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1.
J Med Chem ; 67(4): 2849-2863, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38330051

RESUMO

Human African trypanosomiasis (HAT) still faces few therapeutic options and emerging drug resistance, stressing an urgency for novel antitrypanosomal drug discovery. Here, we describe lead optimization efforts aiming at improving antitrypanosomal efficacy and better physicochemical properties based on our previously reported optimized hit NPD-2975 (pIC50 7.2). Systematic modification of the 5-phenylpyrazolopyrimidinone NPD-2975 led to the discovery of a R4-substituted analogue 31c (NPD-3519), showing higher in vitro potency (pIC50 7.8) against Trypanosoma brucei and significantly better metabolic stability. Further, in vivo pharmacokinetic evaluation of 31c and experiments in an acute T. brucei mouse model confirmed improved oral bioavailability and antitrypanosomal efficacy at 50 mg/kg with no apparent toxicity. With good physicochemical properties, low toxicity, improved pharmacokinetic features, and in vivo efficacy, 31c may serve as a promising candidate for future drug development for HAT.


Assuntos
Antiprotozoários , Tripanossomicidas , Trypanosoma brucei brucei , Tripanossomíase Africana , Animais , Camundongos , Humanos , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Antiprotozoários/uso terapêutico , Desenvolvimento de Medicamentos
2.
Future Med Chem ; 16(3): 221-238, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38269432

RESUMO

Aim: To synthesize novel more potent trypanocidal and leishmanicidal agents. Methods: Hantzsch's synthetic strategy was used to synthesize 1,3-thiazole-4-carboxylates and their N-benzylated derivatives. Results: 28 new thiazole-carboxylates and their N-benzylated derivatives were established to test their trypanocidal and leishmanicidal activities. From both series, compounds 3b, 4f, 4g, 4j and 4n exhibited a better or comparable trypanocidal profile to benznidazole. Among all tested compounds, 4n was found to be the most potent and was better than benznidazole. Conclusion: Further variation of substituents around 1,3-thiazole-4-carboxylates and or hydrazinyl moiety may assist in establishing better and more potent trypanocidal and leishmanicidal agents.


Chagas disease and leishmaniasis are neglected tropical diseases. Herein, 28 1,3-thiazoles have been synthesized from thiosemicarbazones in a rapid, efficient and cost-effective manner. In vitro assays were performed against intracellular amastigotes of Trypanosoma cruzi (T. cruzi) and promastigotes and intracellular amastigote forms of Leishmania infantum (L. infantum) and Leishmania amazonensis (L. amazonensis). Some of the 1,3-thiazole-4-carboxylates inhibited the amastigote form of T. cruzi without affecting macrophage viability, compound 4n being the most potent and better than benznidazole. Our synthesized compounds exhibited promising activity against T. cruzi, thus broadening options for scaffold and lead compound optimization. Concerning the leishmanicidal activity, compound 4g was the best prototype in terms of potency and selectivity. Compounds 4g and 3m showed moderate selectivity and potency against intracellular amastigotes of L. amazonensis and L. infantum, respectively.


Assuntos
Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Tiazóis/farmacologia , Ésteres/farmacologia , Tripanossomicidas/farmacologia
3.
BMC Vet Res ; 20(1): 32, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38279149

RESUMO

BACKGROUND: Animal trypanosomiasis is a major livestock problem due to its socioeconomic impacts in tropical countries. Currently used trypanocides are toxic, expensive, and the parasites have developed resistance to the existing drugs, which calls for an urgent need of new effective and safe chemotherapeutic agents from alternative sources such as medicinal plants. In Ethiopian traditional medicine fresh leaves of Ranunculus multifidus Forsk, are used for the treatment of animal trypanosomiasis. The present study aimed to evaluate the antitrypanosomal activity of the fresh leaves of R. multifidus and its major compound anemonin against Trypanosoma congolense field isolate. METHODS: Fresh leaves of R. multifidus were extracted by maceration with 80% methanol and hydro-distillation to obtain the corresponding extracts. Anemonin was isolated from the hydro-distilled extract by preparative TLC. For the in vitro assay, 0.1, 0.4, 2 and 4 mg/ml of the test substances were incubated with parasites and cessation or drop in motility of the parasites was monitored for a total duration of 1 h. In the in vivo assay, the test substances were administered intraperitoneally daily for 7 days to mice infected with Trypanosoma congolense. Diminazene aceturate and 1% dimethylsulfoxide (DMSO) were used as positive and negative controls, respectively. RESULTS: Both extracts showed antitrypanosomal activity although the hydro-distilled extract demonstrated superior activity compared to the hydroalcoholic extract. At a concentration of 4 mg/ml, the hydro-distilled extract drastically reduced motility of trypanosomes within 20 min. Similarly, anemonin at the same concentration completely immobilized trypanosomes within 5 min of incubation, while diminazene aceturate (28.00 mg/kg/day) immobilized the parasites within 10 min. In the in vivo antitrypanosomal assay, anemonin eliminates parasites at all the tested doses (8.75, 17.00 and 35.00 mg/kg/day) and prevented relapse, while in diminazene aceturate-treated mice the parasites reappeared on days 12 to 14. CONCLUSIONS: The current study demonstrated that the fresh leaves of R. multifidus possess genuine antitrypanosomal activity supporting the use of the plant for the treatment of animal trypanosomiasis in traditional medicine. Furthermore, anemonin appears to be responsible for the activity suggesting its potential as a scaffold for the development of safe and cost effective antitrypanosomal agent.


Assuntos
Furanos , Ranunculus , Tripanossomicidas , Tripanossomíase Africana , Animais , Camundongos , Diminazena/farmacologia , Diminazena/uso terapêutico , Músculos Paraespinais , Extratos Vegetais/uso terapêutico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma congolense , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/veterinária
4.
Future Med Chem ; 16(3): 253-269, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38193294

RESUMO

Background: Chagas disease is caused by the parasite Trypanosoma cruzi, and the lack of effective and safe treatments makes identifying new classes of compounds with anti-T. cruzi activity of paramount importance. Methods: Hit-to-lead exploration of a metabolically stable N-imidazoylpiperazine was performed. Results: Compound 2, a piperazine derivative active against T. cruzi, was selected to perform the hit-to-lead exploration, which involved the design, synthesis and biological evaluation of 39 new derivatives. Conclusion: Compounds 6e and 10a were identified as optimized compounds with low micromolar in vitro activity, low cytotoxicity and suitable preliminary absorption, distribution, metabolism and excretion and physicochemical properties. Both compounds reduced parasitemia in mouse models of Chagas disease, providing a promising opportunity for further exploration of new antichagasic compounds.


Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Animais , Camundongos , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Relação Estrutura-Atividade , Parasitemia/tratamento farmacológico
5.
Eur J Med Chem ; 263: 115954, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37984297

RESUMO

Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei gambiense and rhodesiense, is a parasitic disease endemic to sub-Saharan Africa. Untreated cases of HAT can be severely debilitating and fatal. Although the number of reported cases has decreased progressively over the last decade, the number of effective and easily administered medications is very limited. In this work, we report the antitrypanosomal activity of a series of potent compounds. A subset of molecules in the series are highly selective for trypanosomes and are metabolically stable. One of the compounds, (E)-N-(4-(methylamino)-4-oxobut-2-en-1-yl)-5-nitrothiophene-2-carboxamide (10), selectively inhibited the growth of T. b. brucei, T. b. gambiense and T. b. rhodesiense, have excellent oral bioavailability and was effective in treating acute infection of HAT in mouse models. Based on its excellent bioavailability, compound 10 and its analogs are candidates for lead optimization and pre-clinical investigations.


Assuntos
Tripanossomicidas , Trypanosoma brucei brucei , Tripanossomíase Africana , Animais , Camundongos , Humanos , Trypanosoma brucei rhodesiense , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Trypanosoma brucei gambiense
6.
PLoS Pathog ; 19(11): e1011627, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37956215

RESUMO

Benznidazole is the front-line drug used to treat infections with Trypanosoma cruzi, the causative agent of Chagas disease. However, for reasons that are unknown, treatment failures are common. When we examined parasites that survived benznidazole treatment in mice using highly sensitive in vivo and ex vivo bioluminescence imaging, we found that recrudescence is not due to persistence of parasites in a specific organ or tissue that preferentially protects them from drug activity. Surviving parasites are widely distributed and located in host cells where the vast majority contained only one or two amastigotes. Therefore, infection relapse does not arise from a small number of intact large nests. Rather, persisters are either survivors of intracellular populations where co-located parasites have been killed, or amastigotes in single/low-level infected cells exist in a state where they are less susceptible to benznidazole. To better assess the nature of parasite persisters, we exposed infected mammalian cell monolayers to a benznidazole regimen that reduces the intracellular amastigote population to <1% of the pre-treatment level. Of host cells that remained infected, as with the situation in vivo, the vast majority contained only one or two surviving intracellular amastigotes. Analysis, based on non-incorporation of the thymidine analogue EdU, revealed these surviving parasites to be in a transient non-replicative state. Furthermore, treatment with benznidazole led to widespread parasite DNA damage. When the small number of parasites which survive in mice after non-curative treatment were assessed using EdU labelling, this revealed that these persisters were also initially non-replicative. A possible explanation could be that triggering of the T. cruzi DNA damage response pathway by the activity of benznidazole metabolites results in exit from the cell cycle as parasites attempt DNA repair, and that metabolic changes associated with non-proliferation act to reduce drug susceptibility. Alternatively, a small percentage of the parasite population may pre-exist in this non-replicative state prior to treatment.


Assuntos
Doença de Chagas , Nitroimidazóis , Parasitos , Tripanossomicidas , Trypanosoma cruzi , Animais , Camundongos , Trypanosoma cruzi/genética , Nitroimidazóis/farmacologia , Doença de Chagas/parasitologia , Dano ao DNA , Tripanossomicidas/farmacologia , Tripanossomicidas/metabolismo , Mamíferos
7.
PLoS One ; 18(11): e0292946, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38032881

RESUMO

Severe infections with potentially fatal outcomes are caused by parasites from the genera Trypanosoma and Leishmania (class Kinetoplastea). The diseases affect people of remote areas in the tropics and subtropics with limited access to adequate health care. Besides insufficient diagnostics, treatment options are limited, with tenuous developments in recent years. Therefore, new antitrypanosomal antiinfectives are required to fight these maladies. In the presented approach, new compounds were developed and tested on the target trypanothione synthetase (TryS). This enzyme is crucial to the kinetoplastids' unique trypanothione-based thiol redox metabolism and thus for pathogen survival. Preceding studies have shown that N5-substituted paullones display antitrypanosomal activity as well as TryS inhibition. Herein, this compound class was further examined regarding the structure-activity relationships (SAR). Diverse benzazepinone derivatives were designed and tested in cell-based assays on bloodstream Trypanosoma brucei brucei (T. b. brucei) and intracellular amastigotes of Leishmania infantum (L. infantum) as well as in enzyme-based assays on L. infantum TryS (LiTryS) and T. b. brucei TryS (TbTryS). While an exchange of just the substituent in the 9-position of paullones led to potent inhibitors on LiTryS and T. b. brucei parasites, new compounds lacking the indole moiety showed a total loss of activity in both assays. Conclusively, the indole as part of the paullone structure is pivotal for keeping the TryS inhibitory and antitrypanosomal activity of this substance class.


Assuntos
Tripanossomicidas , Trypanosoma brucei brucei , Humanos , Benzazepinas , Oxirredução , Indóis/farmacologia , Tripanossomicidas/farmacologia
8.
PLoS Negl Trop Dis ; 17(11): e0011519, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37988389

RESUMO

BACKGROUND: Chagas disease, chronic infection with Trypanosoma cruzi, mainly manifests as cardiac disease. However, the liver is important for both controlling parasite burdens and metabolizing drugs. Notably, high doses of anti-parasitic drug benznidazole (BNZ) causes liver damage. We previously showed that combining low dose BNZ with a prototype therapeutic vaccine is a dose sparing strategy that effectively reduced T. cruzi induced cardiac damage. However, the impact of this treatment on liver health is unknown. Therefore, we evaluated several markers of liver health after treatment with low dose BNZ plus the vaccine therapy in comparison to a curative dose of BNZ. METHODOLOGY: Female BALB/c mice were infected with a bioluminescent T. cruzi H1 clone for approximately 70 days, then randomly divided into groups of 15 mice each. Mice were treated with a 25mg/kg BNZ, 25µg Tc24-C4 protein/ 5µg E6020-SE (Vaccine), 25mg/kg BNZ followed by vaccine, or 100mg/kg BNZ (curative dose). At study endpoints we evaluated hepatomegaly, parasite burden by quantitative PCR, cellular infiltration by histology, and expression of B-cell translocation gene 2(BTG2) and Peroxisome proliferator-activated receptor alpha (PPARα) by RT-PCR. Levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were quantified from serum. RESULTS: Curative BNZ treatment significantly reduced hepatomegaly, liver parasite burdens, and the quantity of cellular infiltrate, but significantly elevated serum levels of ALT, AST, and LDH. Low BNZ plus vaccine did not significantly affect hepatomegaly, parasite burdens or the quantity of cellular infiltrate, but only elevated ALT and AST. Low dose BNZ significantly decreased expression of both BTG2 and PPARα, and curative BNZ reduced expression of BTG2 while low BNZ plus vaccine had no impact. CONCLUSIONS: These data confirm toxicity associated with curative doses of BNZ and suggest that while dose sparing low BNZ plus vaccine treatment does not reduce parasite burdens, it better preserves liver health.


Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Vacinas , Feminino , Animais , Camundongos , Hepatomegalia/tratamento farmacológico , Infecção Persistente , PPAR alfa/farmacologia , PPAR alfa/uso terapêutico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/prevenção & controle , Doença de Chagas/parasitologia , Tripanossomicidas/farmacologia
9.
Molecules ; 28(22)2023 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-38005183

RESUMO

Chagas disease (CD), which is caused by Trypanosoma cruzi and was discovered more than 100 years ago, remains the leading cause of death from parasitic diseases in the Americas. As a curative treatment is only available for the acute phase of CD, the search for new therapeutic options is urgent. In this study, nitroazole and azole compounds were synthesized and underwent molecular modeling, anti-T. cruzi evaluations and nitroreductase enzymatic assays. The compounds were designed as possible inhibitors of ergosterol biosynthesis and/or as substrates of nitroreductase enzymes. The in vitro evaluation against T. cruzi clearly showed that nitrotriazole compounds are significantly more potent than nitroimidazoles and triazoles. When their carbonyls were reduced to hydroxyl groups, the compounds showed a significant increase in activity. In addition, these substances showed potential for action via nitroreductase activation, as the substances were metabolized at higher rates than benznidazole (BZN), a reference drug against CD. Among the compounds, 1-(2,4-difluorophenyl)-2-(3-nitro-1H-1,2,4-triazol-1-yl)ethanol (8) is the most potent and selective of the series, with an IC50 of 0.39 µM and selectivity index of 3077; compared to BZN, 8 is 4-fold more potent and 2-fold more selective. Moreover, this compound was not mutagenic at any of the concentrations evaluated, exhibited a favorable in silico ADMET profile and showed a low potential for hepatotoxicity, as evidenced by the high values of CC50 in HepG2 cells. Furthermore, compared to BZN, derivative 8 showed a higher rate of conversion by nitroreductase and was metabolized three times more quickly when both compounds were tested at a concentration of 50 µM. The results obtained by the enzymatic evaluation and molecular docking studies suggest that, as planned, nitroazole derivatives may utilize the nitroreductase metabolism pathway as their main mechanism of action against Trypanosoma cruzi. In summary, we have successfully identified and characterized new nitrotriazole analogs, demonstrating their potential as promising candidates for the development of Chagas disease drug candidates that function via nitroreductase activation, are considerably selective and show no mutagenic potential.


Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Humanos , Trypanosoma cruzi/metabolismo , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Mutagênicos/farmacologia , Tripanossomicidas/farmacologia , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Triazóis/química , Nitrorredutases/metabolismo
10.
J Bioenerg Biomembr ; 55(6): 409-421, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37919636

RESUMO

Current treatment of Chagas disease (CD) is based on two substances, nifurtimox (NT) and benzonidazole (BZ), both considered unsatisfactory mainly due to their low activities and high toxicity profile. One of the main challenges faced in CD management concerns the identification of new drugs active in the acute and chronic phases and with good pharmacokinetic profiles. In this work, we studied the bioactivity of twenty 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole derivatives against Trypanosoma cruzi epimastigotes and trypomastigotes. We identified seven derivatives with promising activity against epimastigote forms with IC50 values ranging from 6 µM to 44 µM. Most of the compounds showed no significant toxicity against murine macrophages. Our initial investigation on the mechanism of action indicates that this series of compounds may exert their anti-parasitic effect, inducing cell membrane damage. The results in trypomastigotes showed that one derivative, PDAN 78, satisfactorily inhibited metabolic alteration at all concentrations. Moreover, we used molecular modeling to understand how tridimensional and structural aspects might influence the observed bioactivities. Finally, we also used in silico approaches to assess the potential pharmacokinetic and toxicological properties of the most active compounds. Our initial results indicate that this molecular scaffold might be a valuable prototype for novel and safe trypanocidal compounds.


Assuntos
Doença de Chagas , Tiadiazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Camundongos , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Doença de Chagas/tratamento farmacológico , Tiadiazóis/farmacologia , Tiadiazóis/uso terapêutico
11.
Mem Inst Oswaldo Cruz ; 118: e220295, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37878830

RESUMO

BACKGROUND: Trypanosoma cruzi, which causes Chagas disease (CD), is a versatile haemoparasite that uses several strategies to evade the host's immune response, including adipose tissue (AT), used as a reservoir of infection. As it is an effective barrier to parasite evasion, the effectiveness of the drug recommended for treating CD, Benznidazole (BZ), may be questionable. OBJECTIVE: To this end, we evaluated the parasite load and immunomodulation caused by BZ treatment in the culture of adipocytes differentiated from human adipose tissue-derived stem cells (ADSC) infected with T. cruzi. METHODS: The ADSC were subjected to adipogenic differentiation. We then carried out four cultures in which we infected the differentiated AT with trypomastigote forms of the Y strain of T. cruzi and treated them with BZ. After the incubation, the infected AT was subjected to quantitative polymerase chain reaction (qPCR) to quantify the parasite load and transmission electron microscopy (TEM) to verify the infection. The supernatant was collected to measure cytokines, chemokines, and adipokines. FINDINGS: We found elevated secretion of IL-6, CXCL-10/IP-10, CCL2/MCP-1, CCL5/RANTES, and leptin in infected fat cells. However, treatment with BZ promoted a decrease in IL-6. MAIN CONCLUSION: Therefore, we believe that BZ has a beneficial role as it reduces inflammation in infected fat cells.


Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Humanos , Interleucina-6 , Doença de Chagas/parasitologia , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Tecido Adiposo , Adipócitos , Diferenciação Celular , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
12.
Nat Commun ; 14(1): 6769, 2023 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-37880260

RESUMO

Post-infectious conditions present major health burdens but remain poorly understood. In Chagas disease (CD), caused by Trypanosoma cruzi parasites, antiparasitic agents that successfully clear T. cruzi do not always improve clinical outcomes. In this study, we reveal differential small molecule trajectories between cardiac regions during chronic T. cruzi infection, matching with characteristic CD apical aneurysm sites. Incomplete, region-specific, cardiac small molecule restoration is observed in animals treated with the antiparasitic benznidazole. In contrast, superior restoration of the cardiac small molecule profile is observed for a combination treatment of reduced-dose benznidazole plus an immunotherapy, even with less parasite burden reduction. Overall, these results reveal molecular mechanisms of CD treatment based on simultaneous effects on the pathogen and on host small molecule responses, and expand our understanding of clinical treatment failure in CD. This link between infection and subsequent persistent small molecule perturbation broadens our understanding of infectious disease sequelae.


Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Coração , Progressão da Doença
14.
ACS Infect Dis ; 9(11): 2173-2189, 2023 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-37883691

RESUMO

Chagas disease (CD), caused by Trypanosoma cruzi (T. cruzi) protozoa, is a complicated parasitic illness with inadequate medical measures for diagnosing infection and monitoring treatment success. To address this gap, we analyzed changes in the metabolome of T. cruzi-infected mice via liquid chromatography tandem mass spectrometry of clinically accessible biofluids: saliva, urine, and plasma. Urine was the most indicative of infection status across mouse and parasite genotypes. Metabolites perturbed by infection in urine include kynurenate, acylcarnitines, and threonylcarbamoyladenosine. Based on these results, we sought to implement urine as a tool for the assessment of CD treatment success. Strikingly, it was found that mice with parasite clearance following benznidazole antiparasitic treatment had an overall urine metabolome comparable to that of mice that failed to clear parasites. These results provide a complementary hypothesis to explain clinical trial data in which benznidazole treatment did not improve patient outcomes in late-stage disease, even in patients with successful parasite clearance. Overall, this study provides insights into new small-molecule-based CD diagnostic methods and a new approach to assess functional responses to treatment.


Assuntos
Doença de Chagas , Parasitos , Tripanossomicidas , Trypanosoma cruzi , Humanos , Camundongos , Animais , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Doença de Chagas/parasitologia
15.
J Biol Inorg Chem ; 28(8): 711-723, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37768364

RESUMO

In this work, two analogous coumarin-thio and semicarbazone hybrid compounds were prepared and evaluated as a potential antichagasic agents. Furthermore, palladium and platinum complexes with the thiosemicarbazone derivative as ligand (L1) were obtained in order to establish the effect of metal complexation on the antiparasitic activity. All compounds were fully characterized both in solution and in solid state including the resolution of the crystal structure of the palladium complex by X-ray diffraction methods. Unexpectedly, all experimental and theoretical characterizations in the solid state, demonstrated that the obtained palladium and platinum complexes are structurally different: [PdCl(L1)] and [PtCl2(HL1)]. All the studied compounds lower the proliferation of the amastigote form of Trypanosoma cruzi while some of them also have an effect on the trypomastigote stage. Additionally, the compounds inhibit T. cruzi release from host cells in variable extents. The Pd compound presented a remarkable profile in all the in vitro experiments, and it showed no toxicity for mammalian cells in the assayed concentrations. In this sense, in vivo experiments were performed for this compound using an acute model of Chagas disease. Results showed that the complex significantly lowered the parasite count in the mice blood with no significant toxicity.


Assuntos
Tiossemicarbazonas , Tripanossomicidas , Trypanosoma cruzi , Animais , Camundongos , Paládio/farmacologia , Paládio/química , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Ligantes , Parasitemia , Platina/química , Tripanossomicidas/farmacologia , Cumarínicos/farmacologia , Mamíferos
16.
BMC Complement Med Ther ; 23(1): 346, 2023 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-37770899

RESUMO

BACKGROUND: Vitellaria paradoxa is used in traditional medicine for the treatment of various diseases in tropical countries; however, nothing is known about its anti-trypanosomal activity. Human African trypanosomiasis is a neglected tropical disease of Sub-Saharan Africa's poorest rural regions, and the efficacy of its treatment remains a challenge. This study investigates the as-yet-unknown trypanocidal activity of this plant. METHODS: V. paradoxa, commonly known as shea tree, was selected for study based on an ethnobotanical investigation. Ultrasonicated extracts from bark and seeds were successively treated with ethyl acetate and water. Column chromatography, NMR spectroscopy and mass spectrometry were used to identify isolated compounds. Purified trypanosomes (Trypanosoma brucei brucei) were incubated with serial dilutions of the extracts and isolated compounds at 37 °C in 5% CO2 for 24 h. Parasite viability was evaluated under a microscope. RESULTS: The ethyl acetate extracts of the bark showed the higher in vitro trypanocidal activity against T. brucei brucei with median inhibitory concentration (IC50) of 3.25 µg/mL. However, the triterpene 1α,2ß,3ß,19α-tretrahydroxyurs-12-en-28-oic acid and the pentadecanoic acid isolated from the ethyl acetate extract of the seeds showed in vitro trypanocidal activity with IC50 of 11.30 and 70.1 µM, respectively. CONCLUSION: The results obtained contribute to the validation of the traditional medicinal use of V. paradoxa. Our results encourage further investigations of this plant, mainly with respect to its in vivo efficacy and toxicity.


Assuntos
Plantas Medicinais , Tripanossomicidas , Trypanosoma brucei brucei , Humanos , Extratos Vegetais/farmacologia , Tripanossomicidas/farmacologia
17.
J Med Chem ; 66(18): 13043-13057, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37722077

RESUMO

We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome Trypanosoma brucei. Of these, a dicationic benzothiazole compound (9a) exhibited sub-nanomolar in vitro potency with remarkable selectivity over mammalian cells (>26,000-fold). Unsubstituted 5-amidine groups and a cyclohexyl spacer were the crucial determinants of trypanocidal activity. In all cases, mice treated with a single dose of 20 mg kg-1 were cured of stage 1 trypanosomiasis. The compound displayed a favorable in vitro ADME profile, with the exception of low membrane permeability. However, we found evidence that uptake by T. brucei is mediated by endocytosis, a process that results in lysosomal sequestration. The compound was also active in low nanomolar concentrations against cultured asexual forms of the malaria parasite Plasmodium falciparum. Therefore, 9a has exquisite cross-species efficacy and represents a lead compound with considerable therapeutic potential.


Assuntos
Tripanossomicidas , Trypanosoma brucei brucei , Trypanosoma , Tripanossomíase Africana , Tripanossomíase , Camundongos , Animais , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Tripanossomíase/tratamento farmacológico , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Mamíferos
18.
Future Med Chem ; 15(16): 1449-1467, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37701989

RESUMO

Background: Chagas disease and human African trypanosomiasis cause substantial death and morbidity, particularly in low- and middle-income countries, making the need for novel drugs urgent. Methodology & results: Therefore, an explainable multitask pipeline to profile the activity of compounds against three trypanosomes (Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Trypanosoma cruzi) were created. These models successfully discovered four new experimental hits (LC-3, LC-4, LC-6 and LC-15). Among them, LC-6 showed promising results, with IC50 values ranging 0.01-0.072 µM and selectivity indices >10,000. Conclusion: These results demonstrate that the multitask protocol offers predictivity and interpretability in the virtual screening of new antitrypanosomal compounds and has the potential to improve hit rates in Chagas and human African trypanosomiasis projects.


Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma brucei brucei , Trypanosoma cruzi , Tripanossomíase Africana , Animais , Humanos , Tripanossomíase Africana/tratamento farmacológico , Tripanossomicidas/farmacologia , Doença de Chagas/tratamento farmacológico
19.
Parasite Immunol ; 45(10): e13005, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37467029

RESUMO

Chagas disease is a neglected tropical disease with only two drugs available for treatment and the plant Cecropia pachystachya has several compounds with antimicrobial and anti-inflammatory activities. This study aimed to evaluate a supercritical extract from C. pachystachya leaves in vitro and in vivo against Trypanosoma cruzi. A supercritical CO2 extraction was used to obtain the extract (CPE). Cytotoxicity and immunostimulation ability were evaluated in macrophages, and the in vitro trypanocidal activity was evaluated against epimastigotes and trypomastigotes forms. In vivo tests were done by infecting BALB/c mice with blood trypomastigotes forms and treating animals orally with CPE for 10 days. The parasitemia, survival rate, weight, cytokines and nitric oxide dosage were evaluated. CPE demonstrated an effect on the epi and trypomastigotes forms of the parasite (IC50 17.90 ± 1.2 µg/mL; LC50 26.73 ± 1.2 µg/mL) and no changes in macrophages viability, resulting in a selectivity index similar to the reference drug. CPE-treated animals had a worsening compared to non-treated, demonstrated by higher parasitemia and lower survival rate. This result was attributed to the anti-inflammatory effect of CPE, demonstrated by the higher IL-10 and IL-4 values observed in the treated mice compared to the control ones. CPE demonstrated a trypanocidal effect in vitro and a worsening in the in vivo infection due to its anti-inflammatory activity.


Assuntos
Doença de Chagas , Triterpenos , Tripanossomicidas , Trypanosoma cruzi , Camundongos , Animais , Parasitemia/tratamento farmacológico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Doença de Chagas/tratamento farmacológico , Trypanosoma cruzi/fisiologia , Camundongos Endogâmicos BALB C , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
20.
J Med Chem ; 66(15): 10413-10431, 2023 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-37506194

RESUMO

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.


Assuntos
Doença de Chagas , Leishmaniose Visceral , Tripanossomicidas , Trypanosoma cruzi , Camundongos , Animais , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Complexo de Endopeptidases do Proteassoma , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Tripanossomicidas/química
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