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1.
Parasitology ; 148(11): 1392-1400, 2021 09.
Article in English | MEDLINE | ID: mdl-34162452

ABSTRACT

Acanthamoeba spp. are widely distributed in the environment and cause serious infections in humans. Treatment of Acanthamoeba infections is very challenging and not always effective which requires the development of more efficient drugs against Acanthamoeba spp. The purpose of the present study was to test medicinal plants that may be useful in the treatment of Acanthamoeba spp. Here we evaluated the trophozoital and cysticidal activity of 13 flavonoid glycosides isolated from Delphinium gracile, D. staphisagria, Consolida oliveriana and from Aconitum napellus subsp. Lusitanicum against the amoeba Acanthamoeba castellanii. AlamarBlue Assay Reagent® was used to determine the activity against trophozoites of A. castellanii, and cytotoxic using Vero cells. Cysticidal activity was assessed on treated cysts by light microscopy using a Neubauer chamber to quantify cysts and trophozoites. Flavonoids 1, 2, 3 and 4 showed higher trophozoital activity and selectivity indexes than the reference drug chlorhexidine digluconate. In addition, flavonoid 2 showed 100% cysticidal activity at a concentration of 50 µm, lower than those of the reference drug and flavonoid 3 (100 µm). These results suggest that flavonoids 2 and 3 might be used for the development of novel therapeutic approaches against Acanthamoeba infections after satisfactory in vivo evaluations.


Subject(s)
Acanthamoeba/drug effects , Aconitum/chemistry , Delphinium/chemistry , Glycosides/pharmacology , Plant Extracts/pharmacology , Ranunculaceae/chemistry , Acanthamoeba/growth & development , Animals , Chlorocebus aethiops , Flavonoids/chemistry , Flavonoids/isolation & purification , Flavonoids/pharmacology , Flavonoids/toxicity , Glycosides/chemistry , Glycosides/isolation & purification , Glycosides/toxicity , Inhibitory Concentration 50 , Molecular Structure , Plant Extracts/isolation & purification , Trophozoites/drug effects , Trophozoites/growth & development , Vero Cells/drug effects
2.
J Antimicrob Chemother ; 75(6): 1537-1545, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32129856

ABSTRACT

OBJECTIVES: We report the in vivo trypanocidal activity of the bacteriocin AS-48 (lacking toxicity), which is produced by Enterococcus faecalis, against the flagellated protozoan Trypanosoma cruzi, the aetiological agent of Chagas' disease. METHODS: We determined the in vivo activity of AS-48 against the T. cruzi Arequipa strain in BALB/c mice (in both acute and chronic phases of Chagas' disease). We evaluated the parasitaemia, the reactivation of parasitaemia after immunosuppression and the nested parasites in the chronic phase by PCR in target tissues. RESULTS: AS-48 reduced the parasitaemia profile in acute infection and showed a noteworthy reduction in the parasitic load in chronic infection after immunosuppression according to the results obtained by PCR (double-checking to demonstrate cure). CONCLUSIONS: AS-48 is a promising alternative that provides a step forward in the development of a new therapy against Chagas' disease.


Subject(s)
Chagas Disease , Trypanosoma cruzi , Animals , Chagas Disease/drug therapy , Mice , Mice, Inbred BALB C , Parasite Load , Parasitemia/drug therapy
3.
J Nat Prod ; 83(12): 3571-3583, 2020 12 24.
Article in English | MEDLINE | ID: mdl-33253573

ABSTRACT

The life-long and life-threatening Chagas disease is one of the most neglected tropical diseases caused by the protozoan parasite Trypanosoma cruzi. It is a major public health problem in Latin America, as six to seven million people are infected, being the principal cause of mortality in many endemic regions. Moreover, Chagas disease has become widespread due to migrant populations. Additionally, there are no vaccines nor effective treatments to fight the disease because of its long-term nature and complex pathology. Therefore, these facts emphasize how crucial the international effort for the development of new treatments against Chagas disease is. Here, we present the in vitro and in vivo trypanocidal activity of some oxygenated abietane diterpenoids and related compounds. The 1,4-benzoquinone 15, not yet reported, was identified as a fast-acting trypanocidal drug with efficacy against different strains in vitro and higher activity and lower toxicity than benznidazole in both phases of murine Chagas disease. The mode of action was also evaluated, suggesting that quinone 15 kills T. cruzi by inducing mitochondrion-dependent necrosis through a bioenergetics collapse caused by a mitochondrial membrane depolarization and iron-containing superoxide dismutase inhibition. Therefore, the abietane 1,4-benzoquinone 15 can be considered as a new candidate molecule for the development of an appropriate and commercially accessible anti-Chagas drug.


Subject(s)
Abietanes/pharmacology , Mitochondria/metabolism , Trypanocidal Agents/pharmacology , Abietanes/chemistry , Animals , Humans , Mice , Necrosis
4.
Parasitol Res ; 119(9): 2943-2954, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32607710

ABSTRACT

Trypanosomatidae is a family of unicellular parasites belonging to the phylum Euglenozoa, which are causative agents in high impact human diseases such as Leishmaniasis, Chagas disease and African sleeping sickness. The impact on human health and local economies, together with a lack of satisfactory chemotherapeutic treatments and effective vaccines, justifies stringent research efforts to search for new disease therapies. Here, we present in vitro trypanocidal activity data and mode of action data, repositioning leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salts against Trypanosoma cruzi, the aetiological agent of Chagas disease. This disease is one of the most neglected tropical diseases and is a major public health issue in Central and South America. The disease affects approximately 6-7 million people and is widespread due to increased migratory movements. We screened a suite of leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salt compounds, of which compounds 13, 20 and 21 were identified as trypanocidal drugs. These compounds caused cell death in a mitochondrion-dependent manner through a bioenergetic collapse. Moreover, compounds 13 and 20 showed a remarkable inhibition of iron superoxide dismutase activity of T. cruzi, a key enzyme in the protection from the damage produced by oxidative stress.


Subject(s)
Chagas Disease/drug therapy , Pyridinium Compounds/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Cell Death/drug effects , Drug Repositioning , Humans , Leishmaniasis/drug therapy , Mitochondrial Membranes/metabolism , Oxidative Stress/drug effects , South America , Superoxide Dismutase/metabolism , Trypanosomiasis, African/drug therapy
5.
Bioorg Med Chem ; 27(17): 3902-3917, 2019 09 01.
Article in English | MEDLINE | ID: mdl-31345745

ABSTRACT

The current chemotherapy against Chagas disease is inadequate and insufficient. A series of ten Mannich base-type derivatives have been synthesized to evaluate their in vitro antichagasic activity. After a preliminary screening, compounds 7 and 9 were subjected to in vivo assays in a murine model. Both compounds caused a substantial decrease in parasitemia in the chronic phase, which was an even better result than that of the reference drug benznidazole. In addition, compound 9 also showed better antichagasic activity during the acute phase. Moreover, metabolite excretion, effect on mitochondrial membrane potential and the inhibition of superoxide dismutase (SOD) studies were also performed to identify their possible mechanism of action. Finally, docking studies proposed a binding mode of the Fe-SOD enzyme similar to our previous series, which validated our design strategy. Therefore, the results suggest that these compounds should be considered for further preclinical evaluation as antichagasic agents.


Subject(s)
Chagas Disease/drug therapy , Mannich Bases/pharmacology , Superoxide Dismutase/antagonists & inhibitors , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Cells, Cultured , Chagas Disease/metabolism , Chlorocebus aethiops , Cyclophosphamide/administration & dosage , Cyclophosphamide/pharmacology , Dose-Response Relationship, Drug , Humans , Injections, Intraperitoneal , Mannich Bases/chemical synthesis , Mannich Bases/chemistry , Mice , Mice, Inbred BALB C , Molecular Docking Simulation , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Superoxide Dismutase/metabolism , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry , Trypanosoma cruzi/metabolism , Vero Cells
6.
Bioorg Med Chem ; 27(5): 865-879, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30728107

ABSTRACT

Chagas Disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi and affects more than 10 million people. It is a paradigmatic example of a chronic disease without an effective treatment in Latin America where the current therapies, based on Benznidazole and Nifurtimox, are characterised by limited efficacy, toxic side-effects and frequent failures in the treatment. We present a series of new long-chain squaramides, identified based on their 1H and 13C NMR spectra, and their trypanocidal activity and cytotoxicity were tested in vitro through the determination of IC50 values. Compounds 4 and 7 were more active and less toxic than the reference drug Benznidazole, and these results were the basis of promoting in vivo assays, where parasitaemia levels, assignment of cure, reactivation of parasitaemia and others parameters were determined in mice treated in both the acute and chronic phases. Finally, the mechanisms of action were elucidated at metabolic and mitochondrial levels and superoxide dismutase inhibition. The experiments allowed us to select compound 7 as a promising candidate for treating Chagas Disease, where the activity, stability and low cost make long-chain squaramides appropriate molecules for the development of an affordable anti-chagasic agent versus current treatments.


Subject(s)
Chagas Disease/drug therapy , Cyclobutanes/therapeutic use , Trypanocidal Agents/therapeutic use , Animals , Chlorocebus aethiops , Cyclobutanes/chemical synthesis , Cyclobutanes/toxicity , DNA/metabolism , Female , Membrane Potential, Mitochondrial/drug effects , Mice, Inbred BALB C , RNA/metabolism , Splenomegaly/drug therapy , Superoxide Dismutase/metabolism , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/toxicity , Trypanosoma cruzi/drug effects , Vero Cells
7.
Bioorg Chem ; 92: 103274, 2019 11.
Article in English | MEDLINE | ID: mdl-31539744

ABSTRACT

Leishmaniasis is a widespread neglected tropical disease complex that is responsible of one million new cases per year. Current treatments are outdated and pose many problems that new drugs need to overcome. With the goal of developing new, safe, and affordable drugs, we have studied the in vitro activity of 12 different 5-nitroindazole derivatives that showed previous activity against different strains of Trypanosoma cruzi in a previous work. T. cruzi belongs to the same family as Leishmania spp., and treatments for the disease it produces also needs renewal. Among the derivatives tested, compounds 1, 2, 9, 10, 11, and 12 showed low J774.2 macrophage toxicity, while their effect against both intracellular and extracellular forms of the studied parasites was higher than the ones found for the reference drug Meglumine Antimoniate (Glucantime®). In addition, their Fe-SOD inhibitory effect, the infection rates, metabolite alteration, and mitochondrial membrane potential of the parasites treated with the selected drugs were studied in order to gain insights into the action mechanism, and the results of these tests were more promising than those found with glucantime, as the leishmanicidal effect of these new drug candidates was higher. The promising results are encouraging to test these derivatives in more complex studies, such as in vivo studies and other experiments that could find out the exact mechanism of action.


Subject(s)
Alcohols/pharmacology , Antiprotozoal Agents/pharmacology , Enzyme Inhibitors/pharmacology , Ethylamines/pharmacology , Indazoles/pharmacology , Leishmania/drug effects , Alcohols/chemistry , Alcohols/metabolism , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/metabolism , Cell Line , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Ethylamines/chemistry , Ethylamines/metabolism , Indazoles/chemistry , Indazoles/metabolism , Macrophages/drug effects , Macrophages/parasitology , Membrane Potential, Mitochondrial/drug effects , Mice , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Superoxide Dismutase/antagonists & inhibitors , Superoxide Dismutase/metabolism
8.
Molecules ; 24(1)2018 Dec 31.
Article in English | MEDLINE | ID: mdl-30602705

ABSTRACT

The spectrum and efficacy of available antileishmanial drugs is limited. In the present work we evaluated in vitro the antiproliferative activity of 11 compounds based on tetradentate polyamines compounds against three Leishmania species (L. braziliensis, L. donovani and L. infantum) and the possible mechanism of action. We identified six compounds (3, 5, 6, 7, 8 and 10) effective against all three Leishmania spp both on extracellular and intracellular forms. These six most active leishmanicidal compounds also prevent the infection of host cells. Nevertheless, only compound 7 is targeted against the Leishmania SOD. Meanwhile, on the glucose metabolism the tested compounds have a species-specific effect on Leishmania spp.: L. braziliensis was affected mainly by 10 and 8, L. donovani by 7, and L. infantum by 5 and 3. Finally, the cellular ultrastructure was mainly damaged by 11 in the three Leishmania spp. studied. These identified antileishmania candidates constitute a good alternative treatment and will be further studied.


Subject(s)
Antiprotozoal Agents/chemical synthesis , Leishmania/enzymology , Polyamines/chemical synthesis , Superoxide Dismutase/antagonists & inhibitors , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Cell Line , Gene Expression Regulation, Enzymologic/drug effects , Leishmania/drug effects , Leishmania/pathogenicity , Macrophages/cytology , Macrophages/drug effects , Macrophages/parasitology , Mice , Microscopy, Electron, Transmission , Molecular Structure , Parasitic Sensitivity Tests , Polyamines/chemistry , Polyamines/pharmacology , Protozoan Proteins/antagonists & inhibitors
9.
Article in English | MEDLINE | ID: mdl-28320721

ABSTRACT

The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.


Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania braziliensis/drug effects , Leishmania infantum/drug effects , Meglumine/pharmacology , Organometallic Compounds/pharmacology , Animals , Humans , Leishmania braziliensis/metabolism , Leishmania infantum/metabolism , Meglumine Antimoniate , Parasitic Sensitivity Tests , Selenium/metabolism , Superoxide Dismutase/metabolism
10.
Parasitology ; 144(9): 1133-1143, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28367781

ABSTRACT

The synthesis and antiprotozoal activity of some simple dialkyl pyrazole-3,5-dicarboxylates (compounds 2-6) and their sodium salts (pyrazolates) (compounds 7-9) against Trypanosoma cruzi, Leishmania infantum and Leishmania braziliensis are reported. In most cases the studied compounds showed, especially against the clinically significant amastigote forms, in vitro activities higher than those of the reference drugs (benznidazole for T. cruzi and glucantime for Leishmania spp.); furthermore, the low non-specific cytotoxicities against Vero cells and macrophages shown by these compounds led to good selectivity indexes, which are 8-72 times higher for T. cruzi amastigotes and 15-113 times higher for Leishmania spp. amastigotes than those of the respective reference drugs. The high efficiency of diethyl ester 3 and its sodium salt 8 against the mentioned protozoa was confirmed by further in vitro assays on infection rates and by an additional in vivo study in a murine model of acute and chronic Chagas disease. The inhibitory capacity of compounds 3 and 8 on the essential iron superoxide dismutase of the aforementioned parasites may be related to the observed anti-trypanosomatid activity. The low acute toxicity of compounds 3 and 8 in mice is also reported in this article.


Subject(s)
Chagas Disease/drug therapy , Leishmania braziliensis/drug effects , Leishmania infantum/drug effects , Pyrazoles/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Chagas Disease/parasitology , Chlorocebus aethiops , Dicarboxylic Acids/chemistry , Dicarboxylic Acids/isolation & purification , Dicarboxylic Acids/pharmacology , Female , Macrophages , Mice , Mice, Inbred BALB C , Parasitemia , Pyrazoles/chemistry , Pyrazoles/isolation & purification , Trypanocidal Agents/chemistry , Trypanocidal Agents/isolation & purification , Vero Cells
11.
Parasitology ; 144(13): 1783-1790, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28789716

ABSTRACT

Leishmaniasis is one of the world's most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, we present 20 arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani and Leishmania braziliensis strains. Six out of the 20 Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy.


Subject(s)
Leishmania braziliensis/drug effects , Leishmania donovani/drug effects , Leishmania infantum/drug effects , Mannich Bases/pharmacology , Superoxide Dismutase/metabolism , Trypanocidal Agents/pharmacology , Animals , Cell Line , Mannich Bases/chemistry , Mice , Parasitic Sensitivity Tests , Trypanocidal Agents/chemistry
12.
Exp Parasitol ; 164: 20-30, 2016 May.
Article in English | MEDLINE | ID: mdl-26874306

ABSTRACT

In order to identify new compounds to treat Chagas disease during the acute phase with higher activity and lower toxicity than the reference drug benznidazole (Bz), a series of tetraamine-based compounds was prepared and their trypanocidal effects against Trypanosoma cruzi were evaluated by light microscopy through the determination of IC50 values. Cytotoxicity was determined by flow cytometry assays against Vero cells. In vivo assays were performed in BALB/c mice, in which the parasitemia levels were quantified by fresh blood examination; the assignment of a cure was determined by PCR and reactivation of blood parasitemia levels after immunosuppression. The mechanism of action was elucidated at metabolic and ultra-structural levels by (1)H NMR and TEM studies. Finally, as tetraamines are potentially capable of casuing oxidative damage in the parasites, the study was completed by assessing their activity as potential iron superoxide dismutase (Fe-SOD) and trypanothione reductase (TR) inhibitors. High-selectivity indexes observed in vitro were the basis of promoting three of the tested compounds to in vivo assays. The tests on the murine model for the acute phase of Chagas disease showed better parasitemia inhibition values than those found for Bz. Tetraamines 2 and 3 induced a remarkable decrease in the reactivation of parasitemia after immunosuppression and curative rates of 33 and 50%, respectively. Tetraamine 3 turned out to be a great inhibitor of Fe-SOD and TR. The high anti-parasitic activity and low toxicity render these tetraamines appropriate molecules for the development of an affordable anti-Chagas agent.


Subject(s)
Chagas Disease/drug therapy , Polyamines/pharmacology , Trypanosoma cruzi/drug effects , Animals , Chagas Disease/parasitology , Chlorocebus aethiops , Female , Mice , NADH, NADPH Oxidoreductases/antagonists & inhibitors , Polyamines/chemistry , Superoxide Dismutase/antagonists & inhibitors , Trypanosoma cruzi/metabolism , Trypanosoma cruzi/ultrastructure , Vero Cells
13.
Exp Parasitol ; 170: 36-49, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27480054

ABSTRACT

In order to evaluate the in vitro leishmanicidal activity of N,N'-Squaramides derivatives, compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites, against Leishmania infantum, Leishmania braziliensis and Leishmania donovani a series of 18compounds was prepared and assayed on extracellular and intracellular parasite forms. Infectivity and cytotoxicity tests were performed on J774.2 macrophage cells using meglumine antimoniate (Glucantime) as the reference drug. Changes in metabolite excretion by 1H-NMR and the ultrastructural alterations occurring in the parasites treated using transmission electron microscopy (TEM), was analyzed. Compounds 1, 7, 11, 14 and 17 were the more active and less toxic. Infection rates showed that the order of effectiveness was 17 > 11 > 14 > 7 for both L. infantum and L. braziliensis and in the same way, the compound 1 for L. donovani. All these compounds have altered the typical structure of the promastigotes, glycosomes and mitochondria. These severe modifications by the compounds are the ultimate reasons for the alterations observed in the excretion products. The Squaramide 17 (3-(butylamino)-4-((3-(dimetilamino)propyl)(methyl)amino)cyclobut-3-en-1,2-dione) was clearly the most efficient of all compounds. The data appear to confirm that the severe modifications generated in organelles such as glycosomes or mitochondria by the compounds are the ultimate reasons for the alterations observed in the excretion products of all species. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-leishmanial agent.


Subject(s)
Leishmania braziliensis/drug effects , Leishmania donovani/drug effects , Leishmania infantum/drug effects , Macrophages/parasitology , Quinine/analogs & derivatives , Animals , Cell Line , Flow Cytometry , Inhibitory Concentration 50 , Leishmania braziliensis/metabolism , Leishmania braziliensis/ultrastructure , Leishmania donovani/metabolism , Leishmania donovani/ultrastructure , Leishmania infantum/metabolism , Leishmania infantum/ultrastructure , Macrophages/drug effects , Mice , Microscopy, Electron, Transmission , Quinine/chemistry , Quinine/pharmacology , Quinine/toxicity
14.
Parasit Vectors ; 17(1): 40, 2024 Jan 29.
Article in English | MEDLINE | ID: mdl-38287455

ABSTRACT

BACKGROUND: The emergence of diseases of public health concern is enhanced by factors associated with global change, such as the introduction of invasive species. The Asian tiger mosquito (Aedes albopictus), considered a competent vector of different viruses and parasites, has been successfully introduced into Europe in recent decades. Molecular screening of parasites in mosquitoes (i.e. molecular xenomonitoring) is essential to understand the potential role of different native and invasive mosquito species in the local circulation of vector-borne parasites affecting both humans and wildlife. METHODS: The presence of avian Plasmodium parasites was molecularly tested in mosquitoes trapped in five localities with different environmental characteristics in southern Spain from May to November 2022. The species analyzed included the native Culex pipiens and Culiseta longiareolata and the invasive Ae. albopictus. RESULTS: Avian Plasmodium DNA was only found in Cx. pipiens with 31 positive out of 165 mosquito pools tested. None of the Ae. albopictus or Cs. longiareolata pools were positive for avian malaria parasites. Overall, eight Plasmodium lineages were identified, including a new lineage described here. No significant differences in parasite prevalence were found between localities or sampling sessions. CONCLUSIONS: Unlike the invasive Ae. albopictus, Cx. pipiens plays a key role in the transmission of avian Plasmodium in southern Spain. However, due to the recent establishment of Ae. albopictus in the area, further research on the role of this species in the local transmission of vector-borne pathogens with different reservoirs is required.


Subject(s)
Aedes , Culex , Malaria, Avian , Plasmodium , Animals , Humans , Spain/epidemiology , Mosquito Vectors/parasitology , Aedes/parasitology , Plasmodium/genetics , Culex/parasitology , Malaria, Avian/parasitology
15.
Pharmaceuticals (Basel) ; 16(10)2023 Sep 28.
Article in English | MEDLINE | ID: mdl-37895851

ABSTRACT

Leishmaniasis and Chagas disease are still considered neglected illnesses due to the lack of investment in research, despite the fact that almost one million new cases are reported every year. Four 7-oxo-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine (HftpO) first-row transition complexes (Cu, Co, Ni, Zn) have been studied for the first time in vitro against five different species of Leishmania spp. (L. infantum, L. braziliensis, L. donovani, L. peruviana and L. mexicana) as well as Trypanosoma cruzi, showing higher efficacy than the reference commercial drugs. UV and luminescence properties were also evaluated. As a proof of concept, anchoring of a model high-effective-metal complex as an antiparasitic agent on silica nanoparticles was carried out for the first time, and drug-release behaviour was evaluated, assessing this new approach for drug vehiculation.

16.
Pharmaceutics ; 15(3)2023 Mar 20.
Article in English | MEDLINE | ID: mdl-36986853

ABSTRACT

Due to the urgent need for finding effective and free of secondary effect treatments for every clinical form of Leishmaniasis, a series of synthetic xylene, pyridine and, pyrazole azamacrocycles were tested against three Leishmania species. A total of 14 compounds were tested against J774.2 macrophage cells which were models for host cells, and against promastigote and amastigote forms of each studied Leishmania parasite. Amongst these polyamines, one proved effective against L. donovani, another one for L. braziliensis and L. infantum, and another one was selective solely for L. infantum. These compounds showed leishmanicidal activity and reduced parasite infectivity and dividing ability. Action mechanism studies gave a hint that compounds were active against Leishmania due to their ability to alter parasite metabolic pathways and reduce (except Py33333) parasitic Fe-SOD activity.

17.
Vet Parasitol Reg Stud Reports ; 44: 100911, 2023 09.
Article in English | MEDLINE | ID: mdl-37652628

ABSTRACT

Trypanosoma cruzi, the causal agent of American trypanosomiasis, and Leishmania spp., the causal agents of Leishmaniasis, are prevalent in more than 20 American countries, including Mexico. Dogs have been reported as incidental hosts for both parasites and may be helpful as transmission sentinels. We surveyed the dog population in a rural locality of the Merida municipality in Yucatan, Mexico, to evaluate the seroreactivity against T. cruzi and Leishmania spp. using two antigens, parasite homogenate (H) and iron superoxide dismutase extract (FeSODe), with two serological techniques (ELISA and Western Blot). Our study found that 3.33% of the tested dogs were seroreactive to T. cruzi using ELISA-H, and 29.5% were seroreactive to FeSODe antigen, with a 94.4% consistency between the two tests. Similarly, for L. mexicana, 1.6% were seroreactive using ELISA-H, and 9.8% were seroreactive using ELISA-FeSODe, with an 83.3% consistency between tests. For L. braziliensis, no dogs were seroreactive using ELISA-H, but 16.4% were seroreactive using ELISA-FeSODe, with a 90% consistency between tests. Finally, for L. infantum, 4.9% were seropositive using ELISA-H, and 6.6% were seropositive using ELISA-FeSODe, with a 75% consistency between tests. These results show noticeable evidence of exposure of dogs to trypanosomatid parasites and highlight the potential disease risk for the people and their companion animals in the region.


Subject(s)
Chagas Disease , Leishmania , Parasites , Trypanosoma cruzi , Animals , Mexico/epidemiology , Chagas Disease/epidemiology , Chagas Disease/veterinary
18.
J Antimicrob Chemother ; 67(2): 387-97, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22127582

ABSTRACT

OBJECTIVES: To evaluate the in vitro leishmanicidal activity of imidazole-based (1-4) and pyrazole-based (5-6) benzo[g]phthalazine derivatives against Leishmania infantum and Leishmania braziliensis. METHODS: The in vitro activity of compounds 1-6 was assayed on extracellular promastigote and axenic amastigote forms, and on intracellular amastigote forms of the parasites. Infectivity and cytotoxicity tests were performed on J774.2 macrophage cells using meglumine antimoniate (Glucantime) as the reference drug. The mechanisms of action were analysed by iron superoxide dismutase (Fe-SOD) and copper/zinc superoxide dismutase (CuZn-SOD) inhibition, metabolite excretion and transmission electronic microscopy (TEM). RESULTS: Compounds 1-6 were more active and less toxic than meglumine antimoniate. Data on infection rates and amastigote mean numbers showed that 2, 4 and 6 were more active than 1, 3 and 5 in both L. infantum and L. braziliensis. The inhibitory effect of these compounds on the antioxidant enzyme Fe-SOD of promastigote forms of the parasites was remarkable, whereas inhibition of human CuZn-SOD was negligible. The ultrastructural alterations observed in treated promastigote forms confirmed the greater cell damage caused by the most active compounds 2, 4 and 6. The modifications observed by (1)H-NMR in the nature and amounts of catabolites excreted by the parasites after treatment with 1-6 suggested that the catabolic mechanisms could depend on the structure of the side chains linked to the benzo[g]phthalazine moiety. CONCLUSIONS: All the compounds assayed were active in vitro against the two Leishmania species and were less toxic against mammalian cells than the reference drug, but the monosubstituted compounds were significantly more effective and less toxic than their disubstituted counterparts.


Subject(s)
Antiprotozoal Agents/pharmacology , Imidazoles/pharmacology , Leishmania braziliensis/drug effects , Leishmania infantum/drug effects , Phthalazines/pharmacology , Pyrazoles/pharmacology , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/toxicity , Cell Survival/drug effects , Female , Humans , Imidazoles/chemistry , Imidazoles/toxicity , Macrophages/parasitology , Mice , Mice, Inbred BALB C , Microscopy, Electron, Transmission , Parasitic Sensitivity Tests , Phthalazines/chemistry , Phthalazines/toxicity , Pyrazoles/chemistry , Pyrazoles/toxicity , Structure-Activity Relationship , Superoxide Dismutase/metabolism
19.
Mem Inst Oswaldo Cruz ; 107(3): 370-6, 2012 May.
Article in English | MEDLINE | ID: mdl-22510833

ABSTRACT

The activity of five (1-5) abietane phenol derivatives against Leishmania infantum and Leishmania braziliensis was studied using promastigotes and axenic and intracellular amastigotes. Infectivity and cytotoxicity tests were performed with J774.2 macrophage cells using Glucantime as a reference drug. The mechanisms of action were analysed by performing metabolite excretion and transmission electron microscopy ultrastructural studies. Compounds 1-5 were more active and less toxic than Glucantime. The infection rates and mean number of parasites per cell observed in amastigote experiments showed that derivatives 2, 4 and 5 were the most effective against both L. infantum and L. braziliensis. The ultrastructural changes observed in the treated promastigote forms confirmed that the greatest cell damage was caused by the most active compound (4). Only compound 5 caused changes in the nature and amounts of catabolites excreted by the parasites, as measured by ¹H nuclear magnetic resonance spectroscopy. All of the assayed compounds were active against the two Leishmania species in vitro and were less toxic in mammalian cells than the reference drug.


Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania braziliensis/drug effects , Leishmania infantum/drug effects , Macrophages/parasitology , Terpenes/pharmacology , Animals , Antiprotozoal Agents/chemistry , Female , Inhibitory Concentration 50 , Leishmania braziliensis/ultrastructure , Leishmania infantum/ultrastructure , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred BALB C , Microscopy, Electron, Transmission , Parasitic Sensitivity Tests , Terpenes/chemistry
20.
ScientificWorldJournal ; 2012: 203646, 2012.
Article in English | MEDLINE | ID: mdl-22666092

ABSTRACT

OBJECTIVES: To evaluate the in vitro leishmanicidal activity of nine flavonoid derivatives from Delphinium staphisagria against L. infantum and L. braziliensis. DESIGN AND METHODS: The in vitro activity of compounds 1-9 was assayed on extracellular promastigote and axenic amastigote forms and on intracellular amastigote forms of the parasites. Infectivity and cytotoxicity tests were carried on J774.2 macrophage cells using Glucantime as the reference drug. The mechanisms of action were analysed performing metabolite excretion and transmission electronic microscope ultrastructural alteration studies. RESULTS: Nine flavonoids showed leishmanicidal activity against promastigote as well as amastigote forms of Leishmania infantum and L. braziliensis. These compounds were nontoxic to mammalian cells and were effective at similar concentrations up to or lower than that of the reference drug (Glucantime). The results showed that 2(″)-acetylpetiolaroside (compound 8) was clearly the most active. CONCLUSION: This study has demonstrated that flavonoid derivatives are active against L. infantum and L. braziliensis.


Subject(s)
Antiprotozoal Agents/pharmacology , Delphinium/chemistry , Flavonoids/pharmacology , Leishmania braziliensis/drug effects , Leishmania infantum/drug effects , Animals , Cell Line , Flavonoids/isolation & purification , Leishmania braziliensis/ultrastructure , Leishmania infantum/ultrastructure , Mice , Microscopy, Electron, Transmission
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