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1.
Mem Inst Oswaldo Cruz ; 115: e190348, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32049098

RESUMEN

BACKGROUND: It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide. OBJETIVES: To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity. METHODS: CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis. FINDINGS CMC-20: showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole. MAIN CONCLUSIONS: The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.


Asunto(s)
Albendazol/farmacología , Antiprotozoarios/farmacología , Proteínas del Citoesqueleto/efectos de los fármacos , Giardia lamblia/efectos de los fármacos , Tiazoles/farmacología , Albendazol/química , Animales , Antiprotozoarios/química , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Ratones , Pruebas de Sensibilidad Parasitaria , Tiazoles/química , Factores de Tiempo
2.
J Enzyme Inhib Med Chem ; 35(1): 432-459, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31899980

RESUMEN

A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays.


Asunto(s)
Antiprotozoarios/química , Antiprotozoarios/farmacología , Diseño de Drogas , Quinolinas/química , Quinolinas/farmacología , Antiprotozoarios/síntesis química , Células Hep G2 , Humanos , Leishmania donovani/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Quinolinas/síntesis química , Relación Estructura-Actividad , Trypanosoma brucei brucei/efectos de los fármacos
3.
Exp Parasitol ; 210: 107831, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31926147

RESUMEN

Babesia (B.) bovis is one of the main etiological agents of bovine babesiosis, causes serious economic losses to the cattle industry. Control of bovine babesiosis has been hindered by the limited treatment selection for B. bovis, thus, new options are urgently needed. We explored the drug library and unbiasedly screened 640 food and drug administration (FDA) approved drug compounds for their inhibitory activities against B. bovis in vitro. The initial screening identified 13 potentially effective compounds. Four potent compounds, namely mycophenolic acid (MPA), pentamidine (PTD), doxorubicin hydrochloride (DBH) and vorinostat (SAHA) exhibited the lowest IC50 and then selected for further evaluation of their in vitro efficacies using viability, combination inhibitory and cytotoxicity assays. The half-maximal inhibitory concentration (IC50) values of MPA, PTD, DBH, SAHA were 11.38 ± 1.66, 13.12 ± 4.29, 1.79 ± 0.15 and 45.18 ± 7.37 µM, respectively. Of note, DBH exhibited IC50 lower than that calculated for the commonly used antibabesial drug, diminazene aceturate (DA). The viability result revealed the ability of MPA, PTD, DBH, SAHA to prevent the regrowth of treated parasite at 4 × and 2 × of IC50. Antagonistic interactions against B. bovis were observed after treatment with either MPA, PTD, DBH or SAHA in combination with DA. Our findings indicate the richness of FDA approved compounds by novel potent antibabesial candidates and the identified potent compounds especially DBH might be used for the treatment of animal babesiosis caused by B. bovis.


Asunto(s)
Antiprotozoarios/farmacología , Babesia bovis/efectos de los fármacos , Animales , Antiprotozoarios/toxicidad , Babesia bovis/crecimiento & desarrollo , Babesiosis/tratamiento farmacológico , Babesiosis/parasitología , Bovinos , Enfermedades de los Bovinos/tratamiento farmacológico , Enfermedades de los Bovinos/parasitología , Perros , Doxorrubicina/farmacología , Doxorrubicina/toxicidad , Aprobación de Drogas , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Concentración 50 Inhibidora , Células de Riñón Canino Madin Darby/efectos de los fármacos , Ácido Micofenólico/farmacología , Ácido Micofenólico/toxicidad , Pentamidina/farmacología , Pentamidina/toxicidad , Bibliotecas de Moléculas Pequeñas , Espectrometría de Fluorescencia , Vorinostat/farmacología , Vorinostat/toxicidad
4.
Exp Parasitol ; 210: 107833, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31935358

RESUMEN

Safety precautions prior to contact lens usage is essential for preventing Acanthamoeba keratitis. Contact lens disinfecting solutions containing 3% hydrogen peroxide (H2O2) are known to exert amoebicidal effect against Acanthamoeba. Yet, these solutions need to be neutralized to prevent ocular irritation, which consequently may result in incomplete disinfection. In this study, amoebicidal effect of tert-butyl hydroperoxide (tBHP) was investigated and its efficacy was compared to those of hydrogen peroxide (H2O2). H2O2 and tBHP showed dose dependent amoebicidal effect, however high concentration of these compounds demonstrated cytotoxicity in human corneal epithelial (HCE) cells. To reduce their cytotoxicity, the concentrations of both compounds were diluted to 50 µM and subsequently combined with 10 µM vorinostat to enhance amoebicidal effect. Addition of vorinostat induced high amoebicidal effect against Acanthamoeba trophozoites, even at low concentrations of H2O2 or tBHP. Cellular damage induced by combined treatment of H2O2 or tBHP with vorinostat in Acanthamoeba were determined by assessing cell cycle arrest and apoptosis via FACS analysis. While 50 µM H2O2 combined with 10 µM vorinostat showed 36.26% cytotoxicity on HCE cells during 24 h exposure, 50 µM tBHP with 10 µM vorinostat did not show cytotoxicity on HCE cells. These findings suggest that the application of tBHP and vorinostat for Acanthamoeba keratitis treatment and contact lens disinfection system is highly plausible.


Asunto(s)
Acanthamoeba/efectos de los fármacos , Antiprotozoarios/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Vorinostat/farmacología , terc-Butilhidroperóxido/farmacología , Acanthamoeba/citología , Acanthamoeba/genética , Antiinfecciosos Locales/farmacología , Apoptosis/efectos de los fármacos , Células Cultivadas , Córnea/citología , Córnea/efectos de los fármacos , Córnea/parasitología , ADN Protozoario/efectos de los fármacos , ADN Protozoario/fisiología , Combinación de Medicamentos , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/parasitología , Humanos , Peróxido de Hidrógeno/farmacología
5.
Chem Biol Interact ; 315: 108850, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31634447

RESUMEN

1,2,3-triazolium salts are poorly understood regarding their antileishmanial activity. Hence, as an effort to identify novel chemical scaffolds as antileishmanial agents, a series of 1,2,3-triazolium salts (TS) and corresponding 1,2,3-triazole (T) precursors including new epoxide derivatives were synthesized and assayed against Leishmania amazonensis promastigote and intracellular amastigote forms. Among them, the compound TS-6 exhibited promising activity on promastigotes (IC50 = 3.61 µM) and intracellular amastigotes (IC50 = 7.61 µM) of L. amazonensis, superior to miltefosine (IC50 > 10.0 µM), used as reference drug. In addition, TS-6 showed negligible cytotoxicity on murine peritoneal macrophages with a SI of about 10. Studies on the mode of action of TS-6 indicate mitochondrial dysfunction through an increase in 'total' and mitochondrial-ROS as well as depolarization of mitochondrial membrane potential of L. amazonensis promastigotes. In silico physicochemical studies indicate that the TS-6 could potentially be used as an oral drug.


Asunto(s)
Antiprotozoarios/farmacología , Leishmania mexicana/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Triazoles/farmacología , Animales , Leishmania mexicana/metabolismo , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/parasitología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos BALB C , Mitocondrias/metabolismo , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacología
6.
Chem Biol Interact ; 315: 108899, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31738906

RESUMEN

Parasitic diseases still represent serious public health problems, since the high and steady emergence of resistant strains is evident. Because parasitic infections are distributed predominantly in developing countries, less toxic, more efficient, safer and more accessible drugs have become desirable in the treatment of the infected population. This is the case of leishmaniasis, an infectious disease caused by a protozoan of the genus Leishmania sp., responsible for triggering pathological processes from the simplest to the most severe forms leading to high rates of morbidity and mortality throughout the world. In the search for new leishmanicidal drugs, the thiosemicarbazones and the indole fragments have been identified as promising structures for leishmanicidal activity. The present study proposes the synthesis and structural characterization of new indole-thiosemicarbazone derivatives (2a-j), in addition to performing in vitro evaluations through cytotoxicity assays using macrophages (J774) activity against forms of Leishmania infantum and Leishmania amazonensis promastigote as well as ultrastructural analyzes in promastigotes of L. infantum. Results show that the indole-thiosemicarbazone derivatives were obtained with yield values varying from 32.09 to 94.64%. In the evaluation of cytotoxicity, the indole-thiosemicarbazone compounds presented CC50 values between 53.23 and 357.97 µM. Concerning the evaluation against L. amazonensis promastigote forms, IC50 values ranged between 12.31 and  > 481.52 µM, while the activity against L. infantum promastigotes obtained IC50 values between 4.36 and 23.35 µM. The compounds 2d and 2i tested against L. infantum were the most promising in the series, as they showed the lowest IC50 values: 5.60 and 4.36 respectively. The parasites treated with the compounds 2d and 2i showed several structural alterations, such as shrinkage of the cell body, shortening and loss of the flagellum, intense mitochondrial swelling and vacuolization of the cytoplasm leading the parasite to cellular unviability. Therefore, the indole-thiosemicarbazone compounds are promising because they yield considerable synthesis, have low cytotoxicity to mammalian cells and act as leishmanicidal agents.


Asunto(s)
Antiprotozoarios/farmacología , Indoles/farmacología , Leishmania infantum/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Tiosemicarbazonas/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Leishmaniasis/parasitología , Macrófagos/efectos de los fármacos , Mitocondrias/efectos de los fármacos
7.
Eur J Med Chem ; 186: 111895, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31771825

RESUMEN

A series of eight alkyl gallium complexes of general formulae [GaMe2(L)] and [Ga(Me)2L] have been synthesised, characterised and their antimicrobial activity against bacteria, cancer cells and Leishmania assessed. All eight complexes are novel, with the solid-state structures of all complexes successfully authenticated by single crystal X-ray diffraction. The dimethyl complexes all adopt a four-coordinate tetrahedral confirmation, while the monomethyl complexes are five-coordinate trigonal bipyramidal. All complexes were screened for their anti-bacterial activity either by solution state diffusion, or a solid-state stab test. The five soluble complexes underwent testing against two differing mammalian cell controls, with excellent selectivity observed against COS-7 cells, with an IC50 range of 88.5 µM to ≥100 µM. Each soluble complex was also tested for their anti-cancer capabilities, with no significant activity observed. Excellent activity was exhibited against the protozoan parasite Leishmania major (strain: V121) in both the promastigote and amastigote forms, with IC50 values ranging from 1.11 µM-13.4 µM for their anti-promastigote activity and % infection values of 3.5% ± 0.65-11.5% ± 0.65 for the more clinically relevant amastigote. Selectivity indices for each were found to be in the ranges of 6.61-64.7, with significant selectivity noted for two of the complexes. At minimum, the gallium complexes show a 3-fold enhancement in activity towards the Leishmaniaamastigotes over the parent quinolinols alone.


Asunto(s)
Antiprotozoarios/farmacología , Complejos de Coordinación/farmacología , Galio/farmacología , Hidroxiquinolinas/farmacología , Leishmania major/efectos de los fármacos , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Células COS , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Relación Dosis-Respuesta a Droga , Galio/química , Células HeLa , Humanos , Hidroxiquinolinas/química , Leishmania major/metabolismo , Ratones , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Especies Reactivas de Oxígeno/análisis , Relación Estructura-Actividad
8.
Med Chem ; 16(1): 24-38, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31218962

RESUMEN

More than 10 million people around the world are afflicted by Neglected Tropical Diseases, such as Chagas Disease, Human African Trypanosomiasis, and Leishmania. These diseases mostly occur in undeveloped countries that suffer from a lack of economic incentive, research, and policy for new compound development. Sulfonamide moieties are effective scaffolds present in several compounds that are determinants to treat various diseases, principally neglected tropical diseases. This review article examines the contribution of these scaffolds in medicinal chemistry in the last five years, focusing on three trypanosomatid parasites: Trypanosoma cruzi, Trypanosoma brucei, and Leishmania ssp. We also present perspectives for their use in drug designs in an effort to contribute to new drug development. In addition, we consider the physicochemical parameters, whose molecules all presented according to Lipinski's rule. The correlation between the selective index and LogP was evaluated, showing that sulfonamide derivatives can act differently against each trypanosomatid parasite. Moreover, the approaches of novel drugs and technologies are very important for the eventual drug discovery against trypanosomatid diseases.


Asunto(s)
Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Sulfonamidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química
9.
Eur J Med Chem ; 186: 111860, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31759728

RESUMEN

Methionine aminopeptidase 1 of Leishmania donovani (LdMetAP1) is a novel antileishmanial target for its role in vital N-terminal methionine processing. After LdMetAP1 expression and purification, we employed a series of biochemical assays to determine optimal conditions for catalysis, metal dependence and substrate preferences for this ubiquitous enzyme. Screening of newly synthesized quinoline-carbaldehyde derivatives in inhibition assays led to the identification of HQ14 and HQ15 as novel and specific inhibitors for LdMetAP1 which compete with substrate for binding to the catalytic active site. Both leads bind LdMetAP1 with high affinity and possess druglikeness. Biochemical studies suggested HQ14 and HQ15 to be comparatively less effective against purified HsMetAP1 and showed no or less toxicity. We further show selectivity and inhibition of lead inhibitors is sensed through a non-catalytic Thr residue unique to LdMetAP1. Finally, structural studies highlight key differences in the binding modes of HQ14 and HQ15 to LdMetAP1 and HsMetAP1 providing structural basis for differences in inhibition. The study demonstrates the feasibility of deploying small drug like molecules to selectively target the catalytic activity of LdMetAP1 which may provide an effective treatment of leishmaniasis.


Asunto(s)
Aldehídos/farmacología , Aminopeptidasas/antagonistas & inhibidores , Antiprotozoarios/farmacología , Leishmania donovani/efectos de los fármacos , Quinolinas/farmacología , Aldehídos/síntesis química , Aldehídos/química , Aminopeptidasas/metabolismo , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Leishmania donovani/enzimología , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-Actividad
10.
Fitoterapia ; 140: 104420, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31733344

RESUMEN

We report for the first time the isolation of 2-furyl(phenyl)methanol (5) from the chloroform extracts of the Atractylis gummifera roots. A. gummifera is a thistle belonging to the Asteraceae family that produces the ent-kaurane diterpenoid glycoside atractyloside (ATR). ATR (1) was isolated and chemically modified to obtain its aglycone atractyligenin (2) and the methylated derivatives ATR-OMe (3) and genine-OMe (4). The compounds 1-5 were structurally characterised and evaluated against the intracellular amastigote, cultured within macrophages, and the extracellular promastigote of Leishmania donovani, the protozoan parasite responsible for the highly infective disease visceral leishmaniasis, which is fatal if untreated. The 2-furyl(phenyl)methanol 5 exhibited notable activity against the promastigote.


Asunto(s)
Antiprotozoarios/farmacología , Atractylis/química , Leishmania donovani/efectos de los fármacos , Metanol/farmacología , Animales , Antiprotozoarios/aislamiento & purificación , Italia , Macrófagos/parasitología , Metanol/análogos & derivados , Metanol/aislamiento & purificación , Ratones Endogámicos BALB C , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Extractos Vegetales , Rizoma/química
11.
Eur J Med Chem ; 186: 111887, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31787363

RESUMEN

The current treatment of Chagas disease is based on the use of two drugs, nifurtimox (Nfx) and benznidazole (Bnz), both of which present limited efficacy in the chronic stage of the disease and toxic side effects. Thus, the discovery of novel compounds is urgently required. Herein, we report the successful synthesis of 4-nitroimidazole analogs of Bnz via nucleophilic aromatic substitution or cycloaddition reactions. The analogs were biologically evaluated, and compound 4 (4-cyclopropyl-1-(1-methyl-4-nitro-1H-imidazole-5-yl)-1H-1,2,3-triazole) was identified as the most potent against both the trypomastigote (IC50 = 5.4 µM) and amastigote (IC50 = 12.0 µM) forms of T. cruzi, showing activity in the same range as Bnz (IC50 = 8.8 and 8.7 µM, respectively). The cytotoxic and genotoxic activities of compounds 5, 4 and 11 were assessed. These three compounds were cytotoxic and genotoxic to RAW and HepG2 cells and mutagenic to Salmonella enterica strains. However, 4 exhibited toxic effects only at concentrations higher than those needed for trypanocidal activity. Molecular docking of 4 showed the importance of the size and π-π interactions between the nitroimidazole and the cofactor (flavin mononucleotide) of T.cruzi-nitroreductase (TcNTR). Moreover, the residues His503 and Tyr545 are relevant for binding to TcNTR. Our design strategy was capable of generating novel and active Bnz analogs.


Asunto(s)
Antiprotozoarios/farmacología , Nitroimidazoles/farmacología , Salmonella enterica/efectos de los fármacos , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Nitroimidazoles/síntesis química , Nitroimidazoles/química , Nitrorreductasas/antagonistas & inhibidores , Nitrorreductasas/metabolismo , Células RAW 264.7 , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/química , Trypanosoma cruzi/enzimología
12.
Med Chem ; 16(1): 39-51, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31208311

RESUMEN

BACKGROUND: Leishmaniasis is a neglected disease that does not have adequate treatment. It affects around 12 million people around the world and is classified as a neglected disease by the World Health Organization. In this context, strategies to obtain new, more active and less toxic drugs should be stimulated. Sources of natural products combined with synthetic and chemoinformatic methodologies are strategies used to obtain molecules that are most likely to be effective against a specific disease. Computer-Aided Drug Design has become an indispensable tool in the pharmaceutical industry and academia in recent years and has been employed during various stages of the drug design process. OBJECTIVES: Perform structure- and ligand-based approaches, synthesize and characterize some compounds with materials available in our laboratories to verify the method's efficiency. METHODS: We created a database with 33 cyclic imides and evaluated their potential anti- Leishmanial activity (L. amazonensis and L. donovani) through ligand- and structure-based virtual screening. A diverse set selected from ChEMBL databanks of 818 structures (L. donovani) and 722 structures (L. amazonensis), with tested anti-Leishmanial activity against promastigotes forms, were classified according to pIC50 values to generate and validate a Random Forest model that shows higher statistical indices values. The structures of four different L. donovani enzymes were downloaded from the Protein Data Bank and the imides' structures were submitted to molecular docking. So, with available materials and technical feasibility of our laboratories, we have synthesized and characterized seven compounds through cyclization reactions between isosafrole and maleic anhydride followed by treatment with different amines to obtain new cyclic imides to evaluate their anti-Leishmanial activity. RESULTS: In silico study allowed us to suggest that the cyclic imides 516, 25, 31, 24, 32, 2, 3, 22 can be tested as potential multitarget molecules for leishmanial treatment, presenting activity probability against four strategic enzymes (Topoisomerase I, N-myristoyltransferase, cyclophilin and Oacetylserine sulfhydrylase). The compounds synthesized and tested presented pIC50 values less than 4.7 for Leishmania amazonensis. CONCLUSION: After combined approach evaluation, we have synthesized and characterized seven cyclic imides by IR, 1H NMR, 13C-APT NMR, COSY, HETCOR and HMBC. The compounds tested against promastigote forms of L. amazonensis presented pIC50 values less than 4.7, showing that our method was efficient in predicting true negative molecules.


Asunto(s)
Antiprotozoarios/farmacología , Imidas/farmacología , Leishmania/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Imidas/síntesis química , Imidas/química , Ligandos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Especificidad de la Especie , Relación Estructura-Actividad
13.
J Enzyme Inhib Med Chem ; 35(1): 377-382, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31856608

RESUMEN

The inhibition of δ- and η-class carbonic anhydrases (CAs; EC 4.2.1.1) was poorly investigated so far. Only one δ-CA, TweCA from the diatom Thalassiosira weissflogii, and one η-CA, PfCA, from Plasmodium falciparum, have been cloned and characterised to date. To enrich δ- and η-CAs inhibition profiles, a panel of 22 phenols was investigated for TweCA and PfCA inhibition. Some derivatives showed effective, sub-micromolar inhibition of TweCA (KIs 0.81-65.4 µM) and PfCA (KIs 0.62-78.7 µM). A subset of compounds demonstrated a significant selectivity for the target CAs over the human physiologically relevant ones. This study promotes the identification of new potent and selective inhibitors of TweCA and PfCA, which could be considered as leads for finding molecular probes in the study of carbon fixation processes (in which TweCA and orthologue enzymes are involved) or drug candidates in the treatment of malaria.


Asunto(s)
Antiprotozoarios/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Diatomeas/enzimología , Fenoles/farmacología , Plasmodium falciparum/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Fenoles/síntesis química , Fenoles/química , Plasmodium falciparum/enzimología , Relación Estructura-Actividad
14.
J Enzyme Inhib Med Chem ; 35(1): 199-210, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31752556

RESUMEN

Previous reports have validated the glycogen synthase kinase-3 (GSK-3) as a druggable target against the human protozoan parasite Leishmania. This prompted us to search for new leishmanicidal scaffolds as inhibitors of this enzyme from our in-house library of human GSK-3ß inhibitors, as well as from the Leishbox collection of leishmanicidal compounds developed by GlaxoSmithKline. As a result, new leishmanicidal inhibitors acting on Leishmania GSK-3 at micromolar concentrations were found. These inhibitors belong to six different chemical classes (thiadiazolidindione, halomethylketone, maleimide, benzoimidazole, N-phenylpyrimidine-2-amine and oxadiazole). In addition, the binding mode of the most active compounds into Leishmania GSK-3 was approached using computational tools. On the whole, we have uncovered new chemical scaffolds with an appealing prospective in the development and use of Leishmania GSK-3 inhibitors against this infectious protozoan.


Asunto(s)
Antiprotozoarios/farmacología , Descubrimiento de Drogas , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Leishmania/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Leishmania/citología , Leishmania/enzimología , Simulación del Acoplamiento Molecular , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad
15.
J Ethnopharmacol ; 247: 112270, 2020 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-31589965

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Primates forage on a variety of plant parts to balance their dietary intake to meet requirements of energy, nutrition and maintenance, however the reason(s) leading them to ingest some plants which have no nutritional value and/or contain bioactive or even toxic secondary metabolites is recently gaining closer attention. The growing literature suggests that primates consume plants for medicinal purposes (self-medication) as well, particularly when infected with parasites and pathogens (bacteria, viruses, microbes). Interestingly, some of the plants they consume are also used by humans for similar purposes or may have potential uses for humans. MATERIALS AND METHODS: As part of a 16-month study of the parasite ecology of a sub-species of Japanese macaques (Macaca fuscata yakui) on the island of Yakushima, we surveyed their feeding habits and collected a subset of plants and plant parts observed being ingested by macaques. The ethnomedicinal value of these plants was surveyed and methanolic extracts of 45 plant parts were tested in vitro against important parasites of humans, including four protozoan parasites Plasmodium falciparum, Trypanosoma brucei rhodesiense, T. cruzi and Leishmania donovani, and the trematode flatworm Schistosoma mansoni. Potential toxicity of the extracts was also assessed on mammalian cells. RESULTS: A wide range of ethnomedicinal uses in Asia for these plants is noted, with 37% associated with the treatment of parasites, pathogens and related symptoms. Additionally, the 45 extracts tested showed broad and significant activity against our test organisms. All extracts were active against T. b. rhodesiense. The majority (over 80%) inhibited the growth of P. falciparum and L. donovani. Half of the extracts also displayed antiprotozoal potential against T. cruzi while only several extracts were active against both larval and adult stages of S. mansoni. Cytotoxicity was generally low, although several extracts lacked specific toxicity to test parasites. CONCLUSIONS: Our results indicated a number of plants and their parts to have antiparasitic activity not previously reported in the ethnopharmacological literature. Enhanced understanding of the primate diets, particularly during periods of intensified parasite infection risk may help to further narrow down plants of interest for lead compound development. The study of animal self-medication is a complementary approach, with precedence, to drug discovery of new lead drug compounds against human parasitic diseases.


Asunto(s)
Antihelmínticos/farmacología , Antiprotozoarios/farmacología , Extractos Vegetales/farmacología , Plantas Medicinales/química , Infecciones Protozoarias en Animales/tratamiento farmacológico , Esquistosomiasis mansoni/tratamiento farmacológico , Animales , Antihelmínticos/uso terapéutico , Antiprotozoarios/uso terapéutico , Etnofarmacología , Conducta Alimentaria , Femenino , Islas , Japón , Leishmania donovani/efectos de los fármacos , Leishmania donovani/aislamiento & purificación , Masculino , Medicina Tradicional/métodos , Pruebas de Sensibilidad Parasitaria , Extractos Vegetales/uso terapéutico , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/aislamiento & purificación , Infecciones Protozoarias en Animales/parasitología , Schistosoma mansoni/aislamiento & purificación , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/veterinaria , Automedicación/veterinaria , Pruebas de Toxicidad , Trypanosoma brucei rhodesiense/aislamiento & purificación , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/aislamiento & purificación
16.
Exp Parasitol ; 209: 107823, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31862270

RESUMEN

Typically, antimicrobial peptides (AMPs) are short positive charged peptides serving a key role in innate immunity as well as antimicrobial activity. Discovering novel therapeutic agents is considered as an undeniable demand due to increasing microbial species with antibiotic resistance. In this direction, the unique ability of AMPs to modulate immune responses highlighted them as novel drug candidates in the field of microbiology. Patients affected by leishmaniasis; a neglected tropical disease, confront serious problems for their treatment including resistance to common drugs as well as toxicity and high cost of therapy. So, there is a need for development of new drug candidates to control the diseases. Jellein, a peptide derived from royal jelly of honeybee has been shown to have promising effect against several bacterial and fungal species. In current study, anti-leishmanial effect of Jellein and its lauric acid conjugated form was investigated against two forms of Leishmania major (L. major) parasite. Moreover, cytotoxic effect of these peptides was studied in THP1 cell line and human Red Blood Cells (RBCs). Furthermore, the mechanism of action of peptides on L. major promastigotes was assessed through different methods. The results demonstrated that, conjugation of lauric acid to Jellein not only had no effect on the elevation of antimicrobial activity but also halted it completely. Moreover, Jellein caused a limitation in the number of L. major promastigotes by pore formation as well as changing the membrane potential rather than induction of apoptosis or activation of caspases.


Asunto(s)
Péptidos Catiónicos Antimicrobianos/farmacología , Antiprotozoarios/farmacología , Leishmania major/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Oligopéptidos/química , Antígenos de Diferenciación de Linfocitos B/farmacología , Péptidos Catiónicos Antimicrobianos/uso terapéutico , Péptidos Catiónicos Antimicrobianos/toxicidad , Antiprotozoarios/uso terapéutico , Antiprotozoarios/toxicidad , Caspasas/efectos de los fármacos , Caspasas/metabolismo , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Ácidos Grasos/química , Citometría de Flujo , Hemólisis , Antígenos de Histocompatibilidad Clase II/farmacología , Humanos , Ácidos Láuricos/farmacología , Ácidos Láuricos/uso terapéutico , Ácidos Láuricos/toxicidad , Leishmania major/ultraestructura , Potenciales de la Membrana/efectos de los fármacos , Microscopía Electrónica de Rastreo , Enfermedades Desatendidas/tratamiento farmacológico , Enfermedades Desatendidas/parasitología , Oligopéptidos/farmacología , Oligopéptidos/uso terapéutico , Oligopéptidos/toxicidad
17.
PLoS Negl Trop Dis ; 13(12): e0007885, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31790397

RESUMEN

Monitoring the drug susceptibility of Leishmania isolates still largely relies on standard in vitro cell-based susceptibility assays using (patient-isolated) promastigotes for infection. Although this assay is widely used, no fully standardized/harmonized protocol is yet available hence resulting in the application of a wide variety of host cells (primary cells and cell lines), different drug exposure times, detection methods and endpoint criteria. Advocacy for standardization to decrease inter-laboratory variation and improve interpretation of results has already repeatedly been made, unfortunately still with unsatisfactory progress. As a logical next step, it would be useful to reach at least some agreement on the type of host cell and basic experimental design for routine amastigote susceptibility determination. The present laboratory study using different L. infantum strains as a model for visceral leishmaniasis species compared primary cells (mouse peritoneal exudate (PEC), mouse bone marrow derived macrophages and human peripheral blood monocyte derived macrophages) and commercially available cell lines (THP-1, J774, RAW) for either their susceptibility to infection, their role in supporting intracellular amastigote multiplication and overall feasibility/accessibility of experimental assay protocol. The major findings were that primary cells are better than cell lines in supporting infection and intracellular parasite multiplication, with PECs to be preferred for technical reasons. Cell lines require drug exposure of >96h with THP-1 to be preferred but subject to a variable response to PMA stimulation. The fast dividing J774 and RAW cells out-compete parasite-infected cells precluding proper assay read-out. Some findings could possibly also be applicable to cutaneous Leishmania strains, but this still needs cross-checking. Besides inherent limitations in a clinical setting, susceptibility testing of clinical isolates may remain problematic because of the reliance on patient-derived promastigotes which may exhibit variable degrees of metacyclogenesis and infectivity.


Asunto(s)
Antiprotozoarios/farmacología , Leishmania infantum/efectos de los fármacos , Pruebas de Sensibilidad Parasitaria/métodos , Animales , Células Cultivadas , Femenino , Humanos , Leishmania infantum/crecimiento & desarrollo , Leishmania infantum/aislamiento & purificación , Leishmaniasis Visceral/parasitología , Ratones , Pruebas de Sensibilidad Parasitaria/normas
18.
Int J Nanomedicine ; 14: 7593-7607, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31802863

RESUMEN

Background: Amphotericin B (Amp) and Betulinic acid (BA) as antileishmanial agents have negligible water solubility and high toxicity. To solve these problems, for the first time, chitosan nanoparticles and Anionic Linear Globular Dendrimer (D) were synthesized for the treatment of Leishmania major (L. major). Method: Chitosan and dendrimer nanoparticles were synthesized, and Amp and BA were loaded into the nanoparticles. The particles were then characterized using various methods and their efficacy was evaluated in vitro and in vivo environments (parasite burden was confirmed using pathological studies and real-time PCR methods). Result: The results of docking showed that Amp and BA can be loaded into chitosan and dendrimer nanoparticles. The results of physically drug loading efficiency for AK (Amphotericin B-chitosan), BK (Betulinic acid-chitosan), AD (Amphotericin B-Dendrimer) and BD (Betulinic acid- Dendrimer) were 90, 93, 84 and 96 percent, respectively. The characterization results indicated that the drugs were loaded into nanoparticles physically. Moreover, the increased solubility rate for AD=478, BD=790, AK=80 and BK=300 folds. Furthermore, the results of the drug delivery system showed the slow controlled drug release pattern with cellular uptake of more than 90%. The treatment results showed a 100 percent decrease of toxicity for the all nanodrugs was observed in vivo and in vitro environments. Moreover, AK10 and BK20 mg/kg reduced parasite burden by 83 percent (P<0.001), while AD50 and BD40 mg/kg reduced it to a lesser extent compared to glucantime. Conclusion: All the synthesized nanodrugs were completely succeeded by 100% to recovery the L. major induced pathological effects in the infected footpad. Also, the results of present study were confirmed with real-time PCR and the results showed that AK and BK were succeeded in a large extent to the treatment of L. major infection (P<0.001), therefore AK and BK could be considered as proper alternatives of choices drugs.


Asunto(s)
Anfotericina B/farmacología , Quitosano/química , Dendrímeros/química , Leishmania major/efectos de los fármacos , Leishmania major/genética , Nanopartículas/química , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Triterpenos/química , Anfotericina B/química , Animales , Antiprotozoarios/farmacología , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Simulación del Acoplamiento Molecular , Nanopartículas/uso terapéutico , Nanopartículas/toxicidad , Parásitos/efectos de los fármacos , Parásitos/genética , Solubilidad , Termodinámica
19.
Parasitol Res ; 118(12): 3565-3570, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31701295

RESUMEN

The flagellated protozoon Trichomonas vaginalis, responsible for trichomoniasis, can establish a symbiotic relationship with the bacterium Mycoplasma hominis and can harbor double-stranded RNA Trichomonasvirus (TVV). In this study, we investigated by real-time PCR the prevalence of the four TVVs and of M. hominis among 48 T. vaginalis strains isolated in Italy, and we evaluated a possible association with metronidazole resistance. Fifty percent of the analyzed trichomonad strains tested positive for at least one TVV T. vaginalis, with TVV2 being the most prevalent, followed by TVV1 and TVV3. Two T. vaginalis strains were infected by TVV4, detected in Europe for the first time. Interestingly, we found more than one TVV species in 75% of positive trichomonad strains. M. hominis was present in 81.25% of T. vaginalis isolates tested, and no statistically significant association was observed with the infection by any TVV. Metronidazole sensitivity of T. vaginalis isolates was evaluated in vitro, and no correlation was observed between minimal lethal concentration and the presence of TVVs. This is the first report on TVV infection of T. vaginalis in Italy. Even if no association of TVV positive isolates with the presence of the symbiont M. hominis or with metronidazole resistance was observed, further studies are needed to shed light on the effective role of infecting microorganisms on the pathophysiology of T. vaginalis.


Asunto(s)
Mycoplasma hominis/aislamiento & purificación , Virus ARN/aislamiento & purificación , Trichomonas vaginalis/microbiología , Trichomonas vaginalis/virología , Antiprotozoarios/farmacología , Resistencia a Medicamentos , Humanos , Italia , Metronidazol/farmacología , Mycoplasma hominis/clasificación , Mycoplasma hominis/genética , Mycoplasma hominis/fisiología , Prevalencia , Virus ARN/clasificación , Virus ARN/genética , Virus ARN/fisiología , ARN Bicatenario/genética , ARN Viral/genética , Simbiosis , Tricomoniasis/parasitología , Trichomonas vaginalis/efectos de los fármacos , Trichomonas vaginalis/fisiología
20.
SAR QSAR Environ Res ; 30(12): 919-933, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31702401

RESUMEN

Folates are essential biomolecules required to carry out many crucial processes in leishmania parasite. Dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) involved in folate biosynthesis in leishmania have been established as suitable targets for development of chemotherapy against leishmaniasis. In the present study, various computational tools such as homology modelling, pharmacophore modelling, docking, molecular dynamics and molecular mechanics have been employed to design dual DHFR-TS and PTR1 inhibitors. Two designed molecules, i.e. 2-(4-((4-nitrobenzyl)oxy)phenyl)-1H-benzo[d]imidazole and 2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]oxazolemolecules were synthesized. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to evaluate in vitro activity of molecules against promastigote form of Leishmania donovani using Miltefosine as standard. 2-(4-((4-nitrobenzyl)oxy)phenyl)-1H-benzo[d]imidazole and 2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]oxazolemolecules were found to be moderately active with showed IC50 = 68 ± 2.8 µM and 57 ± 4.2 µM, respectively.


Asunto(s)
Antiprotozoarios/farmacología , Leishmania donovani/efectos de los fármacos , Complejos Multienzimáticos/química , Oxidorreductasas/química , Proteínas Protozoarias/química , Tetrahidrofolato Deshidrogenasa/química , Timidilato Sintasa/química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/farmacología , Benzoxazoles/síntesis química , Benzoxazoles/química , Benzoxazoles/farmacología , Descubrimiento de Drogas , Concentración 50 Inhibidora , Leishmania donovani/metabolismo , Modelos Moleculares , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacología , Relación Estructura-Actividad
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