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1.
Eur J Med Chem ; 236: 114328, 2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35385806

RESUMO

In this paper, we developed a new series of dipeptide nitriles that were demonstrated to be reversible rhodesain inhibitors at nanomolar level, with EC50 values against cultured T. b. brucei in the micromolar range. We also proved that our dipeptide nitriles directly bind to the active site of rhodesain acting as competitive inhibitors. Within the most interesting compounds, the dipeptide nitrile 2b showed the highest binding affinity towards rhodesain (Ki = 16 nM) coupled with a good antiparasitic activity (EC50 = 14.1 µM). Moreover, for the dipeptide nitrile 3e, which showed a Ki = 122 nM towards the trypanosomal protease, we obtained the highest antiparasitic activity (EC50 = 8.8 µM). Thus, given the obtained results both compounds could certainly represent new lead compounds for the discovery of new drugs to treat Human African Trypanosomiasis.


Assuntos
Inibidores de Cisteína Proteinase , Dipeptídeos , Nitrilas , Tripanossomicidas , Trypanosoma brucei rhodesiense , Cisteína Endopeptidases , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos
2.
Molecules ; 27(7)2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35408605

RESUMO

Species of the genus Pleiocarpa are used in traditional medicine against fever and malaria. The present study focuses on the isolation and identification of bioactive compounds from P. bicarpellata extracts, and the evaluation of their antiprotozoal activity. Fractionation and isolation combined to LC-HRMS/MS-based dereplication provided 16 compounds: seven indole alkaloids, four indoline alkaloids, two secoiridoid glycosides, two iridoid glycosides, and one phenolic glucoside. One of the quaternary indole alkaloids (7) and one indoline alkaloid (15) have never been reported before. Their structures were elucidated by analysis of spectroscopic data, including 1D and 2D NMR experiments, UV, IR, and HRESIMS data. The absolute configurations were determined by comparison of the experimental and calculated ECD data. The extracts and isolated compounds were evaluated for their antiprotozoal activity towards Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum, as well as for their cytotoxicity against rat skeletal myoblast L6 cells. The dichloromethane/methanol (1:1) root extract showed strong activity against P. falciparum (IC50 value of 3.5 µg/mL). Among the compounds isolated, tubotaiwine (13) displayed the most significant antiplasmodial activity with an IC50 value of 8.5 µM and a selectivity index of 23.4. Therefore, P. bicarpallata extract can be considered as a source of indole alkaloids with antiplasmodial activity.


Assuntos
Antimaláricos , Antiprotozoários , Apocynaceae , Leishmania donovani , Malária Falciparum , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plasmodium falciparum , Ratos , Trypanosoma brucei rhodesiense
3.
BMC Res Notes ; 15(1): 97, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35255971

RESUMO

OBJECTIVE: Currently, the only available staging criterion for T. b. rhodesiense requires a lumber puncture to collect and later examine cerebrospinal fluid (CSF). This study examined the potential of plasma Neuron-Specific Enolase (NSE) in discriminating between early and late-stage patients. RESULTS: When median NSE levels were compared between early and late-stage patients, results showed a significant (P < 0.02) upregulation among late-stage patients (599.8 ng/mL). No significant differences (P > 0.9) in NSE levels were observed between early-stage patients (300 ng/mL) and controls (454 ng/mL). We used Receiver Operator Characteristic (ROC) curves to explore the likelihood of using plasma NSE as a potential stage biomarker in discriminating between early and late-stage HAT patients. Our results showed that NSE demonstrated an area under the curve (AUC) of 0.702 (95% CI 0.583-0.830). A high staging accuracy for NSE was obtained by using a cutoff of > 346.5 ng/mL with a sensitivity of 68.6% (95% CI 55-79.7%) and a specificity of 93.3% (95% CI 70.2-99.7%). Although our results demonstrate that plasma NSE is upregulated in T. b. rhodesiense sleeping sickness patients, its value in discriminating between late and early-stage patients is limited. However, future studies could consider improving its specificity by combining it with other identified plasma biomarkers.


Assuntos
Trypanosoma brucei rhodesiense , Tripanossomíase Africana , Animais , Biomarcadores/líquido cefalorraquidiano , Humanos , Fosfopiruvato Hidratase , Plasma , Tripanossomíase Africana/diagnóstico
4.
PLoS Negl Trop Dis ; 16(1): e0010047, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35041668

RESUMO

BACKGROUND: In the 20th century, epidemics of human African trypanosomiasis (HAT) ravaged communities in a number of African countries. The latest surge in disease transmission was recorded in the late 1990s, with more than 35,000 cases reported annually in 1997 and 1998. In 2013, after more than a decade of sustained control efforts and steady progress, the World Health Assembly resolved to target the elimination of HAT as a public health problem by 2020. We report here on recent progress towards this goal. METHODOLOGY/PRINCIPAL FINDINGS: With 992 and 663 cases reported in 2019 and 2020 respectively, the first global target was amply achieved (i.e. fewer than 2,000 HAT cases/year). Areas at moderate or higher risk of HAT, where more than 1 case/10,000 people/year are reported, shrunk to 120,000 km2 for the five-year period 2016-2020. This reduction of 83% from the 2000-2004 baseline (i.e. 709,000 km2) is slightly below the target (i.e. 90% reduction). As a result, the second global target for HAT elimination as a public health problem cannot be considered fully achieved yet. The number of health facilities able to diagnose and treat HAT expanded (+9.6% compared to a 2019 survey), thus reinforcing the capacity for passive detection and improving epidemiological knowledge of the disease. Active surveillance for gambiense HAT was sustained. In particular, 2.8 million people were actively screened in 2019 and 1.6 million in 2020, the decrease in 2020 being mainly caused by COVID-19-related restrictions. Togo and Côte d'Ivoire were the first countries to be validated for achieving elimination of HAT as a public health problem at the national level; applications from three additional countries are under review by the World Health Organization (WHO). CONCLUSIONS/SIGNIFICANCE: The steady progress towards the elimination of HAT is a testament to the power of multi-stakeholder commitment and coordination. At the end of 2020, the World Health Assembly endorsed a new road map for 2021-2030 that set new bold targets for neglected tropical diseases. While rhodesiense HAT remains among the diseases targeted for elimination as a public health problem, gambiense HAT is targeted for elimination of transmission. The goal for gambiense HAT is expected to be particularly arduous, as it might be hindered by cryptic reservoirs and a number of other challenges (e.g. further integration of HAT surveillance and control into national health systems, availability of skilled health care workers, development of more effective and adapted tools, and funding for and coordination of elimination efforts).


Assuntos
Trypanosoma brucei brucei/patogenicidade , Trypanosoma brucei gambiense/patogenicidade , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/prevenção & controle , África ao Sul do Saara/epidemiologia , Animais , Doenças Endêmicas , Humanos , Controle de Insetos , Insetos Vetores/parasitologia , Tripanossomíase Africana/epidemiologia , Moscas Tsé-Tsé/parasitologia , Organização Mundial da Saúde
5.
Trends Parasitol ; 38(2): 104-108, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34887168

RESUMO

The human serum protein apolipoprotein L1 (APOL1) kills Trypanosoma brucei but not the sleeping sickness agent Trypanosoma rhodesiense. APOL1 C-terminal variants can kill T. rhodesiense but they also induce kidney disease. Given topological and functional differences between intracellular and extracellular APOL1 isoforms, I propose that trypanolysis and kidney disease result from distinct APOL1 activities.


Assuntos
Nefropatias , Podócitos , Trypanosoma , Tripanossomíase Africana , Animais , Apolipoproteína L1/genética , Apolipoproteína L1/metabolismo , Humanos , Nefropatias/metabolismo , Podócitos/metabolismo , Trypanosoma brucei rhodesiense
6.
Indian J Med Microbiol ; 40(1): 169-171, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34238635

RESUMO

A young female patient from Ahmedabad city presented with acute febrile illness and bicytopenia (leukopenia and thrombocytopenia). She returned to India after recent visit to East Africa. Human African Trypanosomiasis (Sleeping sickness) was diagnosed by identification of Trypanosoma brucei rhodesiense in peripheral blood smear. She treated successfully with suramin. In India, we account this as second case of HAT after first report before 18 years in the published literature.


Assuntos
Tripanossomíase Africana , Animais , Feminino , Febre , Humanos , Índia , Trypanosoma brucei rhodesiense , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/tratamento farmacológico
7.
Eur J Med Chem ; 226: 113861, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34624822

RESUMO

Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei (T. b.), and affects communities in sub-Saharan Africa. Previously, analogues of a tetrahydroisoquinoline scaffold were reported as having in vitro activity (IC50 = 0.25-70.5 µM) against T. b. rhodesiense. In this study the synthesis and antitrypanosomal activity of 80 compounds based around a core tetrahydroisoquinoline scaffold are reported. A detailed structure activity relationship was revealed, and five derivatives (two of which have been previously reported) with inhibition of T. b. rhodesiense growth in the sub-micromolar range were identified. Four of these (3c, 12b, 17b and 26a) were also found to have good selectivity over mammalian cells (SI > 50). Calculated logD values and preliminary ADME studies predict that these compounds are likely to have good absorption and metabolic stability, with the ability to passively permeate the blood brain barrier. This makes them excellent leads for a blood-brain barrier permeable antitrypanosomal scaffold.


Assuntos
Tetra-Hidroisoquinolinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química , Tripanossomicidas/síntese química , Tripanossomicidas/química
8.
J Org Chem ; 86(17): 11763-11770, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479407

RESUMO

Bromoiesol sulfates A (1) and B (2), new polyhalogenated aryl sulfates, were isolated from a Salileptolyngbya sp. marine cyanobacterium along with their hydrolyzed compounds, bromoiesols A (3) and B (4). To pick up the candidates of their structures, we used Small Molecule Accurate Recognition Technology (SMART), an artificial intelligence-based structure-prediction tool, and their structures were elucidated on the basis of single-crystal X-ray diffraction analysis of bromoiesols (3 and 4). In addition, to verify the structures, the total synthesis of bromoiesol A sulfate (1) and bromoiesol A (3) was achieved. The bromoiesol family, especially bromoiesols (3 and 4), selectively inhibited the growth of the bloodstream form of Trypanosoma brucei rhodesiense, the causative agent of human African sleeping sickness.


Assuntos
Antiprotozoários , Tripanossomíase Africana , Animais , Antiprotozoários/farmacologia , Inteligência Artificial , Humanos , Sulfatos , Trypanosoma brucei rhodesiense
9.
ChemistryOpen ; 10(9): 922-927, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34553828

RESUMO

This study identified the isoindolone ring as a scaffold for novel agents against Trypanosoma brucei rhodesiense and explored the structure-activity relationships of various aromatic ring substitutions. The compounds were evaluated in an integrated in vitro screen. Eight compounds exhibited selective activity against T. b. rhodesiense (IC50 <2.2 µm) with no detectable side activity against T. cruzi and Leishmania infantum. Compound 20 showed low nanomolar potency against T. b. rhodesiense (IC50 =40 nm) and no toxicity against MRC-5 and PMM cell lines and may be regarded as a new lead template for agents against T. b. rhodesiense. The isoindolone-based compounds have the potential to progress into lead optimization in view of their highly selective in vitro potency, absence of cytotoxicity and acceptable metabolic stability. However, the solubility of the compounds represents a limiting factor that should be addressed to improve the physicochemical properties that are required to proceed further in the development of in vivo-active derivatives.


Assuntos
Isoindóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Animais , Linhagem Celular , Estabilidade de Medicamentos , Feminino , Humanos , Isoindóis/síntese química , Isoindóis/metabolismo , Isoindóis/toxicidade , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Solubilidade , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Tripanossomicidas/toxicidade
10.
Exp Parasitol ; 228: 108135, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34284027

RESUMO

Trypanosoma brucei rhodesiense is the causative agent for Rhodesian human African trypanosomiasis. The disease is considered acute, but varying clinical outcomes including chronic infections have been observed. The basis for these different clinical manifestations is thought to be associated with a combination of parasite and host factors. In the current study, Trypanosoma brucei rhodesiense strains responsible for varying infection outcomes were sought using mouse model. Clinical rHAT parasite isolates were subjected to PCR tests to confirm presence of the serum resistance associated (SRA) gene. Thereafter, four T. b. rhodesiense isolates were subjected to a comparative pathogenicity study using female Swiss white mice; the parasite strains were compared on the basis of parasitaemia, host survival time, clinical and postmortem biomarkers of infection severity. Isolates identified to cause acute and chronic disease were compared for establishment in insect vector, tsetse fly. The mouse survival time was significantly different (Log-rankp = 0.0001). With mice infected with strain KETRI 3801 exhibiting the shortest survival time (20 days) as compared to those infected with KETRI 3928 that, as controls, survived past the 60 days study period. In addition, development of anaemia was rapid in KETRI 3801 and least in KETRI 3928 infections, and followed the magnitude of survival time. Notably, hepatosplenomegaly was pronounced with longer survival. Mouse weight and feed intake reduced (KETRI 3801 > KETRI 2636 > EATRO 1762) except in KETRI 3928 infections which remained similar to controls. Comparatively, acute to chronic infection outcomes is in the order of KETRI 3801 > KETRI 2636 > EATRO 1762 > KETRI 3928, indicative of predominant role of strain dependent factors. Further, KETRI 3928 strain established better in tsetse as compared to KETRI 3801, suggesting that transmission of strains causing chronic infections could be common. In sum, we have identified Trypanosoma brucei rhodesiense strains that cause acute and chronic infections in mice, that will be valuable in investigating pathogen - host interactions responsible for varying disease outcomes and transmission in African trypanosomiasis.


Assuntos
Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/parasitologia , Moscas Tsé-Tsé/parasitologia , Animais , Ingestão de Alimentos , Feminino , Modelos Lineares , Fígado/patologia , Masculino , Camundongos , Tamanho do Órgão , Parasitemia/parasitologia , Baço/patologia , Trypanosoma brucei rhodesiense/isolamento & purificação , Virulência
11.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 33(3): 293-296, 2021 Jun 18.
Artigo em Chinês | MEDLINE | ID: mdl-34286532

RESUMO

OBJECTIVE: To investigate the prognosis of two rare imported patients with human African trypanosomias (HAT) after treatment in a follow-up study, and to evaluate the therapeutic efficacy, so as to provide insights into the treatment of imported HAT patients. METHODS: The white blood cells in cerebrospinal fluid samples and the trypomastigotes in cerebrospinal fluid and blood samples were monitored in an imported case with Trypanosoma brucei rhodesiense infection 1, 3, 11 and 25 months post-treatment and in an imported case with T. brucei gambiense infection 1, 3, 8 and 12 months post-treatment to evaluate the therapeutic efficacy and prognosis. RESULTS: There were 1, 1, 4 and 2 white blood cells in per µL of cerebrospinal fluid in the case with T. brucei rhodesiense infection 1, 3, 11 and 25 months post-treatment, and there were 3, 6, 4 and 3 white blood cells in per µL of cerebrospinal fluid in the case with T. brucei gambiense infection 1, 3, 8 and 12 months post-treatment. In addition, no trypomastigotes were identified in the cerebrospinal fluid or blood samples of either case with T. brucei rhodesiense or T. brucei gambiense infection. CONCLUSIONS: Following standardized treatment, two imported cases with human African trypanosomiasis cases recover satisfactorily, without any signs of relapse.


Assuntos
Tripanossomíase Africana , Animais , Seguimentos , Humanos , Prognóstico , Trypanosoma brucei gambiense , Trypanosoma brucei rhodesiense , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/tratamento farmacológico
12.
Mol Biochem Parasitol ; 245: 111395, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34246720

RESUMO

Rhodesain is the generic name for the cathepsin L-like peptidase of Trypanosoma brucei rhodesiense. The term rhodesain was derived from the subspecies epithet rhodesiense which itself originated form Rhodesia, a historical region in southern Africa named after the 19th century British imperialist and white supremacist Cecil Rhodes. This tainting could be grounds for discontinuing the name, however, there are also scientific grounds. Specifically, protein sequence comparisons and frequency-based difference profiling reveal that rhodesain is essentially identical (99.87-98.44%) to the cathepsin L-like peptidases of both T. b. brucei and T. b. gambiense. Accordingly, and based on a previously proposed terminology for kinetoplastid C1 peptidases (Caffrey and Steverding, 2009), we suggest the use of the formal term, TbrCATL, to denote the cathepsin L-like peptidases of the T. brucei subspecies. The earlier and informal term, 'brucipain', could also be used.


Assuntos
Trypanosoma brucei brucei , Tripanossomíase Africana , Sequência de Aminoácidos , Animais , Cisteína Endopeptidases , Peptídeo Hidrolases , Trypanosoma brucei rhodesiense
13.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199682

RESUMO

African trypanosomes cause diseases in humans and livestock. Human African trypanosomiasis is caused by Trypanosoma brucei rhodesiense and T. b. gambiense. Animal trypanosomoses have major effects on livestock production and the economy in developing countries, with disease management depending mainly on chemotherapy. Moreover, only few drugs are available and these have adverse effects on patients, are costly, show poor accessibility, and parasites develop drug resistance to them. Therefore, novel trypanocidal drugs are urgently needed. Here, the effects of synthesized nitrofurantoin analogs were evaluated against six species/strains of animal and human trypanosomes, and the treatment efficacy of the selected compounds was assessed in vivo. Analogs 11 and 12, containing 11- and 12-carbon aliphatic chains, respectively, showed the highest trypanocidal activity (IC50 < 0.34 µM) and the lowest cytotoxicity (IC50 > 246.02 µM) in vitro. Structure-activity relationship analysis suggested that the trypanocidal activity and cytotoxicity were related to the number of carbons in the aliphatic chain and electronegativity. In vivo experiments, involving oral treatment with nitrofurantoin, showed partial efficacy, whereas the selected analogs showed no treatment efficacy. These results indicate that nitrofurantoin analogs with high hydrophilicity are required for in vivo assessment to determine if they are promising leads for developing trypanocidal drugs.


Assuntos
Nitrofuranos/administração & dosagem , Nitrofuranos/síntese química , Nitrofurantoína/análogos & derivados , Tripanossomicidas/administração & dosagem , Tripanossomicidas/síntese química , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Camundongos , Estrutura Molecular , Nitrofuranos/química , Nitrofuranos/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos
14.
Eur J Med Chem ; 222: 113625, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34146914

RESUMO

Dicationic diamidines have been well established as potent antiparasitic agents with proven activity against tropical diseases like trypanosomiasis and malaria. This work presents the synthesis of new mono and diflexible triaryl amidines (6a-c, 13a,b and 17), their aza analogues (23 and 27) and respective methoxyamidine prodrugs (5, 7, 12a,b, 22 and 26). All diamidines were assessed in vitro against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) where they displayed potent to moderate activities at the nanomolar level with IC50s = 11-378 nM for T. b. r. and 4-323 nM against P. f.. In vivo efficacy testing against T. b. r. STIB900 has shown the monoflexible diamidine 6c as the most potent derivative in this study eliciting 4/4 cures of infected mice for a treatment period of >60 days upon a 4 × 5 mg/kg dose i. p. treatment. Moreover, thermal melting analysis measurement ΔTm for this series of diamidines/poly (dA-dT) complexes fell between 0.5 and 19 °C with 6c showing the highest binding to the DNA minor groove. Finally, a 50 ns molecular dynamics study of an AT-rich DNA dodecamer with compound 6c revealed a strong binding complex supported by vdW and electrostatic interactions.


Assuntos
Amidinas/farmacologia , Antiparasitários/farmacologia , Compostos Aza/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Pró-Fármacos/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Amidinas/síntese química , Amidinas/química , Antiparasitários/síntese química , Antiparasitários/química , Compostos Aza/síntese química , Compostos Aza/química , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/enzimologia
15.
PLoS Negl Trop Dis ; 15(6): e0009526, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34153047

RESUMO

Trypanosoma brucei rhodesiense is one of the causative agents of Human African Trypanosomiasis (HAT), known as sleeping sickness. The parasite invades the central nervous system and causes severe encephalitis that is fatal if left untreated. We have previously identified ecotin-like inhibitors of serine peptidases, named ISPs, in trypanosomatid parasitic protozoa. Here, we investigated the role of ISP2 in bloodstream form T. b. rhodesiense. We generated gene-deficient mutants lacking ISP2 (Δisp2), which displayed a growth profile in vitro similar to that of wild-type (WT) parasites. C57BL/6 mice infected with Δisp2 displayed lower blood parasitemia, a delayed hind leg pathological phenotype and survived longer. The immune response was examined at two time-points that corresponded with two peaks of parasitemia. At 4 days, the spleens of Δisp2-infected mice had a greater percentage of NOS2+ myeloid cells, IFN-γ+-NK cells and increased TNF-α compared to those infected with WT and parasites re-expressing ISP2 (Δisp2:ISP2). By 13 days the increased NOS2+ population was sustained in Δisp2-infected mice, along with increased percentages of monocyte-derived dendritic cells, as well as CD19+ B lymphocytes, and CD8+ and CD4+ T lymphocytes. Taken together, these findings indicate that ISP2 contributes to T. b. rhodesiense virulence in mice and attenuates the inflammatory response during early infection.


Assuntos
Inibidores de Serino Proteinase/metabolismo , Trypanosoma brucei rhodesiense/genética , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/imunologia , Animais , Animais Geneticamente Modificados , Anticorpos Monoclonais , Feminino , Inflamação , Camundongos Endogâmicos C57BL , Inibidores de Serino Proteinase/genética , Baço/parasitologia , Virulência
16.
Eur J Med Chem ; 221: 113545, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34091216

RESUMO

A series of monocationic new guanidinobenzimidazole derivatives were prepared in a four step process starting from 2-nitro-1,4-phenylendiamine. Their antiparasitic activity against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani were evaluated in vitro. Two out of 20 tested monocationic compounds (7, 14) showed close activity with reference drug chloroquine against P. Falciparum. To understand the interactions between DNA minor groove and in vitro active compounds (7, 14) molecular docking studies were carried out. Stability and binding energies of DNA-ligand complexes formed by DNA with compounds 7 and 14 were measured by molecular dynamics simulations throughout 200 ns time. Root mean square deviation (RMSD) values of the ligands remained stable below 0.25 mm and root mean square fluctuation (RMSF) values of the active site residues with which it interacted decreased compared to the apo form. All compounds exhibited theoretical absorption, distribution, metabolism and excretion (ADME) profiles conforming to Lipinski's and Ghose's restrictive rules.


Assuntos
Antiprotozoários/farmacologia , Benzimidazóis/farmacologia , Guanidina/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Benzimidazóis/síntese química , Benzimidazóis/química , Cátions/síntese química , Cátions/química , Cátions/farmacologia , Relação Dose-Resposta a Droga , Guanidina/síntese química , Guanidina/química , Leishmania donovani/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos
17.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072147

RESUMO

As part of our studies on antiprotozoal activity of approved herbal medicinal products, we previously found that a commercial tincture from Salvia officinalis L. (common Sage, Lamiaceae) possesses high activity against Trypanosoma brucei rhodesiense (Tbr), causative agent of East African Human Trypanosomiasis. We have now investigated in detail the antitrypanosomal constituents of this preparation. A variety of fractions were tested for antitrypanosomal activity and analyzed by UHPLC/+ESI QqTOF MS. The resulting data were used to generate a partial least squares (PLS) regression model that highlighted eight particular constituents that were likely to account for the major part of the bioactivity. These compounds were then purified and identified and their activity against the pathogen tested. All identified compounds (one flavonoid and eight diterpenes) displayed significant activity against Tbr, in some cases higher than that of the total tincture. From the overall results, it can be concluded that the antitrypanosomal activity of S. officinalis L. is, for the major part, caused by abietane-type diterpenes of the rosmanol/rosmaquinone group.


Assuntos
Antiprotozoários/farmacologia , Salvia officinalis/metabolismo , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Abietanos/química , Animais , Calibragem , Cromatografia Líquida de Alta Pressão , Diterpenos/química , Flavonoides/química , Concentração Inibidora 50 , Análise dos Mínimos Quadrados , Espectroscopia de Ressonância Magnética , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Testes de Sensibilidade Parasitária , Extratos Vegetais , Preparações de Plantas/farmacologia , Plantas Medicinais , Ratos , Espectrometria de Massas por Ionização por Electrospray , Tripanossomíase/parasitologia
18.
ACS Infect Dis ; 7(6): 1578-1583, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33971090

RESUMO

We now describe the physicochemical profiling, in vitro ADME, and antiparasitic activity of eight N,N'-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD7.4 values ranged from 2.5 to 4.5; kinetic aq. solubilities were ≤6.3 µg/mL, and plasma protein binding ranged from 95 to 99%. All of the compounds had low intrinsic clearance values in human, but not mouse, liver microsomes. Although no N,N'-diarylurea had submicromolar potency against Trypanosoma cruzi, two had submicromolar potencies against Toxoplasma gondii and Trypanosoma brucei rhodesiense, and five had submicromolar potencies against Leishmania donovani. Plasmodium falciparum appeared to be the most susceptible to growth inhibition by this compound series. Most of the N,N'-diarylureas had antiprotozoal selectivities ≥10. One N,N'-diarylurea had demonstrable activity in mouse models of malaria and toxoplasmosis.


Assuntos
Antiprotozoários , Leishmania donovani , Trypanosoma cruzi , Animais , Antiprotozoários/farmacologia , Camundongos , Trypanosoma brucei rhodesiense , Ureia
19.
Molecules ; 26(6)2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33801067

RESUMO

Chemical conversion of the extract of natural resources is a very attractive way to expand the chemical space to discover bioactive compounds. In order to search for new medicines to treat parasitic diseases that cause high morbidity and mortality in affected countries in the world, the ethyl acetate extract from the rhizome of Alpinia galanga (L.) has been chemically converted by epoxidation using dioxirane generated in situ. The biological activity of chemically converted extract (CCE) of A. galanga (L.) significantly increased the activity against Leishmania major up to 82.6 ± 6.2 % at 25 µg/mL (whereas 2.7 ± 0.8% for the original extract). By bioassay-guided fractionation, new phenylpropanoids (1-6) and four known compounds, hydroquinone (7), 4-hydroxy(4-hydroxyphenyl)methoxy)benzaldehyde (8), isocoumarin cis 4-hydroxymelein (9), and (2S,3S,6R,7R,9S,10S)-humulene triepoxide (10) were isolated from CCE. The structures of isolated compounds were determined by spectroscopic analyses of 1D and 2D NMR, IR, and MS spectra. The most active compound was hydroquinone (7) with IC50 = 0.37 ± 1.37 µg/mL as a substantial active principle of CCE. In addition, the new phenylpropanoid 2 (IC50 = 27.8 ± 0.34 µg/mL) also showed significant activity against L. major compared to the positive control miltefosine (IC50 = 7.47 ± 0.3 µg/mL). The activities of the isolated compounds were also evaluated against Plasmodium falciparum, Trypanosoma brucei gambisense and Trypanosoma brucei rhodeisense. Interestingly, compound 2 was selectively active against trypanosomes with potent activity. To the best of our knowledge, this is the first report on the bioactive "unnatural" natural products from the crude extract of A. galanga (L.) by chemical conversion and on its activities against causal pathogens of leishmaniasis, trypanosomiasis, and malaria.


Assuntos
Alpinia/química , Antimaláricos , Extratos Vegetais/química , Plasmodium falciparum/crescimento & desenvolvimento , Propanóis , Trypanosoma brucei gambiense/crescimento & desenvolvimento , Trypanosoma brucei rhodesiense/crescimento & desenvolvimento , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Propanóis/química , Propanóis/isolamento & purificação , Propanóis/farmacologia , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificação , Tripanossomicidas/farmacologia
20.
J Nat Prod ; 84(4): 1335-1344, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33843232

RESUMO

Spirombandakamine A3 (7) is only the third known naphthylisoquinoline dimer with a spiro-fused novel molecular framework and the first such representative to possess a relative trans-configuration at the two chiral centers in both tetrahydroisoquinoline subunits. It was found in the leaves of a botanically as yet unidentified Congolese Ancistrocladus plant, which is morphologically closely related to the Central African taxon Ancistrocladus ealaensis. Likewise isolated were the new cyclombandakamines A8 (8) and A9 (9), which belong to another most recently discovered type of unusual oxygen-bridged naphthylisoquinoline dimers and two previously described "open-chain" analogues, mbandakamines C (10) and D (11). The full absolute stereostructures of these compounds were assigned by combining spectroscopic, chemical, and chiroptical methods. Preliminary biomimetic investigations indicated that both spirombandakamine- and cyclombandakamine-type dimers result from the oxidation of their open-chain mbandakamine-type congeners. The new dimeric alkaloids 7-9 displayed potent growth-inhibitory activity against Plasmodium falciparum, the protozoal pathogen causing malaria, and moderate effects on Trypanosoma brucei rhodesiense, the parasite responsible for African sleeping sickness.


Assuntos
Alcaloides/farmacologia , Antiprotozoários/farmacologia , Caryophyllales/química , Isoquinolinas/farmacologia , Alcaloides/isolamento & purificação , Animais , Antiprotozoários/isolamento & purificação , Linhagem Celular , República Democrática do Congo , Isoquinolinas/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Plasmodium falciparum/efeitos dos fármacos , Ratos , Trypanosoma brucei rhodesiense/efeitos dos fármacos
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