Evaluating alternative compounds for strongyloidiasis therapy: Novel insights from larval migration inhibition test.

Strongyloidiasis is a neglected tropical disease estimated to affect more than 600 million people worldwide. Recently, the World Health Organization road map on neglected tropical diseases 2021-2030 has put the focus on strongyloidiasis, including this disease within its mass drug administration campaigns. With the use of ivermectin in extensive treatment of all populations at-risk, identifying effective therapeutic alternatives is crucial in case ivermectin resistance arises. The objective of the present study was the development of a larval migration inhibition assay to evaluate the anthelmintic efficacy of commercial drugs and diamine and aminoalcohol derivatives against infective Strongyloides ratti third stage larvae. Through this technique, we successfully screened and estimated the in vitro anthelmintic efficacy of six commercial drugs, seven diamine derivatives and eight aminoalcohol derivatives. Unexpectedly, the half-maximal effective concentration of ivermectin and moxidectin (2.21 and 2.34 µM, respectively) were observed as the highest value obtained among all commercial drugs tested by this in vitro technique. Moreover, some diamine and aminoalcohol derivatives showed superior efficacy inhibiting S. ratti motility compared to ivermectin, with five compounds (AA23, AA34, AO2 AO7 and AO14b) also displaying selectivity indexes on HepG2 and Caco2 higher than 1. These findings underscore the potential of these derivatives as promising alternatives for strongyloidiasis treatment, warranting further investigation and in vivo efficacy assessment.

Free Radical Production Induced by Nitroimidazole Compounds Lead to Cell Death in Leishmania infantum Amastigotes.

Leishmania infantum is the vector-borne trypanosomatid parasite causing visceral leishmaniasis in the Mediterranean basin. This neglected tropical disease is treated with a limited number of obsolete drugs that are not exempt from adverse effects and whose overuse has promoted the emergence of resistant pathogens. In the search for novel antitrypanosomatid molecules that help overcome these drawbacks, drug repurposing has emerged as a good strategy. Nitroaromatic compounds have been found in drug discovery campaigns as promising antileishmanial molecules. Fexinidazole (recently introduced for the treatment of stages 1 and 2 of African trypanosomiasis), and pretomanid, which share the nitroimidazole nitroaromatic structure, have provided antileishmanial activity in different studies. In this work, we have tested the in vitro efficacy of these two nitroimidazoles to validate our 384-well high-throughput screening (HTS) platform consisting of L. infantum parasites emitting the near-infrared fluorescent protein (iRFP) as a biomarker of cell viability. These molecules showed good efficacy in both axenic and intramacrophage amastigotes and were poorly cytotoxic in RAW 264.7 and HepG2 cultures. Fexinidazole and pretomanid induced the production of ROS in axenic amastigotes but were not able to inhibit trypanothione reductase (TryR), thus suggesting that these compounds may target thiol metabolism through a different mechanism of action.

Treatment and Healing of Leishmaniasis in a Wolf in Semi-Captivity Regime from an Educational Center of Zamora Province (Spain).

Leishmaniasis in wild canids is a vector-borne disease caused in Europe by the protozoan parasite Leishmania infantum. To date, there is limited information on clinical signs and laboratory abnormalities in wolves due to leishmaniasis. The current clinical case report described a female Iberian wolf (Canis lupus signatus) housed in semi-captivity conditions at the Centro del Lobo Ibérico "Félix Rodríguez de la Fuente", in Robledo de Sanabria, Zamora (Spain), with an interdigital ulcerous wound at the right forepaw, hyper-gammaglobulinemia, and abnormal liver blood parameters. Definitive serodiagnosis of leishmaniasis was established using antileishmanial serum antibodies and PCR analysis of different biological samples. A gold-standard anti-L. infantum treatment protocol consisting in subcutaneous meglumine antimoniate and oral allopurinol combination was installed. However, the presence of pain at the site of injection due to meglumine antimoniate administration forced its substitution by oral miltefosine. A progressive reduction of the levels of anti-L. infantum serum antibodies and the concentrations of gamma-globulin fraction was detected after antileishmanial treatment as well as a decline of liver GPT. To our knowledge, this is the first case of leishmaniasis diagnosed in a wolf housed in semi-captivity conditions, with the condition subsequently treated and successfully cured.

Targeting Trypanothione Metabolism in Trypanosomatids.

Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected Tropical Diseases affecting millions of people worldwide, mainly in vulnerable territories of tropical and subtropical areas. In general, current treatments against these diseases are old-fashioned, showing adverse effects and loss of efficacy due to misuse or overuse, thus leading to the emergence of resistance. For these reasons, searching for new antitrypanosomatid drugs has become an urgent necessity, and different metabolic pathways have been studied as potential drug targets against these parasites. Considering that trypanosomatids possess a unique redox pathway based on the trypanothione molecule absent in the mammalian host, the key enzymes involved in trypanothione metabolism, trypanothione reductase and trypanothione synthetase, have been studied in detail as druggable targets. In this review, we summarize some of the recent findings on the molecules inhibiting these two essential enzymes for Trypanosoma and Leishmania viability.

Promising effects of 1,8 Cineole to control Giardia lamblia infection: Targeting the inflammation, oxidative stress, and infectivity.

Reportedly, synthetic drugs such as metronidazole, furazolidone, tinidazole, and quinacrine are used for the treatment of giardiasis but are associated with adverse effects. In this study, we aimed to investigate the in vitro and in vivo effects of eucalyptol (ECT, 1,8 cineole) alone and in combination with metronidazole (MNZ) on Giardia lamblia. The effects of ECT on cell viability, plasma membrane permeability, and gene expression levels of adenylate cyclase (AK) and extracellular signal kinases 1 and 2 (ERK1 and ERK2) in trophozoites of G. lamblia were assessed. In vivo, the effects of ECT alone and in combination with MNZ were assessed on mice infected with G. lamblia. In addition, the gene expression of inflammatory genes (e.g., TNF-α, IL-1ß, and IL-10) and antioxidant genes (catalase (CAT), superoxide dismutase 1 (SOD1), glutathione peroxidase 2 (GPX2)) was determined by real-time PCR. The IC50 values of ECT, MNZ, and ECT+MNZ on trophozoites were 30.2 µg/mL, 21.6 µg/mL, and 8.5 µg/mL, respectively. The estimated Fractional inhibitory concentration index (FICI) values for ECT and MNZ were 0.28 and 0.39, respectively. The application of ECT on G. lamblia trophozoites resulted in a dose-dependent increase in plasma membrane permeability, particularly at concentrations of ½ IC50 and IC50 (P < 0.05). The treatment of infected mice with various doses of ECT, mainly in combination with MNZ for 7 days, resulted in a significant decrease (P < 0.001) in the average number and viability of cysts. ECT, especially when combined with MNZ, caused a significant (P < 0.001) reduction in the expression of TNF-α and IL-6 genes, and an increase (P < 0.05) in the expression of IL-10 genes. ECT alone and mainly in combination with MNZ leads to a significant (P < 0.001) increase in the gene expression of CAT, SOD, and GPX genes. These findings demonstrate that the use of ECT in these doses, even for 14 days, does not have any toxic effects on the function of vital liver and kidney tissues. The study findings confirmed the promising effects of ECT against G. lamblia infection both in vitro and in vivo. Considering the possible mechanisms, ECT increases plasma membrane permeability and reduces the expression levels of infectivity-related genes. In addition, ECT suppresses inflammation and oxidative stress, controlling giardiasis in mice. More studies are needed to clarify these findings.

New benzimidazole derivative compounds with in vitro fasciolicidal properties.

BACKGROUND: Control of the zoonotic food-borne parasite Fasciola hepatica remains a major challenge in humans and livestock. It is estimated that annual economic losses due to fasciolosis can reach US$3.2 billion in agriculture and livestock. Moreover, the wide distribution of drug-resistant parasite populations and the absence of a vaccine threaten sustainable control, reinforcing the need for novel flukicides. METHODS: The present work analyses the flukicidal activity of a total of 70 benzimidazole derivatives on different stages of F. hepatica. With the aim to select the most potent ones, and screenings were first performed on eggs at decreasing concentrations ranging from 50 to 5 µM and then on adult worms at 10 µM. Only the most effective compounds were also evaluated using a resistant isolate of the parasite. RESULTS: After the first screenings at 50 and 10 µM, four hit compounds (BZD31, BZD46, BZD56, and BZD59) were selected and progressed to the next assays. At 5 µM, all hit compounds showed ovicidal activities higher than 71% on the susceptible isolate, but only BZD31 remained considerably active (53%) when they were tested on an albendazol-resistant isolate, even with values superior to the reference drug, albendazole sulfoxide. On the other hand, BZD59 displayed a high motility inhibition when tested on adult worms from an albendazole-resistant isolate after 72 h of incubation. CONCLUSIONS: BZD31 and BZD59 compounds could be promising candidates for the development of fasciolicidal compounds or as starting point for the new synthesis of structure-related compounds.

In Vitro and Ex Vivo Synergistic Effect of Pyrvinium Pamoate Combined with Miltefosine and Paromomycin against Leishmania.

One of the major drawbacks of current treatments for neglected tropical diseases is the low safety of the drugs used and the emergence of resistance. Leishmaniasis is a group of neglected diseases caused by protozoa of the trypanosomatidae family that lacks preventive vaccines and whose pharmacological treatments are scarce and unsafe. Combination therapy is a strategy that could solve the above-mentioned problems, due to the participation of several mechanisms of action and the reduction in the amount of drug necessary to obtain the therapeutic effect. In addition, this approach also increases the odds of finding an effective drug following the repurposing strategy. From the previous screening of two collections of repositioning drugs, we found that pyrvinium pamoate had a potent leishmanicidal effect. For this reason, we decided to combine it separately with two clinically used leishmanicidal drugs, miltefosine and paromomycin. These combinations were tested in axenic amastigotes of Leishmania infantum obtained from bone marrow cells and in intramacrophagic amastigotes obtained from primary cultures of splenic cells, both cell types coming from experimentally infected mice. Some of the combinations showed synergistic behavior, especially in the case of the combination of pyrvinium pamoate with paromomycin, and exhibited low cytotoxicity and good tolerability on intestinal murine organoids, which reveal the potential of these combinations for the treatment of leishmaniasis.

Polyamine Metabolism for Drug Intervention in Trypanosomatids.

Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world's poorest people: African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease and different types of leishmaniasis. Different metabolic pathways have been targeted to find antitrypanosomatid drugs, including polyamine metabolism. Since their discovery, the naturally occurring polyamines, putrescine, spermidine and spermine, have been considered important metabolites involved in cell growth. With a complex metabolism involving biosynthesis, catabolism and interconversion, the synthesis of putrescine and spermidine was targeted by thousands of compounds in an effort to produce cell growth blockade in tumor and infectious processes with limited success. However, the discovery of eflornithine (DFMO) as a curative drug against sleeping sickness encouraged researchers to develop new molecules against these diseases. Polyamine synthesis inhibitors have also provided insight into the peculiarities of this pathway between the host and the parasite, and also among different trypanosomatid species, thus allowing the search for new specific chemical entities aimed to treat these diseases and leading to the investigation of target-based scaffolds. The main molecular targets include the enzymes involved in polyamine biosynthesis (ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase), enzymes participating in their uptake from the environment, and the enzymes involved in the redox balance of the parasite. In this review, we summarize the research behind polyamine-based treatments, the current trends, and the main challenges in this field.

Secretory IgA as Biomarker for Gastrointestinal Nematodes Natural Infection in Different Breed Sheep.

Specific IgA antibody has been shown to play an important role in resistance to gastrointestinal nematode (GIN) infections in sheep, particularly in Teladorsagia circumcincta parasitosis. In some breeds, negative associations have been shown between IgA levels and worm burden in experimentally infected sheep. In the present study, we have studied the relationship between IgA levels in naturally infected sheep (582 ewes in total; 193 younger than one year old and 389 older than one year old) and fecal egg count (FEC) in the Assaf, Castellana, and Churra breeds. ELISA assays were performed to measure IgA levels against the somatic antigen of T. circumcincta third larval stage (L3) and a 203-amino-acid fragment of the protein disulfide isomerase from the same GIN species. A multilevel random intercept model was developed to predict the infection risk according to age or breed. Spearman's correlation rank was used for statistical analysis. The prediction model showed that breed was not an influential factor in this study, although the Assaf breed could be considered slightly more susceptible than the others. In addition, age affected the infection risk, with the young ewes more susceptible to infection than the adult groups, except for the Castellana breed, whose risk of infection was similar at all ages. The most significant positive association was found between FEC and IgA measured in the nasal secretions of young ewes using both antigens (Rho = 0.5; p = 0.00); the correlation of FEC with IgA in serum was moderately significant (Rho = 0.306; p = 0.00). Comparing both antigens, the protein disulfide isomerase antigen was less reactive than the somatic antigen from L3. In conclusion, under natural conditions, specific IgA against GIN was positively associated with FEC in sheep, with nasal secretions from young animals being the sample where this association is stronger, which, therefore, could be used as a marker of infection in further studies.

Occurrence of Leishmaniasis in Iberian Wolves in Northwestern Spain.

Canine leishmaniasis is an important vector-borne protozoan disease in dogs that is responsible for serious deterioration in their health. In the Iberian Peninsula, as in most countries surrounding the Mediterranean Sea, canine leishmaniasis is caused by Leishmania infantum (zymodeme MON-1), a digenetic trypanosomatid that harbors in the parasitophorous vacuoles of host macrophages, causing severe lesions that can lead to death if the animals do not receive adequate treatment. Canine leishmaniasis is highly prevalent in Spain, especially in the Mediterranean coastal regions (Levante, Andalusia and the Balearic Islands), where the population of domestic dogs is very high. However, the presence of this disease has been spreading to other rural and sparsely populated latitudes, and cases of leishmaniasis have been reported for years in wildlife in northwestern Spain. This work describes for the first time the presence of wolves that tested positive for leishmaniasis in the vicinity of the Sierra de la Culebra (Zamora province, northwestern Spain), a protected sanctuary of this canid species, using PCR amplification of L. infantum DNA from different non-invasive samples such as buccal mucosa and those from both ears and hair. In addition to live animals (21), samples from carcasses of mainly roadkill animals (18) were also included and analyzed using the same technique, obtaining a positivity rate of 18 of the 39 wolves sampled (46.1%) regardless of their origin.

Gel-Free Tools for Quick and Simple Screening of Anti-Topoisomerase 1 Compounds.

With the increasing need for effective compounds against cancer or pathogen-borne diseases, the development of new tools to investigate the enzymatic activity of biomarkers is necessary. Among these biomarkers are DNA topoisomerases, which are key enzymes that modify DNA and regulate DNA topology during cellular processes. Over the years, libraries of natural and synthetic small-molecule compounds have been extensively investigated as potential anti-cancer, anti-bacterial, or anti-parasitic drugs targeting topoisomerases. However, the current tools for measuring the potential inhibition of topoisomerase activity are time consuming and not easily adaptable outside specialized laboratories. Here, we present rolling circle amplification-based methods that provide fast and easy readouts for screening of compounds against type 1 topoisomerases. Specific assays for the investigation of the potential inhibition of eukaryotic, viral, or bacterial type 1 topoisomerase activity were developed, using human topoisomerase 1, Leishmania donovani topoisomerase 1, monkeypox virus topoisomerase 1, and Mycobacterium smegmatis topoisomerase 1 as model enzymes. The presented tools proved to be sensitive and directly quantitative, paving the way for new diagnostic and drug screening protocols in research and clinical settings.

Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates.

Due to the lack of specific vaccines, management of the trypanosomatid-caused neglected tropical diseases (sleeping sickness, Chagas disease and leishmaniasis) relies exclusively on pharmacological treatments. Current drugs against them are scarce, old and exhibit disadvantages, such as adverse effects, parenteral administration, chemical instability and high costs which are often unaffordable for endemic low-income countries. Discoveries of new pharmacological entities for the treatment of these diseases are scarce, since most of the big pharmaceutical companies find this market unattractive. In order to fill the pipeline of compounds and replace existing ones, highly translatable drug screening platforms have been developed in the last two decades. Thousands of molecules have been tested, including nitroheterocyclic compounds, such as benznidazole and nifurtimox, which had already provided potent and effective effects against Chagas disease. More recently, fexinidazole has been added as a new drug against African trypanosomiasis. Despite the success of nitroheterocycles, they had been discarded from drug discovery campaigns due to their mutagenic potential, but now they represent a promising source of inspiration for oral drugs that can replace those currently on the market. The examples provided by the trypanocidal activity of fexinidazole and the promising efficacy of the derivative DNDi-0690 against leishmaniasis seem to open a new window of opportunity for these compounds that were discovered in the 1960s. In this review, we show the current uses of nitroheterocycles and the novel derived molecules that are being synthesized against these neglected diseases.

Molecular-level strategic goals and repressors in Leishmaniasis - Integrated data to accelerate target-based heterocyclic scaffolds.

Leishmaniasis is a complex of neglected tropical diseases caused by various species of leishmanial parasites that primarily affect the world's poorest people. A limited number of standard medications are available for this disease that has been used for several decades, these drugs have many drawbacks such as resistance, higher cost, and patient compliance, making it difficult to reach the poor. The search for novel chemical entities to treat leishmaniasis has led to target-based scaffold research. Among several identified potential molecular targets, enzymes involved in the purine salvage pathway include polyamine biosynthetic process, such as arginase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase, trypanothione reductase as well as enzymes in the DNA cell cycle, such as DNA topoisomerases I and II plays vital role in the life cycle survival of leishmanial parasite. This review mainly focuses on various heterocyclic scaffolds, and their specific inhibitory targets against leishmaniasis, particularly those from the polyamine biosynthesis pathway and DNA topoisomerases with estimated activity studies of various heterocyclic analogs in terms of their IC50 or EC50 value, reported molecular docking analysis from available published literatures.

Miltefosine and Nifuratel Combination: A Promising Therapy for the Treatment of Leishmania donovani Visceral Leishmaniasis.

Visceral leishmaniasis is a neglected vector-borne tropical disease caused by Leishmania donovani and Leishmania infantum that is endemic not only in East African countries, but also in Asia, regions of South America and the Mediterranean Basin. For the pharmacological control of this disease, there is a limited number of old and, in general, poorly adherent drugs, with a multitude of adverse effects and low oral bioavailability, which favor the emergence of resistant pathogens. Pentavalent antimonials are the first-line drugs, but due to their misuse, resistant Leishmania strains have emerged worldwide. Although these drugs have saved many lives, it is recommended to reduce their use as much as possible and replace them with novel and more friendly drugs. From a commercial collection of anti-infective drugs, we have recently identified nifuratel-a nitrofurantoin used against vaginal infections-as a promising repurposing drug against a mouse model of visceral leishmaniasis. In the present work, we have tested combinations of miltefosine-the only oral drug currently used against leishmaniasis-with nifuratel in different proportions, both in axenic amastigotes from bone marrow and in intracellular amastigotes from infected Balb/c mouse spleen macrophages, finding a potent synergy in both cases. In vivo evaluation of oral miltefosine/nifuratel combinations using a bioimaging platform has revealed the potential of these combinations for the treatment of this disease.

Inspection of in-house designed novel thiochromone amino-acid conjugate derivatives as Lm-NMT inhibitor - An in-silico analysis.

Leishmaniasis is a complex neglected tropical disease caused by various leishmanial parasites that primarily affect the world's poorest people. A limited number of standard medications are available for this disease that has been used for several decades, which have drawbacks such as resistance, higher cost, and patient compliance, making it difficult to reach the poor. The search for novel chemical entities to treat leishmaniasis has led to target-based scaffold research. Thiochromone moieties in conjugation with aromatic amino acids have been considered for the study, along with possible substitutions of the electron-withdrawing and electron-donating groups. N-myristoyl transferase (NMT) has been selected as the molecular target for the study responsible for protein-protein interaction and ribosylation of proteins necessary for the growth inside the human body of the parasite. The designed novel thiochromone analogs were docked against the selected leishmanial NMT using thein-silico methods, physicochemical and toxicity properties were predicted, and Structure-Activity Relationship was also established in-silico. Finally, a molecular dynamics simulation study for 100 ns gave an idea about the stability of the protein-ligand complex. A time frame analysis of each 10 ns confirmation was also studied to understand better the putative binding pattern designed analogs.

Antileishmanial Effect of 1,5- and 1,8-Substituted Fused Naphthyridines.

In the absence of a vaccine, there is a need to find new drugs for the treatment of neglected tropical diseases, such as leishmaniasis, that can overcome the many drawbacks of those currently used. These disadvantages include cost, the need to maintain a cold chain, the route of administration, the associated adverse effects and the generation of resistance. In this work we have evaluated the antileishmanial effect of 1,5- and 1,8-substituted fused naphthyridines through in vitro and ex vivo assays, using genetically modified axenic and intramacrophagic Leishmania infantum amastigotes. The toxicity of these compounds has been tested in the mammalian host cell using murine splenic macrophages, as well as in murine intestinal organoids (miniguts) in order to assess their potential for oral administration. The 1,8- derivatives showed greater leishmanicidal activity and the presence of a nitrogen atom in the fused ring to the naphthyridine was important to increase the activity of both types of molecules. The aromatization of the pyridine ring also had marked differences in the activity of the compounds.

Microbial community in resistant and susceptible Churra sheep infected by Teladorsagia circumcincta.

Gastrointestinal nematodes (GIN) are a major threat to health and welfare in small ruminants worldwide. Teladorsagia circumcincta is a nematode that inhabits the abomasum of sheep, especially in temperate regions, causing important economic losses. Given that T. circumcincta and microbiome share the same niche, interactions between them and the host are expected. Although it is known that within a sheep breed there are animals that are more resistant than others to infection by GIN, it is not known if the microbiome influences the phenotype of these animals. Under this condition, 12 sheep were classified according to their cumulative faecal egg count (cFEC) at the end of a first experimental infection, 6 as resistant group (RG) and 6 as susceptible group (SG) to T. circumcincta infection. Then, all sheep were experimentally infected with 70,000 L3 of T. circumcincta and at day 7 days post-infection were euthanized. At necropsy, gastric mucosa and gastric content from abomasum were collected to extract bacterial DNA and sequence V3-V4 region from 16S rRNA gene using Ilumina technology. After bioanalysis performed, results showed that α-diversity and ß-diversity remained similar in both groups. However, resistant phenotype sheep showed a higher number of bacteria butyrate-fermenting species as Clostridium sensu stricto 1 (abundance in RG: 1.29% and in SG: 0.069%; p = 0.05), and Turicibacter (abundance in RG: 0.31% and in SG: 0.027%; p = 0.07) in gastric content but also Serratia spp in gastric mucosa (abundance in RG: 0.12% and in SG: 0.041%; p = 0.07). A trend towards a significant negative correlation between cFEC and Clostridium sensu stricto 1 abundance in gastric content was detected (r = - 0.537; p = 0.08). These data suggest that microbiome composition could be another factor associated with the development of the resistant phenotype modifying the interaction with the host and the in last instance affecting the individual risk of infection.

Novel compound shows in vivo anthelmintic activity in gerbils and sheep infected by Haemonchus contortus.

The control of gastrointestinal nematodes in livestock is becoming increasingly difficult due to the limited number of available drugs and the rapid development of anthelmintic resistance. Therefore, it is imperative to develop new anthelmintics that are effective against nematodes. Under this context, we tested the potential toxicity of three compounds in mice and their potential anthelmintic efficacy in Mongolian gerbils infected with Haemonchus contortus. The compounds were selected from previous in vitro experiments: two diamine (AAD-1 and AAD-2) and one benzimidazole (2aBZ) derivatives. 2aBZ was also selected to test its efficacy in sheep. In Mongolian gerbils, the benzimidazole reduced the percentage of pre-adults present in the stomach of gerbils by 95% at a dose of 200 mg/kg. In sheep, there was a 99% reduction in the number of eggs shed in faeces after 7 days at a dose of 120 mg/kg and a 95% reduction in the number of worm adults present in the abomasum. In conclusion, 2aBZ could be considered a promising candidate for the treatment of helminth infections in small ruminants.

Benzimidazole and aminoalcohol derivatives show in vitro anthelmintic activity against Trichuris muris and Heligmosomoides polygyrus.

BACKGROUND: Infections by gastrointestinal nematodes cause significant economic losses and disease in both humans and animals worldwide. The discovery of novel anthelmintic drugs is crucial for maintaining control of these parasitic infections. METHODS: For this purpose, the aim of the present study was to evaluate the potential anthelmintic activity of three series of compounds against the gastrointestinal nematodes Trichuris muris and Heligmosomoides polygyrus in vitro. The compounds tested were derivatives of benzimidazole, lipidic aminoalcohols and diamines. A primary screening was performed to select those compounds with an ability to inhibit T. muris L1 motility by > 90% at a single concentration of 100 µM; then, their respective IC50 values were calculated. Those compounds with IC50 < 10 µM were also tested against the adult stage of T. muris and H. polygyrus at a single concentration of 10 µM. RESULTS: Of the 41 initial compounds screened, only compounds AO14, BZ6 and BZ12 had IC50 values < 10 µM on T. muris L1 assay, showing IC50 values of 3.30, 8.89 and 4.17 µM, respectively. However, only two of them displayed activity against the adult stage of the parasites: BZ12 killed 81% of adults of T. muris (IC50 of 8.1 µM) and 53% of H. polygyrus while BZ6 killed 100% of H. polygyrus adults (IC50 of 5.3 µM) but only 17% of T. muris. CONCLUSIONS: BZ6 and BZ12 could be considered as a starting point for the synthesis of further structurally related compounds.

Design, synthesis and evaluation of novel phenanthridine triazole analogs as potential antileishmanial agents.

Aim: To synthesize and screen phenanthridine and 1,2,3-triazole derivatives for antileishmanial activity. Methodology: Synthesized analogs were tested for antileishmanial activity against transgenic strain of Leishmania infantum promastigotes and ex vivo infections. Results: Compounds T01, T08 and T11 revealed significant activity with EC50 <30 µm and lacked toxicity in mouse spleen and HepG2 cells. T01 with EC50 3.07 µm is fourfold more potent than the drug miltefosine (EC50 12.6 µM) against L. infantum promastigotes. In silico studies indicate that the analogs are nontoxic. A molecular docking analysis was also carried out on the T01 and T08 to investigate the binding pattern at the active site of the chosen target trypanothione reductase. Conclusion: The results of this study reveal that phenanthridine triazoles exhibit antileishmanial activity.