors as promising acaricidal compounds.

Ticks are important ectoparasites with a worldwide distribution. The most commonly used method for tick control involves the use of acaricides. The main problem is that its indiscriminate use has led to the selection of resistant tick populations. Glutathione transferases (GSTs) are enzymes that play an important role in the detoxification of several types of compounds used in commercial tick control products. This work aims to find new bioactive molecules through in vitro assays with a panel of 160 molecules with putative inhibitory activity on the Rhipicephalus microplus GST enzyme (RmGST). Also, selected molecules were tested against GSTs from other tick species; Rhipicephalus decoloratus, Amblyomma variegatum, Rhipicephalus appendiculatus, and Haemaphysalis longicornis. The first screening on RmGST identified 30 compounds with the ability to modify the enzymatic activity of this enzyme. These compounds included different chemical families, like chalcones, diarylideneketones, flavone, thiazoles, thiourea, steroids, thiadiazines, indazoles, and hydrazine. The most potent compounds against RmGST belong to the diarylideneketones family with an inhibition concentration of 50% of activity (IC50) between 7-50 µM. Interestingly, one of the most potent compounds was also an inhibitor of the GST from other tick species. Experiments with R. microplus adults and larvae showed toxicity at 150 µM, suggesting a potential acaricidal effect of these molecules.

Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease.

Chagas disease is caused by the protozoan Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America and is spreading worldwide, affecting over 10 million people. Hundreds of new compounds with trypanosomicidal action have been identified from different sources such as synthetic or natural molecules, but they have been deficient in several stages of drug development (toxicology, scaling-up, and pharmacokinetics). Previously, we described a series of compounds with simple structures, low cost, and environmentally friendly production with potent trypanosomicidal activity in vitro and in vivo. These molecules are from three different families: thiazolidenehydrazines, diarylideneketones, and steroids. From this collection, we explored their capacity to inhibit the triosephosphate isomerase and cruzipain of T. cruzi. Then, the mechanism of action was explored using NMR metabolomics and computational molecular dynamics. Moreover, the mechanism of death was studied by flow cytometry. Consequently, five compounds, 314, 793, 1018, 1019, and 1260, were pre-clinically studied and their pharmacologic profiles indicated low unspecific toxicity. Interestingly, synergetic effects of diarylideneketones 793 plus 1018 and 793 plus 1019 were evidenced in vitro and in vivo. In vivo, the combination of compounds 793 plus 1018 induced a reduction of more than 90% of the peak of parasitemia in the acute murine model of Chagas disease.

Fighting Against Stroke in Latin America: A Joint Effort of Medical Professional Societies and Governments.

Introduction: Stroke is one of the leading causes of death in Latin America, a region with countless gaps to be addressed to decrease its burden. In 2018, at the first Latin American Stroke Ministerial Meeting, stroke physician and healthcare manager representatives from 13 countries signed the Declaration of Gramado with the priorities to improve the region, with the commitment to implement all evidence-based strategies for stroke care. The second meeting in March 2020 reviewed the achievements in 2 years and discussed new objectives. This paper will review the 2-year advances and future plans of the Latin American alliance for stroke. Method: In March 2020, a survey based on the Declaration of Gramado items was sent to the neurologists participants of the Stroke Ministerial Meetings. The results were confirmed with representatives of the Ministries of Health and leaders from the countries at the second Latin American Stroke Ministerial Meeting. Results: In 2 years, public stroke awareness initiatives increased from 25 to 75% of countries. All countries have started programs to encourage physical activity, and there has been an increase in the number of countries that implement, at least partially, strategies to identify and treat hypertension, diabetes, and lifestyle risk factors. Programs to identify and treat dyslipidemia and atrial fibrillation still remained poor. The number of stroke centers increased from 322 to 448, all of them providing intravenous thrombolysis, with an increase in countries with stroke units. All countries have mechanical thrombectomy, but mostly restricted to a few private hospitals. Pre-hospital organization remains limited. The utilization of telemedicine has increased but is restricted to a few hospitals and is not widely available throughout the country. Patients have late, if any, access to rehabilitation after hospital discharge. Conclusion: The initiative to collaborate, exchange experiences, and unite societies and governments to improve stroke care in Latin America has yielded good results. Important advances have been made in the region in terms of increasing the number of acute stroke care services, implementing reperfusion treatments and creating programs for the detection and treatment of risk factors. We hope that this approach can reduce inequalities in stroke care in Latin America and serves as a model for other under-resourced environments.

Preclinical Studies in Anti-Trypanosomatidae Drug Development.

The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or "Pathogen Box" (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 µM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.