RESUMEN
Sorindeia nitidula (Anacardiaceae) is used by traditional practitioners to treat influenza illnesses with cephalgia and febrile aches. However, the potential active ingredients for its remarkable antioxidant, anti-HIV and antitrypanosomal activities remain unexplored. The present study aims to evaluate the antioxidant, anti-HIV and antitrypanosomal activities of the ethyl acetate extract of S. nitidula (SN) in order to screen out the bioactive compounds and to analyze their possible mechanisms of action. Overall, 21 phenolic compounds were annotated, by using the MS and MS/MS information provided by the QTOF-MS. In vitro assays on the extract revealed potent antioxidant (IC50 = 0.0129 ± 0.0001 mg/mL), anti-HIV (IC50 = 1.736 ± 0.036 µM), antitrypanosomal (IC50 = 1.040 ± 0.010 µM) activities. Furthermore, SN did not present cytotoxic effect on HeLa cancer cell lines. The integrated strategy based on LC-ESI-QTOF-MS/MS provided a powerful tool and a multidimensional perspective for further exploration of active ingredients in S. nitidula responsible for the antioxidant, anti-HIV and antitrypanosomal activities.
Asunto(s)
Fármacos Anti-VIH , Extractos Vegetales , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Humanos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Células HeLa , Tripanocidas/farmacología , Tripanocidas/química , Cromatografía Liquida/métodos , Antioxidantes/farmacología , Antioxidantes/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Chagas disease, a silent but widespread disease that mainly affects a socioeconomically vulnerable population, lacks innovative safe drug therapy. The available drugs, benznidazole and nifurtimox, are more than fifty years old, have limited efficacy, and carry harmful side effects, highlighting the need for new therapeutics. This study presents two new series of pyrazole-thiadiazole compounds evaluated for trypanocidal activity using cellular models predictive of efficacy. Derivatives 1c (2,4-diCl) and 2k (4-NO2) were the most active against intracellular amastigotes. Derivative 1c also showed activity against trypomastigotes, with the detachment of the flagellum from the parasite body being a predominant effect at the ultrastructural level. Analogs have favorable physicochemical parameters and are predicted to be orally available. Drug efficacy was also evaluated in 3D cardiac microtissue, an important target tissue of Trypanosoma cruzi, with derivative 2k showing potent antiparasitic activity and a significant reduction in parasite load. Although 2k potentially reduced parasite load in the washout assay, it did not prevent parasite recrudescence. Drug combination analysis revealed an additive profile, which may lead to favorable clinical outcomes. Our data demonstrate the antiparasitic activity of pyrazole-thiadiazole derivatives and support the development of these compounds using new optimization strategies.
Asunto(s)
Pirazoles , Tiadiazoles , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Tripanocidas/farmacología , Tripanocidas/síntesis química , Tripanocidas/química , Animales , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , HumanosRESUMEN
Bromodomains are structural folds present in all eukaryotic cells that bind to other proteins recognizing acetylated lysines. Most proteins with bromodomains are part of nuclear complexes that interact with acetylated histone residues and regulate DNA replication, transcription, and repair through chromatin structure remodeling. Bromodomain inhibitors are small molecules that bind to the hydrophobic pocket of bromodomains, interfering with the interaction with acetylated histones. Using a fluorescent probe, we have developed an assay to select inhibitors of the bromodomain factor 2 of Trypanosoma cruzi (TcBDF2) using fluorescence polarization. Initially, a library of 28,251 compounds was screened in an endpoint assay. The top 350-ranked compounds were further analyzed in a dose-response assay. From this analysis, seven compounds were obtained that had not been previously characterized as bromodomain inhibitors. Although these compounds did not exhibit significant trypanocidal activity, all showed bona fide interaction with TcBDF2 with dissociation constants between 1 and 3 µM validating these assays to search for bromodomain inhibitors.
Asunto(s)
Polarización de Fluorescencia , Ensayos Analíticos de Alto Rendimiento , Proteínas Protozoarias , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/metabolismo , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/metabolismo , Tripanocidas/farmacología , Tripanocidas/química , Ensayos Analíticos de Alto Rendimiento/métodos , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
Folate enzymes, namely, dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) are acknowledged targets for the development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. Based on the amino dihydrotriazine motif of the drug Cycloguanil (Cyc), a known inhibitor of both folate enzymes, we have identified two novel series of inhibitors, the 2-amino triazino benzimidazoles (1) and 2-guanidino benzimidazoles (2), as their open ring analogues. Enzymatic screening was carried out against PTR1, DHFR, and thymidylate synthase (TS). The crystal structures of TbDHFR and TbPTR1 in complex with selected compounds experienced in both cases a substrate-like binding mode and allowed the rationalization of the main chemical features supporting the inhibitor ability to target folate enzymes. Biological evaluation of both series was performed against T. brucei and L. infantum and the toxicity against THP-1 human macrophages. Notably, the 5,6-dimethyl-2-guanidinobenzimidazole 2g resulted to be the most potent (Ki = 9 nM) and highly selective TbDHFR inhibitor, 6000-fold over TbPTR1 and 394-fold over hDHFR. The 5,6-dimethyl tricyclic analogue 1g, despite showing a lower potency and selectivity profile than 2g, shared a comparable antiparasitic activity against T. brucei in the low micromolar domain. The dichloro-substituted 2-guanidino benzimidazoles 2c and 2d revealed their potent and broad-spectrum antitrypanosomatid activity affecting the growth of T. brucei and L. infantum parasites. Therefore, both chemotypes could represent promising templates that could be valorized for further drug development.
Asunto(s)
Antagonistas del Ácido Fólico , Tetrahidrofolato Deshidrogenasa , Triazinas , Trypanosoma brucei brucei , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/enzimología , Humanos , Tetrahidrofolato Deshidrogenasa/metabolismo , Tetrahidrofolato Deshidrogenasa/química , Antagonistas del Ácido Fólico/farmacología , Antagonistas del Ácido Fólico/química , Triazinas/farmacología , Triazinas/química , Tripanocidas/farmacología , Tripanocidas/química , Proguanil/farmacología , Proguanil/química , Timidilato Sintasa/antagonistas & inhibidores , Timidilato Sintasa/química , Timidilato Sintasa/metabolismo , Leishmania infantum/efectos de los fármacos , Leishmania infantum/enzimología , Bencimidazoles/farmacología , Bencimidazoles/química , Relación Estructura-Actividad , Antiprotozoarios/farmacología , Antiprotozoarios/química , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/metabolismo , Proteínas Protozoarias/química , OxidorreductasasRESUMEN
Chagas disease is caused by the parasite Trypanosoma cruzi and affects over 7 million people worldwide. The two actual treatments, Benznidazole (Bzn) and Nifurtimox, cause serious side effects due to their high toxicity leading to treatment abandonment by the patients. In this work, we propose DNA G-quadruplexes (G4) as potential therapeutic targets for this infectious disease. We have found 174 PQS per 100,000 nucleotides in the genome of T. cruzi and confirmed G4 formation of three frequent motifs. We synthesized a family of 14 quadruplex ligands based in the dithienylethene (DTE) scaffold and demonstrated their binding to these identified G4 sequences. Several DTE derivatives exhibited micromolar activity against epimastigotes of four different strains of T. cruzi, in the same concentration range as Bzn. Compounds L3 and L4 presented remarkable activity against trypomastigotes, the active form in blood, of T. cruzi SOL strain (IC50 = 1.5-3.3 µM, SI = 25-40.9), being around 40 times more active than Bzn and displaying much better selectivity indexes.
Asunto(s)
Enfermedad de Chagas , G-Cuádruplex , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , G-Cuádruplex/efectos de los fármacos , Ligandos , Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Humanos , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Parasitaria , Antiparasitarios/farmacología , Antiparasitarios/química , Antiparasitarios/síntesis químicaRESUMEN
Benznidazole (BNZ) serves as the primary drug for treating Chagas Disease and is listed in the WHO Model List of Essential Medicines for Children. Herein, a new child-friendly oral BNZ delivery platform is developed in the form of supramolecular eutectogels (EGs). EGs address BNZ's poor oral bioavailability and provide a flexible twice-daily dose in stick-pack format. This green and sustainable formulation strategy relies on the gelation of drug-loaded Natural Deep Eutectic Solvents (NaDES) with xanthan gum (XG) and water. Specifically, choline chloride-based NaDES form stable and biocompatible 5 mg/mL BNZ-loaded EGs. Rheological and Low-field NMR investigations indicate that EGs are viscoelastic materials comprised of two co-existing regions in the XG network generated by different crosslink distributions between the biopolymer, NaDES and water. Remarkably, the shear modulus and relaxation spectrum of EGs remain unaffected by temperature variations. Upon dilution with simulated gastrointestinal fluids, EGs results in BNZ supersaturation, serving as the primary driving force for its absorption. Interestingly, after oral administration of EGs to rats, drug bioavailability increases by 2.6-fold, with a similar increase detected in their cerebrospinal fluid. The noteworthy correlation between in vivo results and in vitro release profiles confirms the efficacy of EGs in enhancing both peripheral and central BNZ oral bioavailability.
Asunto(s)
Disponibilidad Biológica , Nitroimidazoles , Polisacáridos Bacterianos , Animales , Administración Oral , Nitroimidazoles/administración & dosificación , Nitroimidazoles/farmacocinética , Nitroimidazoles/química , Polisacáridos Bacterianos/química , Masculino , Sistemas de Liberación de Medicamentos/métodos , Ratas , Tripanocidas/administración & dosificación , Tripanocidas/farmacocinética , Tripanocidas/química , Geles , Solventes/química , Ratas Sprague-Dawley , Reología , Liberación de Fármacos , Colina/química , Colina/administración & dosificación , Colina/farmacocinéticaRESUMEN
The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for continued propagation of neglected tropical diseases such as African sleeping sickness, Chagas disease and leishmaniasis respectively. Following a report that captopril targets Leishmania donovani dipeptidyl carboxypeptidase, a series of simple proline amides and captopril analogues were synthesized and found to exhibit 1-2 µM in vitro inhibition and selectivity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. The results were corroborated with computational docking studies. Arguably, the synthetic proline amides represent the structurally simplest examples of in vitro pan antiprotozoal compounds.
Asunto(s)
Captopril , Trypanosoma brucei brucei , Trypanosoma cruzi , Captopril/farmacología , Captopril/química , Captopril/síntesis química , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/enzimología , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/enzimología , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Estructura Molecular , Leishmania/efectos de los fármacos , Leishmania/enzimología , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/síntesis química , HumanosRESUMEN
Here, we report wajeepeptin (1), a new cyclic depsipeptide isolated from a marine Moorena sp. cyanobacterium. The structure was elucidated by a combination of spectroscopic analyses, X-ray diffraction analysis, and degradation reactions. Wajeepeptin (1) showed moderate cytotoxicity (IC50 = 3.7 µM against HeLa cells) and potent antitrypanosomal activity (IC50 = 0.73 ± 0.14 µM against Trypanosoma brucei rhodesiense).
Asunto(s)
Cianobacterias , Depsipéptidos , Depsipéptidos/farmacología , Depsipéptidos/química , Depsipéptidos/aislamiento & purificación , Humanos , Estructura Molecular , Células HeLa , Cianobacterias/química , Trypanosoma brucei rhodesiense/efectos de los fármacos , Biología Marina , Tripanocidas/farmacología , Tripanocidas/química , Ensayos de Selección de Medicamentos Antitumorales , Cristalografía por Rayos X , Resonancia Magnética Nuclear BiomolecularRESUMEN
In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 µM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 µM, SI = 1390). Another compound (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 µM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.
Asunto(s)
Bencimidazoles , Hidrazonas , Leishmania infantum , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Hidrazonas/farmacología , Hidrazonas/química , Hidrazonas/síntesis química , Relación Estructura-Actividad , Leishmania infantum/efectos de los fármacos , Bencimidazoles/farmacología , Bencimidazoles/química , Bencimidazoles/síntesis química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Dosis-Respuesta a Droga , Leishmania/efectos de los fármacos , Tripanocidas/farmacología , Tripanocidas/síntesis química , Tripanocidas/química , Antiprotozoarios/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , AnimalesRESUMEN
The development of new compounds to treat Chagas disease is imperative due to the adverse effects of current drugs and their low efficacy in the chronic phase. This study aims to investigate nitroisoxazole derivatives that produce oxidative stress while modifying the compounds' lipophilicity, affecting their ability to fight trypanosomes. The results indicate that these compounds are more effective against the epimastigote form of T. cruzi, with a 52 ± 4% trypanocidal effect for compound 9. However, they are less effective against the trypomastigote form, with a 15 ± 3% trypanocidal effect. Additionally, compound 11 interacts with a higher number of amino acid residues within the active site of the enzyme cruzipain. Furthermore, it was also found that the presence of a nitro group allows for the generation of free radicals; likewise, the large size of the compound enables increased interaction with aminoacidic residues in the active site of cruzipain, contributing to trypanocidal activity. This activity depends on the size and lipophilicity of the compounds. The study recommends exploring new compounds based on the nitroisoxazole skeleton, with larger substituents and lipophilicity to enhance their trypanocidal activity.
Asunto(s)
Isoxazoles , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Isoxazoles/química , Isoxazoles/farmacología , Proteínas Protozoarias/metabolismo , Proteínas Protozoarias/química , Proteínas Protozoarias/antagonistas & inhibidores , Relación Estructura-Actividad , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Cisteína Endopeptidasas/química , Cisteína Endopeptidasas/metabolismo , Animales , Dominio Catalítico , Estructura MolecularRESUMEN
Human African trypanosomiasis (HAT, sleeping sickness) and American trypanosomiasis (Chagas disease) are endemic zoonotic diseases caused by genomically related trypanosomatid protozoan parasites (Trypanosoma brucei and Trypanosoma cruzi, respectively). Just a few old drugs are available for their treatment, with most of them sharing poor safety, efficacy, and pharmacokinetic profiles. Only fexinidazole has been recently incorporated into the arsenal for the treatment of HAT. In this work, new multifunctional Ru(II) ferrocenyl compounds were rationally designed as potential agents against these pathogens by including in a single molecule 1,1'-bis(diphenylphosphino)ferrocene (dppf) and two bioactive bidentate ligands: pyridine-2-thiolato-1-oxide ligand (mpo) and polypyridyl ligands (NN). Three [Ru(mpo)(dppf)(NN)](PF6) compounds and their derivatives with chloride as a counterion were synthesized and fully characterized in solid state and solution. They showed in vitro activity on bloodstream T. brucei (EC50 = 31-160 nM) and on T. cruzi trypomastigotes (EC50 = 190-410 nM). Compounds showed the lowest EC50 values on T. brucei when compared to the whole set of metal-based compounds previously developed by us. In addition, several of the Ru compounds showed good selectivity toward the parasites, particularly against the highly proliferative bloodstream form of T. brucei. Interaction with DNA and generation of reactive oxygen species (ROS) were ruled out as potential targets and modes of action of the Ru compounds. Biochemical assays and in silico analysis led to the insight that they are able to inhibit the NADH-dependent fumarate reductase from T. cruzi. One representative hit induced a mild oxidation of low molecular weight thiols in T. brucei. The compounds were stable for at least 72 h in two different media and more lipophilic than both bioactive ligands, mpo and NN. An initial assessment of the therapeutic efficacy of one of the most potent and selective candidates, [Ru(mpo)(dppf)(bipy)]Cl, was performed using a murine infection model of acute African trypanosomiasis. This hit compound lacks acute toxicity when applied to animals in the dose/regimen described, but was unable to control parasite proliferation in vivo, probably because of its rapid clearance or low biodistribution in the extracellular fluids. Future studies should investigate the pharmacokinetics of this compound in vivo and involve further research to gain deeper insight into the mechanism of action of the compounds.
Asunto(s)
Compuestos Ferrosos , Rutenio , Tripanocidas , Trypanosoma cruzi , Compuestos Ferrosos/química , Compuestos Ferrosos/farmacología , Compuestos Ferrosos/síntesis química , Trypanosoma cruzi/efectos de los fármacos , Ligandos , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Animales , Rutenio/química , Rutenio/farmacología , Ratones , Metalocenos/química , Metalocenos/farmacología , Metalocenos/síntesis química , Trypanosoma brucei brucei/efectos de los fármacos , Pruebas de Sensibilidad Parasitaria , Estructura Molecular , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis químicaRESUMEN
Several G-quadruplex nucleic acid (G4s) ligands have been developed seeking target selectivity in the past decade. Naphthalene diimide (NDI)-based compounds are particularly promising due to their biological activity and red-fluorescence emission. Previously, we demonstrated the existence of G4s in the promoter region of parasite genomes, assessing the effectiveness of NDI-derivatives against them. Here, we explored the biological activity of a small library of G4-DNA ligands, exploiting the NDI pharmacophore, against both Trypanosoma brucei and Leishmania major parasites. Biophysical and biological assays were conducted. Among the various families analyzed, core-extended NDIs exhibited the most promising results concerning the selectivity and antiparasitic effects. NDI 16 emerged as the most potent, with an IC50 of 0.011 nM against T. brucei and remarkable selectivity vs MRC-5 cells (3454-fold). Fascinating, 16 is 480-fold more potent than the standard drug pentamidine (IC50 = 5.3 nM). Cellular uptake and parasite localization were verified by exploiting core-extended NDI red-fluorescent emission.
Asunto(s)
G-Cuádruplex , Imidas , Leishmania major , Naftalenos , Tripanocidas , Trypanosoma brucei brucei , G-Cuádruplex/efectos de los fármacos , Relación Estructura-Actividad , Naftalenos/farmacología , Naftalenos/química , Imidas/química , Imidas/farmacología , Ligandos , Trypanosoma brucei brucei/efectos de los fármacos , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Humanos , Leishmania major/efectos de los fármacos , Línea CelularRESUMEN
Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development.
Asunto(s)
Pirimidinas , Tripanocidas , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Relación Estructura-Actividad , Pruebas de Sensibilidad Parasitaria , Estructura Molecular , Trypanosoma brucei brucei/efectos de los fármacos , Humanos , Trypanosoma brucei rhodesiense/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Tripanosomiasis Africana/tratamiento farmacológicoRESUMEN
Hydrazones 1-6, azo-pyrazoles 7-9 and azo-pyrimidines 10-15 are compounds that exhibit antibacterial activity. The mode of action and structures of these derivatives have been previously confirmed as antibacterial. In this investigation, biological screening and molecular docking studies were performed for derivatives 1-15, with compounds 2, 7, 8, 14 and 15 yielding the best energy scores (from -20.7986 to -10.5302 kcal/mol). Drug-likeness and in silico ADME prediction for the most potent derivatives, 2, 7, 8, 14 and 15, were predicted (from 84.46 to 96.85%). The latter compounds showed good recorded physicochemical properties and pharmacokinetics. Compound 8 demonstrated the strongest inhibition, which was similar to the positive control (eflornithine) against Trypanosoma brucei brucei (WT), with an EC50 of 25.12 and 22.52µM, respectively. Moreover, compound 14 exhibited the best activity against Leishmania mexicana promastigotes and Leishmania major promastigotes (EC50 =46.85; 40.78µM, respectively).
Asunto(s)
Simulación del Acoplamiento Molecular , Pirazoles , Pirimidinas , Tripanocidas , Trypanosoma brucei brucei , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Trypanosoma brucei brucei/efectos de los fármacos , Pirazoles/farmacología , Pirazoles/química , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Leishmania mexicana/efectos de los fármacos , Leishmania major/efectos de los fármacos , Antiprotozoarios/farmacología , Antiprotozoarios/química , Simulación por Computador , Compuestos Azo/farmacología , Compuestos Azo/química , Compuestos Azo/síntesis química , Relación Estructura-Actividad , Pruebas de Sensibilidad ParasitariaRESUMEN
In pursuit of potential agents to treat Chagas disease and leishmaniasis, we report the design, synthesis, and identification novel naphthoquinone hydrazide-based molecular hybrids. The compounds were subjected to in vitro trypanocide and leishmanicidal activities. N'-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-3,5-dimethoxybenzohydrazide (13) showed the best performance against Trypanosoma cruzi (IC50 1.83 µM) and Leishmania amazonensis (IC50 9.65 µM). 4-Bromo-N'-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzohydrazide (16) exhibited leishmanicidal activity (IC50 12.16 µM). Regarding trypanocide activity, compound 13 was low cytotoxic to LLC-MK2 cells (SI = 95.28). Furthermore, through molecular modeling studies, the cysteine proteases cruzain, rhodesain and CPB2.8 were identified as the potential biological targets.
Asunto(s)
Diseño de Fármacos , Hidrazinas , Leishmania , Naftoquinonas , Tripanocidas , Trypanosoma cruzi , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/síntesis química , Trypanosoma cruzi/efectos de los fármacos , Tripanocidas/farmacología , Tripanocidas/síntesis química , Tripanocidas/química , Leishmania/efectos de los fármacos , Hidrazinas/química , Hidrazinas/farmacología , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Pruebas de Sensibilidad Parasitaria , Concentración 50 Inhibidora , Relación Estructura-Actividad , Cisteína EndopeptidasasRESUMEN
Considering the health relevance of Chagas' disease, recent research efforts have focused on developing more efficient drug delivery systems containing nifurtimox (NFX). This paper comprehensively investigates NFX through conformational analysis and spectroscopic characterization. Using a conformer-rotamer ensemble sampling tool (CREST-xtb), five distinct conformers of NFX were sampled within a 3.0 kcal mol-1 relative energy window. Subsequently, such structures were used as inputs for geometry optimization by density functional theory (DFT) at B3LYP-def2-TZVP level of theory. Notably, harmonic vibrational frequencies were calculated to establish an in-depth comparison with experimental results and existing literature for the NFX or similar molecules and functional groups, thereby achieving a widely reasoned assignment of the mid-infrared band absorptions for the first time. Moreover, UV-VIS spectra of NFX were obtained in several solvents, enabling the determination of the molar absorptivity coefficient for the two electronic transitions observed for NFX. Among the aprotic solvents, a bathochromic effect was observed in the function of the dielectric constants. Furthermore, a hypochromic effect was observed when the drug was dissolved in protic solvents. These findings offer crucial support for new drug delivery systems containing NFX while demonstrating the potential of spectrophotometric studies in establishing quality control assays for NFX drug products.
Asunto(s)
Enfermedad de Chagas , Conformación Molecular , Nifurtimox , Enfermedad de Chagas/tratamiento farmacológico , Nifurtimox/química , Espectrofotometría Ultravioleta , Tripanocidas/química , Modelos Moleculares , Teoría Funcional de la Densidad , Trypanosoma cruzi/efectos de los fármacos , Solventes/químicaRESUMEN
Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the meso, 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against Trypanosoma brucei and Leishmania major parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the meso-substituted BODIPY, with 1-dimethylaminonaphthalene (1b) and anthracene moiety (1c), were the most active against L. major, displaying IC50 = 4.84 and 5.41 µM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues 2b and 2c exhibited the highest toxicity (IC50 = 2.84 and 6.17 µM, respectively) and selectivity (SI = 24 and 11, respectively) against T. brucei. Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP+ linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.
Asunto(s)
Antiprotozoarios , Compuestos de Boro , Leishmania major , Simulación del Acoplamiento Molecular , Trypanosoma brucei brucei , Compuestos de Boro/química , Compuestos de Boro/farmacología , Compuestos de Boro/síntesis química , Trypanosoma brucei brucei/efectos de los fármacos , Humanos , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/síntesis química , Leishmania major/efectos de los fármacos , Diseño de Fármacos , Relación Estructura-Actividad , Línea Celular , Estructura Molecular , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , OxidorreductasasRESUMEN
Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two drugs has recently been linked to aquaglyceroporin 2 of the trypanosome (TbAQP2). TbAQP2 is the first member of the aquaporin family described as capable of drug transport; however, the underlying mechanism remains unclear. Here, we present cryo-electron microscopy structures of TbAQP2 bound to pentamidine or melarsoprol. Our structural studies, together with the molecular dynamic simulations, reveal the mechanisms shaping substrate specificity and drug permeation. Multiple amino acids in TbAQP2, near the extracellular entrance and inside the pore, create an expanded conducting tunnel, sterically and energetically allowing the permeation of pentamidine and melarsoprol. Our study elucidates the mechanism of drug transport by TbAQP2, providing valuable insights to inform the design of drugs against trypanosomiasis.
Asunto(s)
Acuagliceroporinas , Microscopía por Crioelectrón , Melarsoprol , Simulación de Dinámica Molecular , Pentamidina , Trypanosoma brucei brucei , Trypanosoma brucei brucei/metabolismo , Acuagliceroporinas/metabolismo , Acuagliceroporinas/química , Melarsoprol/metabolismo , Melarsoprol/química , Pentamidina/química , Pentamidina/metabolismo , Transporte Biológico , Tripanocidas/química , Tripanocidas/metabolismo , Tripanocidas/farmacología , Proteínas Protozoarias/metabolismo , Proteínas Protozoarias/química , HumanosRESUMEN
New affordable drugs are needed for the treatment of infection with the protozoan parasite Trypanosoma cruzi responsible for the Chagas disease (CD). Only two old drugs are currently available, nifurtimox and benznidazole (Bz) but they exhibit unwanted side effects and display a weak activity in the late chronic phase of the disease. In this context, we evaluated the activity of a series of aryl-pyrazolone derivatives against T cruzi, using both bloodstream trypomastigote and intracellular amastigote forms of the parasite. The test compounds originate from a series of anticancer agents targeting the immune checkpoint ligand PD-L1 and bear an analogy with known anti-trypanosomal pyrazolones. A first group of 6 phenyl-pyrazolones was tested, revealing the activity of a single pyridyl-pyrazolone derivative. Then a second group of 8 compounds with a common pyridyl-pyrazolone core was evaluated. The in vitro testing process led to the identification of two non-cytotoxic and highly potent molecules against the intracellular form of T. cruzi, with an activity comparable to Bz. Moreover, one compound revealed an activity largely superior to that of Bz against bloodstream trypomastigotes, while being non-cytotoxic (selectivity index >1000). Unfortunately, the compound showed little activity in vivo, most likely due to its very limited plasma stability. However, the study opens novel perspectives for the design of new anti-trypanosomal products and the mechanism of action of the compounds is discussed.
Asunto(s)
Enfermedad de Chagas , Pirazolonas , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Pirazolonas/farmacología , Pirazolonas/química , Tripanocidas/farmacología , Tripanocidas/química , Animales , Ratones , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Piridinas/farmacología , Piridinas/química , Concentración 50 Inhibidora , Nitroimidazoles/farmacología , Nitroimidazoles/químicaRESUMEN
In previous studies, we developed anti-trypanosome tubulin inhibitors with promising in vitro selectivity and activity against Human African Trypanosomiasis (HAT). However, for such agents, oral activity is crucial. This study focused on further optimizing these compounds to enhance their ligand efficiency, aiming to reduce bulkiness and hydrophobicity, which should improve solubility and, consequently, oral bioavailability. Using Trypanosoma brucei brucei cells as the parasite model and human normal kidney cells and mouse macrophage cells as the host model, we evaluated 30 new analogs synthesized through combinatorial chemistry. These analogs have fewer aromatic moieties and lower molecular weights than their predecessors. Several new analogs demonstrated IC50s in the low micromolar range, effectively inhibiting trypanosome cell growth without harming mammalian cells at the same concentration. We conducted a detailed structure-activity relationship (SAR) analysis and a docking study to assess the compounds' binding affinity to trypanosome tubulin homolog. The results revealed a correlation between binding energy and anti-Trypanosoma activity. Importantly, compound 7 displayed significant oral activity, effectively inhibiting trypanosome cell proliferation in mice.