Methoxy Chalcone Derivatives: Promising Antimicrobial Agents Against Phytopathogens.

Chalcone (E)-1,3-diphenyl-prop-2-en-1-one and a series of 14 methoxylated derivatives have been synthesized via Claisen-Schmidt aldol condensation and characterized by FTIR, CG/MS/DIC, 1D (1H and 13C), 2D (COSY, HSQC, and HMBC) NMR, and EMAR techniques. All molecules were tested at 1 mM concentration for antifungal (Sclerotium sp., Macrophomina phaesolina and Colletotrichum gloeosporioides), antibacterial (Acidovorax citrulli two strains), and antiprotozoal (Phytomonas serpens) activities. Unmodified chalcone (CH0) and derivatives CH1, CH2, CH8 stood out in terms of antifungal activity. CH0 presented IC50 values of 47.3 µM (9.8 µg/mL) for the fungus C. gloeosporioides. In addition, fluorescence microscopy indicated that CH0 promoted loss of hyphal cell membrane integrity. The CH1 and CH2 derivatives promoted the inhibition of Sclerotium sp. with IC50 of 127.5 µM (32.9 µg/mL) and 110.4 µM (29.6 µg/mL), respectively. All molecules showed high activity against the phytoparasite P. serpens with IC50 values of 0.98, 2.40, 10.25, and 3.11 µM for the derivatives CH2, CH3, CH5 and CH14 respectively. The results demonstrated that derivatives methoxylated in both rings (CH2) as well as derivatives with a furan ring associated with the methoxy group in ring A, as well as unmodified chalcone can be promising agricultural fungicides for controlling the fungi studied.

Trends in Nanoparticles for Leishmania Treatment: A Bibliometric and Network Analysis.

Leishmaniasis is a neglected tropical illness with a wide variety of clinical signs ranging from visceral to cutaneous symptoms, resulting in millions of new cases and thousands of fatalities reported annually. This article provides a bibliometric analysis of the main authors' contributions, institutions, and nations in terms of productivity, citations, and bibliographic linkages to the application of nanoparticles (NPs) for the treatment of leishmania. The study is based on a sample of 524 Scopus documents from 1991 to 2022. Utilising the Bibliometrix R-Tool version 4.0 and VOSviewer software, version 1.6.17 the analysis was developed. We identified crucial subjects associated with the application of NPs in the field of antileishmanial development (NPs and drug formulation for leishmaniasis treatment, animal models, and experiments). We selected research topics that were out of date and oversaturated. Simultaneously, we proposed developing subjects based on multiple analyses of the corpus of published scientific literature (title, abstract, and keywords). Finally, the technique used contributed to the development of a broader and more specific "big picture" of nanomedicine research in antileishmanial studies for future projects.

Computer-aided drug design approaches applied to screen natural product's structural analogs targeting arginase in Leishmania spp.

Introduction: Leishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Methods: Hence, this study aims to screen for natural products' structural analogs as new drug candidates against leishmaniasis. We applied Computer-aided drug design (CADD) approaches, such as virtual screening, molecular docking, molecular dynamics simulation, molecular mechanics-generalized Born surface area (MM-GBSA) binding free estimation, and free energy perturbation (FEP) aiming to select structural analogs from natural products that have shown anti-leishmanial and anti-arginase activities and that could bind selectively against the Leishmania arginase enzyme. Results: The compounds 2H-1-benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), echioidinin, and malvidin showed good results against arginase targets from three parasite species and negative results for potential toxicities. The echioidinin and malvidin ligands generated interactions in the active center at pH 2.0 conditions by MM-GBSA and FEP methods. Conclusions: This work suggests the potential anti-leishmanial activity of the compounds and thus can be further in vitro and in vivo experimentally validated.

Antiparasitic Derivatives of the Furoquinoline Alkaloids Kokusaginine And Flindersiamine.

We report the synthesis of 16 new compounds obtained from kokusaginine and flindersiamine, the main alkaloids isolated from the bark of Balfourodendron riedelianum. The activity of the compounds against axenic cultures of Trypanosoma cruzi epimastigtotes and trypomastigotes, as well as intracellular amastigotes, is described, together with their cytotoxic activity against three different human cell lines. The synthetic strategy for the preparation of the new compounds was based on the reactivity at the C4 position of the furoquinoline core towards nucleophiles. The new derivatives were synthesized by a Buchwald-Hartwig reaction, in most cases under green, solvent-free conditions. Compounds 1 c and 1 e displayed better in-vitro activity against trypomastigotes than benznidazole and nifurtimox (positive controls) with IC50 <4 µM. In addition, both compounds were not cytotoxic against the three human cell lines K562 (erytroleukimia), LM2 (breast cancer), and HaCat (keratinocyte). Interestingly, when evaluated against intracellular amastigotes, compound 1 c was able to significantly reduce the number of this parasite form, compared to the negative control.

Furanocoumarins from Ruta chalepensis with Amebicide Activity.

Entamoeba histolytica (protozoan; family Endomoebidae) is the cause of amoebiasis, a disease related to high morbidity and mortality. Nowadays, this illness is considered a significant public health issue in developing countries. In addition, parasite resistance to conventional medicinal treatment has increased in recent years. Traditional medicine around the world represents a valuable source of alternative treatment for many parasite diseases. In a previous paper, we communicated about the antiprotozoal activity in vitro of the methanolic (MeOH) extract of Ruta chalepensis (Rutaceae) against E. histolytica. The plant is extensively employed in Mexican traditional medicine. The following workup of the MeOH extract of R. chalepensis afforded the furocoumarins rutamarin (1) and chalepin (2), which showed high antiprotozoal activity on Entamoeba histolytica trophozoites employing in vitro tests (IC50 values of 6.52 and 28.95 µg/mL, respectively). Therefore, we offer a full scientific report about the bioguided isolation and the amebicide activity of chalepin and rutamarin.

Synthesis and Antiprotozoal Profile of 3,4,5-Trisubstituted Isoxazoles.

A series of 60 4-aminomethyl 5-aryl-3-substituted isoxazoles were synthesized by an efficient method and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi, protozoa that cause the neglected tropical diseases leishmaniasis and Chagas disease, respectively. Thirteen compounds exhibited a selective index greater than 10. The series of 3-N-acylhydrazone isoxazole derivatives bearing the bithiophene core exhibited the best antiparasitic effects.

Three decades of clinical trials on immunotherapy for human leishmaniases: a systematic review and meta-analysis.

Aim: Current treatments for leishmaniases are not satisfactory, thus alternatives are needed. We searched for clinical trials with immunotherapeutic approaches for patients with leishmaniasis. Materials & methods: Out of 205 articles, 24 clinical trials were selected, and eight submitted to meta-analysis. Results: A reduction in healing time was observed in patients with tegumentary leishmaniasis treated with pentavalent antimony plus granulocyte-macrophage colony-stimulating factor, and therapeutic vaccines. Overall meta-analysis indicated that immunotherapy associated with the standard chemotherapy generated a significantly reduced risk of treatment failure than the pentavalent antimony alone (p = 0.03). Conclusion: Our review confirmed the efficacy of immunotherapies for the treatment of cutaneous and visceral leishmaniasis and highlighted the importance of clinical trials using immunotherapies for leishmaniases.

Comparing the Antileishmanial Activity of Gold(I) and Gold(III) Compounds in L. amazonensis and L. braziliensis in Vitro.

A series of mononuclear coordination or organometallic AuI /AuIII complexes (1-9) have been comparatively studied in vitro for their antileishmanial activity against promastigotes and amastigotes, the clinically relevant parasite form, of Leishmania amazonensis and Leishmania braziliensis. One of the cationic AuI bis-N-heterocyclic carbenes (3) has low EC50 values (ca. 4 µM) in promastigotes cells and no toxicity in host macrophages. Together with two other AuIII complexes (6 and 7), the compound is also extremely effective in intracellular amastigotes from L. amazonensis. Initial mechanistic studies include an evaluation of the gold complexes' effect on L. amazonensis' plasma membrane integrity.

Antiprotozoal Activity against Entamoeba histolytica of Flavonoids Isolated from Lippia graveolens Kunth.

Amebiasis caused by Entamoeba histolytica is nowadays a serious public health problem worldwide, especially in developing countries. Annually, up to 100,000 deaths occur across the world. Due to the resistance that pathogenic protozoa exhibit against commercial antiprotozoal drugs, a growing emphasis has been placed on plants used in traditional medicine to discover new antiparasitics. Previously, we reported the in vitro antiamoebic activity of a methanolic extract of Lippia graveolens Kunth (Mexican oregano). In this study, we outline the isolation and structure elucidation of antiamoebic compounds occurring in this plant. The subsequent work-up of this methanol extract by bioguided isolation using several chromatographic techniques yielded the flavonoids pinocembrin (1), sakuranetin (2), cirsimaritin (3), and naringenin (4). Structural elucidation of the isolated compounds was achieved by spectroscopic/spectrometric analyses and comparing literature data. These compounds revealed significant antiprotozoal activity against E. histolytica trophozoites using in vitro tests, showing a 50% inhibitory concentration (IC50) ranging from 28 to 154 µg/mL. Amebicide activity of sakuranetin and cirsimaritin is reported for the first time in this study. These research data may help to corroborate the use of this plant in traditional Mexican medicine for the treatment of dyspepsia.

Pneumonia por toxoplasmose em paciente imunocompetente / Toxoplasma pneumonia in an immunocompetent patient: case repor

Com grande distribuição mundial e incidência significativa, a toxoplamose é uma doença comum em mamíferos e pássaros, causada pelo protozoário Toxoplasma gondii. No homem, o parasitismo na fase proliferativa intracelular pode se apresentar sem sintomas, ou causar clínica transitória caracterizada por febre, fadiga e linfadenopatia. Por se tratar de patologia com sintomas inespecíficos e comuns a muitas outras, é fundamental a correta pesquisa de diagnósticos diferenciais, como citomegalovírus e Epstein-Barr. Relatamos o caso de um jovem e hígido, que desenvolveu pneumonia e, após confirmação sorológica para toxoplasmose e o tratamento adequado, apresentou melhora clínica.

With great worldwide distribution and significant incidence, toxoplamosis is a common disease in mammals and birds, caused by the protozoan Toxoplasma gondii. In humans, the parasitism in its intracellular proliferative phase may present no symptoms, or cause a transient condition characterized by fever, fatigue, and lymphadenopathy. Because it is a pathology with nonspecific symptoms that are common to many other conditions, it is fundamental to find the correct research of differential diagnoses, such as for Cytomegalovirus and Epstein Barr. We report a case of a young and healthy man who developed pneumonia and, after serological confirmation for toxoplasmosis and the appropriate treatment, presented clinical improvement

Safety and efficacy of current alternatives in the topical treatment of cutaneous leishmaniasis: a systematic review.

Studies of topical treatments for leishmaniasis were systematically reviewed, to evaluate the therapeutic efficacy, safety and any adverse effects of these treatments. The papers identified in the databases PubMed and Web of Knowledge involved eight studies with a total of 1744 patients. The majority of trials was from Iran (4/8), covered a period of 8 years (2003-2011), and included patients 4-85 years of age. The most frequent Leishmania species in the studies were L. tropica (4/8) and L. major (2/8). The treatments administered were thermotherapy, paromomycin and combinations, CO2 laser, 5-aminolevulinic acid hydrochloride (10%) plus visible red light (633 nm) and cryotherapy. Six articles reported cure rates over 80·0%. Six studies reported on failure rates, three of them reporting rates lower than 10%. Four studies did not report relapses or recurrences, while the other studies reported low rates (1·8-6·3%). The most common adverse effects of the topical treatments were redness/erythema, pain, pruritus burning, oedema, vesicles and hyper- or hypopigmentation. The results provide strong evidence that the treatments topical evaluated showed high cure rates, safety and effectiveness, with low side-effects, relapse and recurrence rates, except for cryotherapy, which showed a moderate cure rate.

Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii.

Two obligate intracellular parasites, Trypanosoma cruzi, the agent of Chagas disease, and Toxoplasma gondii, an agent of toxoplasmosis, upregulate the mevalonate pathway of their host cells upon infection, which suggests that this host pathway could be a potential drug target. In this work, a number of compounds structurally related to WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, were designed, synthesized, and evaluated for their effect on T. cruzi and T. gondii growth in tissue culture cells. Two fluorine-containing derivatives, the 3-(3-fluorophenoxy)- and 3-(4-fluorophenoxy)phenoxyethyl thiocyanates, exhibited half-maximal effective concentration (EC50 ) values of 1.6 and 4.9 µm, respectively, against tachyzoites of T. gondii, whereas they showed similar potency to WC-9 against intracellular T. cruzi (EC50 values of 5.4 and 5.7 µm, respectively). In addition, 2-[3- (phenoxy)phenoxyethylthio]ethyl-1,1-bisphosphonate, which is a hybrid inhibitor containing 3-phenoxyphenoxy and bisphosphonate groups, has activity against T. gondii proliferation at sub-micromolar levels (EC50 =0.7 µm), which suggests a combined inhibitory effect of the two functional groups.

New 1,3-thiazole derivatives and their biological and ultrastructural effects on Trypanosoma cruzi.

In previous studies, the compound 3-(bromopropiophenone) thiosemicarbazone was described as a potent anti-Trypanosoma cruzi and cruzain inhibitor. In view to optimize this activity, 1,3-thiazole core was used as building-block strategy to access new lead generation of anti T. cruzi agents. In this way a series of thiazole derivatives were synthesized and most of these derivatives exhibited antiparasitic activity similar to benznidazole (Bzd). Among them, compounds (1c) and (1g) presented better selective index (SI) than Bzd. In addition, compounds showed inhibitory activity against the cruzain protease. As observed by electron microscopy, compound (1c) treatment caused irreversible and specific morphological changes on ultrastructure organization of T. cruzi, demonstrating that this class of compounds is killing parasites.

Diagnóstico de parasitas gastrintestinais de tamanduás-bandeira (Myrmecophaga tridactyla, Linnaeus, 1758) mantidos em cativeiro e terapia farmacológica 0 relato de caso / Diagnosis of gastrointestinal parasites of giant anteaters (Myrmecophaga tridactyla, Linnaeus, 1758) kept in captivity and drug therapy a case report / Diagnóstico de parásitos grastrointestinales de osos hormigueros gigantes (Myrmecophaga tridactyla, Linnaeus, 1758) en cautiverio y su terapéutica farmacológica reporte de un caso

Foram realizados exames coproparasitológicos de sedimentação e flutuação em sete tamanduás-bandeira (Myrmecophaga tridactyla) cativos, mantidos no Laboratório de Pesquisa em Animais Silvestres (Lapas/UFU). Dos sete tamanduás-bandeira examinados, quatro apresentaram ovos de Strongyloides spp, quatro apresentaram oocistos de Entamoeba spp, um apresentou ovos de Ancylostoma spp e um apresentou ovos de acantocéfalo. Os indivíduos que apresentaram ovos ou oocistos nos exames foram medicados com metronidazol por via oral na dose de 40mg/kg, durante três dias, além de 5mg/kg de praziquantel e 14,4mg/kg de pirantel por via oral em dose única. Nos animais submetidos a tratamento antiparasitário, os exames foram repetidos após trinta dias, revelando que os quatro animais previamente infectados por Strongyloides spp continuavam infectados. Os ovos e oocistos dos outros parasitas encontrados antes da medicação estavam ausentes.(AU)

Flotation and sedimentation parasitological exams were carried out in seven captive giant anteaters (Myrmecophaga tridactyla) kept at the Laboratory for Wild Animal Research (LAPAS/UFU). Four animals presented eggs of Strongyloides spp, four presented cysts of Entamoeba spp, one presented eggs of Ancylostoma spp and one presented eggs of acanthocephala. Individuals who were positive for either eggs or cysts were treated orally for three days with 40mg/kg metronidazole, plus a single oral dose of 5mg/kg prazyquantel and 14.4mg/kg pyrantel. Exams were repeated thirty days post treatment, revealing that the four animals infected by Strongyloides spp were still infected. The eggs and cysts of other parasites found prior to medication were absent.(AU)

Resumen: Fueron realizados exámenes coproparasitológicos de sedimentación y flotación en siete osos hormigueros gigantes (Myrmecophaga tridactyla) mantenidos en cautiverio en el Laboratorio de Pesquisa de Animales Silvestres (Lapas/UFU). De los siete animales examinados, cuatro presentaron huevos de Strongyloides spp, cuatro evidenciaron ooquistes de Entamoeba spp, uno presentó huevos de Ancylostoma spp y otro huevos de acantocéfalo. Los animales que presentaron huevos u ooquistes en los exámenes, fueron tratados con metronidazol por vía oral (40mg/kg) durante tres días, además de praziquantel (5mg/kg) y pirantel vía oral a dosis única. En los animales que fueron sometidos al tratamiento antiparasitario, se repitieron los exámenes después de 30 días. En ese momento pudo comprobarse que los cuatro osos que previamente estaban infectados con Strongyloides, continuaban en la misma condición. Los animales que habían presentado huevos y ooquistes en el primer examen, resultaron negativos en esta última evaluación.(AU)

Diagnóstico de parasitas gastrintestinais de tamanduás-bandeira (Myrmecophaga tridactyla, Linnaeus, 1758) mantidos em cativeiro e terapia farmacológica 0 relato de caso / Diagnosis of gastrointestinal parasites of giant anteaters (Myrmecophaga tridactyla, Linnaeus, 1758) kept in captivity and drug therapy – a case report / Diagnóstico de parásitos grastrointestinales de osos hormigueros gigantes (Myrmecophaga tridactyla, Linnaeus, 1758) en cautiverio y su terapéutica farmacológica – reporte de un caso

Foram realizados exames coproparasitológicos de sedimentação e flutuação em sete tamanduás-bandeira (Myrmecophaga tridactyla) cativos, mantidos no Laboratório de Pesquisa em Animais Silvestres (Lapas/UFU). Dos sete tamanduás-bandeira examinados, quatro apresentaram ovos de Strongyloides spp, quatro apresentaram oocistos de Entamoeba spp, um apresentou ovos de Ancylostoma spp e um apresentou ovos de acantocéfalo. Os indivíduos que apresentaram ovos ou oocistos nos exames foram medicados com metronidazol por via oral na dose de 40mg/kg, durante três dias, além de 5mg/kg de praziquantel e 14,4mg/kg de pirantel por via oral em dose única. Nos animais submetidos a tratamento antiparasitário, os exames foram repetidos após trinta dias, revelando que os quatro animais previamente infectados por Strongyloides spp continuavam infectados. Os ovos e oocistos dos outros parasitas encontrados antes da medicação estavam ausentes.

Flotation and sedimentation parasitological exams were carried out in seven captive giant anteaters (Myrmecophaga tridactyla) kept at the Laboratory for Wild Animal Research (LAPAS/UFU). Four animals presented eggs of Strongyloides spp, four presented cysts of Entamoeba spp, one presented eggs of Ancylostoma spp and one presented eggs of acanthocephala. Individuals who were positive for either eggs or cysts were treated orally for three days with 40mg/kg metronidazole, plus a single oral dose of 5mg/kg prazyquantel and 14.4mg/kg pyrantel. Exams were repeated thirty days post treatment, revealing that the four animals infected by Strongyloides spp were still infected. The eggs and cysts of other parasites found prior to medication were absent.

Resumen: Fueron realizados exámenes coproparasitológicos de sedimentación y flotación en siete osos hormigueros gigantes (Myrmecophaga tridactyla) mantenidos en cautiverio en el Laboratorio de Pesquisa de Animales Silvestres (Lapas/UFU). De los siete animales examinados, cuatro presentaron huevos de Strongyloides spp, cuatro evidenciaron ooquistes de Entamoeba spp, uno presentó huevos de Ancylostoma spp y otro huevos de acantocéfalo. Los animales que presentaron huevos u ooquistes en los exámenes, fueron tratados con metronidazol por vía oral (40mg/kg) durante tres días, además de praziquantel (5mg/kg) y pirantel vía oral a dosis única. En los animales que fueron sometidos al tratamiento antiparasitario, se repitieron los exámenes después de 30 días. En ese momento pudo comprobarse que los cuatro osos que previamente estaban infectados con Strongyloides, continuaban en la misma condición. Los animales que habían presentado huevos y ooquistes en el primer examen, resultaron negativos en esta última evaluación.

Parasitoses intestinais: uma revisão sobre seus aspectos sociais, epidemiológicos, clínicos e terapêuticos / Intestinal parasitic diseases: a review of social, epidemiologic, clinical and therapeutic aspects

No presente estudo, as enteroparasitoses mais prevalentes no Brasil foram avaliadas segundo determinantes sociais,aspectos epidemiológicos, clínicos e terapêuticos. Através de breve revisão de literatura e com base nos resultadosde estudos de prevalência, são sintetizados achados que corroboram a associação de sua alta prevalência à pobrezae ao subdesenvolvimento. Foi dedicada especial atenção adoenças tais como a esquistossomose, a giardíase, a ancilostomíase,a amebíase, a estrongiloidíase, a ascaridíase e ateníase. Também estão sumarizadas referências às principaisdrogas antiparasitárias, modo de ação, efeitos adversose avaliação da eficácia de cada tratamento. Destaca-se aimportante atualização dos profissionais da atenção primária nesse assunto e o reconhecimento de que esforços são necessários para maximizar os benefícios adquiridos com o tratamento medicamentoso e manter a qualidadeda saúde da população através da melhoria das condiçõesde saneamento e educação em saúde.

In the present study, the most prevalent enteroparasitosisin Brazil were assessed according to social, epidemiologic,clinical and therapeutic aspects. Through a brief review of the literature, and based on the results of several prevalence studies, high prevalence rates associated with povertyin under developed nations were found and stressed inthe article. Diseases such as schistosomiasis, giardiasis,ancylostomiasis, strongyloidiasis, ascaridiasis and taeniasiswere given more emphasis. There are also references to themain antiparasitc drugs and to their mechanism of action,adverse effects, and efficacy. Primary health care professional smust keep abreast of this subject, and be able toacknowledge that efforts are necessary in order to maximize the benefits of drug treatment and maintain the quality of health of the population, through the improvement of sanitary conditions and health education.

Búsqueda de nuevos agentes antiprotozoarios selectivos / In search of new selective antiprotozoal agents

Se da la información general sobre los fármacos antiprotozoarios que están usándose en clínica, se discuten nuevas dianas de los parásitos protozoarios útiles en la búsqueda de nuevos agentes antiprotozoarios, enfocando la atención al rol biológico de las proteasas de los parásitos protozoarios. Esta información importante será útil para los estudiantes e investigadores que se interesen a los problemas de química medicinal (un área naciente en Colombia) cuál aporta mucho al desarrollo de ciencias médicas. [Kouznetsov V, Meléndez C. Búsqueda de nueveos agentes antiprotozoarios selectivos. MedUNAB 2009; 12:33-45].

The information is given on the antiprotozoal drugs used in clinic, new useful targets of the parasites protozoa in the search of new antiprotozoal agents are discussed, focusing the attention to the biological role of proteasas of the parasites protozoa. This important information will be useful for students and researchers, which are interested in the problems of medicinal chemistry (an appearing area in Colombia) that gives much to the development of medicine sciences. [Kouznetsov V, Meléndez C. In search of new selective antiprotozoal agents. MedUNAB 2009; 12:33-45].