RESUMEN
A series of new ferrocenyl nitroheterocyclic sulfonylhydrazones (1a-4a and 1b-2b) were prepared by the reaction between formyl (R = H) or acetyl (R = CH3) nitroheterocyclic precursors [4/5-NO2(C5H2XCOR), where X = O, S)] and ferrocenyl tosyl hydrazine [(η5-C5H5)Fe(η5-C5H4SO2-NH-NH2)]. All compounds were characterized by conventional spectroscopic techniques. In the solid state, the molecular structures of compounds 1a, 2b, and 3a were determined by single-crystal X-ray diffraction. The compounds showed an E-configuration around the C=N moiety. Evaluation of trypanocidal activity, measured in vitro against the Trypanosoma cruzi and Trypanosoma brucei strains, indicated that all organometallic tosyl hydrazones displayed activity against both parasite species with a higher level of potency toward T. brucei than T. cruzi. Moreover, the biological evaluation showed that the 5-nitroheterocyclic derivatives were more efficient trypanocidal agents than their 4-nitroheterocyclic counterparts.
Asunto(s)
Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Humanos , Metalocenos , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitologíaRESUMEN
Chagas disease is a deadly and centenary neglected disease that is recently surging as a potential global threat. Approximately 30% of infected individuals develop chronic Chagas cardiomyopathy and current treatment with the reference benznidazole (BZN) is ineffective for this stage. We presently report the structural planning, synthesis, characterization, molecular docking prediction, cytotoxicity, in vitro bioactivity and mechanistic studies on the anti-T. cruzi activity of a series of 16 novel 1,3-thiazoles (2-17) derived from thiosemicarbazones (1a, 1b) in a two-step and reproducible Hantzsch-based synthesis approach. The anti-T. cruzi activity was evaluated in vitro against the epimastigote, amastigote and trypomastigote forms of the parasite. In the bioactivity assays, all thiazoles were more potent than BZN against epimastigotes. We found that the compounds presented an overall increased anti-tripomastigote selectivity (Cpd 8 was 24-fold more selective) than BZN, and they mostly presented anti-amastigote activity at very low doses (from 3.65 µM, cpd 15). Mechanistic studies on cell death suggested that the series of 1,3-thiazole compounds herein reported cause parasite cell death through apoptosis, but without compromising the mitochondrial membrane potential. In silico prediction of physicochemical properties and pharmacokinetic parameters showed promising drug-like results, being all the reported compounds in compliance with Lipinski and Veber rules. In summary, our work contributes towards a more rational design of potent and selective antitripanosomal drugs, using affordable methodology to yield industrially viable drug candidates.
Asunto(s)
Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Tiazoles/química , Tripanocidas/química , Diseño de Fármacos , Enfermedad de Chagas/tratamiento farmacológicoRESUMEN
Chagas disease is an enduring public health issue in many Latin American countries, receiving insufficient investment in research and development. Strategies for disease control and management currently lack efficient pharmaceuticals, commercial diagnostic kits with improved sensitivity, and vaccines. Genetic heterogeneity of Trypanosoma cruzi is a key aspect for novel drug design since pharmacological technologies rely on the degree of conservation of parasite target proteins. Therefore, there is a need to expand the knowledge regarding parasite genetics which, if fulfilled, could leverage Chagas disease research and development, and improve disease control strategies. The growing capacity of whole-genome sequencing technology and its adoption as disease surveillance routine may be key for solving this long-lasting problem.
RESUMEN
Current treatments for Chagas disease have a limited impact during the chronic stage and trigger severe side effects. Treatments target Trypanosoma cruzi, the etiological agent of the disease. The aims of this study were to evaluate the trypanocidal activity of four 2-phenylbenzothiazole derivatives (BZT1-4) in vitro by using the infectious and non-infectious forms of T. cruzi (trypomastigotes and epimastigotes, respectively) and to test the most promising compound (BZT4) in vivo in mice. Additionally, the toxicological profile and possible neuronal damage were examined. In relation to trypomastigotes, BZT4 was more selective and effective than the reference drug (benznidazole) during this infective stage, apparently due to the synergistic action of the CF3 and COOH substituents in the molecule. During the first few hours post-administration of BZT4, parasitemia decreased by 40% in an in vivo model of short-term treatment, but parasite levels later returned to the basal state. In the long-term assessment, the compound did not produce a significant antiparasitic effect, only attaining a 30% reduction in parasitemia by day 20 with the dose of 16 mg/kg. The toxicity test was based on repeated dosing of BZT4 (administered orally) during 21 days, which did not cause liver damage. However, the compound altered the concentration of proteins and the proteinic profile of neuronal cells in vitro, perhaps leading to an effect on the central nervous system. Further research on the low trypanocidal activity in vivo compared to the better in vitro effect could possibly facilitate molecular redesign to improve trypanocidal activity.
Asunto(s)
Enfermedad de Chagas , Nitroimidazoles , Tiazoles , Tripanocidas , Trypanosoma cruzi , Animales , Enfermedad de Chagas/tratamiento farmacológico , Ratones , Nitroimidazoles/uso terapéutico , Nitroimidazoles/toxicidad , Tiazoles/uso terapéutico , Tiazoles/toxicidad , Pruebas de Toxicidad , Tripanocidas/uso terapéutico , Tripanocidas/toxicidad , Trypanosoma cruzi/efectos de los fármacosRESUMEN
Styrylquinoline is a quinoline molecule linked to phenyl rings with an unsaturated ethylene linker, resulting in a flat and rigid conformation. The synthesis of the molecule was reported almost a century ago but was not much explored due to its adverse toxicity and poor selectivity. In the last two decades, a plethora of work was reported related to the synthesis and antiretroviral activity of several styrylquinoline derivatives. Later, other activities such as antimicrobial and anticancer abilities of these derivatives were also reported. In this review, we summarize the diverse steps of the development and analyze the spectrum of the activity of styrylquinolines and their utilization in drug design. Styrylquinolines are extensively explored for new pharmacological activities in recent years and this makes the moiety gain more visibility as a potential drug candidate and lead molecule in medicinal chemistry. The data obtained in vitro and ex vivo shed light on their different mechanism of action. Styrylquinoline has proved to be a potential lead molecule in medicinal chemist's toolkit due to the exploration of a variety of avenues of its activity as a drug candidate.
Asunto(s)
Antiinfecciosos/química , Diseño de Fármacos , Quinolinas/química , Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Humanos , Leishmania/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Leishmaniasis/patología , Relación Estructura-Actividad Cuantitativa , Quinolinas/síntesis química , Quinolinas/farmacología , Receptores de Leucotrienos/química , Receptores de Leucotrienos/metabolismo , Trypanosoma/efectos de los fármacos , Virus/efectos de los fármacosRESUMEN
Trypanosomatidae is a family of unicellular parasites belonging to the phylum Euglenozoa, which are causative agents in high impact human diseases such as Leishmaniasis, Chagas disease and African sleeping sickness. The impact on human health and local economies, together with a lack of satisfactory chemotherapeutic treatments and effective vaccines, justifies stringent research efforts to search for new disease therapies. Here, we present in vitro trypanocidal activity data and mode of action data, repositioning leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salts against Trypanosoma cruzi, the aetiological agent of Chagas disease. This disease is one of the most neglected tropical diseases and is a major public health issue in Central and South America. The disease affects approximately 6-7 million people and is widespread due to increased migratory movements. We screened a suite of leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salt compounds, of which compounds 13, 20 and 21 were identified as trypanocidal drugs. These compounds caused cell death in a mitochondrion-dependent manner through a bioenergetic collapse. Moreover, compounds 13 and 20 showed a remarkable inhibition of iron superoxide dismutase activity of T. cruzi, a key enzyme in the protection from the damage produced by oxidative stress.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Compuestos de Piridinio/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Muerte Celular/efectos de los fármacos , Reposicionamiento de Medicamentos , Humanos , Leishmaniasis/tratamiento farmacológico , Membranas Mitocondriales/metabolismo , Estrés Oxidativo/efectos de los fármacos , América del Sur , Superóxido Dismutasa/metabolismo , Tripanosomiasis Africana/tratamiento farmacológicoRESUMEN
In this report, we extend the SAR analysis of a number of lipophilic guanylhydrazone analogues with respect to in vitro growth inhibition of Trypanosoma brucei and Trypanosoma cruzi. Sleeping sickness and Chagas disease, caused by the tropical parasites T. brucei and T. cruzi, constitute a significant socioeconomic burden in low-income countries of sub-Saharan Africa and Latin America, respectively. Drug development is underfunded. Moreover, current treatments are outdated and difficult to administer, while drug resistance is an emerging concern. The synthesis of adamantane-based compounds that have potential as antitrypanosomal agents is extensively reviewed. The critical role of the adamantane ring was further investigated by synthesizing and testing a number of novel lipophilic guanylhydrazones. The introduction of hydrophobic bulky substituents onto the adamantane ring generated the most active analogues, illustrating the synergistic effect of the lipophilic character of the C1 side chain and guanylhydrazone moiety on trypanocidal activity. The n-decyl C1-substituted compound G8 proved to be the most potent adamantane derivative against T. brucei with activity in the nanomolar range (EC50=90 nM). Molecular simulations were also performed to better understand the structure-activity relationships between the studied guanylhydrazone analogues and their potential enzyme target.
Asunto(s)
Mitoguazona/análogos & derivados , Tripanocidas , Trypanosoma brucei brucei , Trypanosoma cruzi , Mitoguazona/farmacología , Relación Estructura-Actividad , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacosRESUMEN
Natural and synthetic coumarins have been described as prototypes of new drug candidates against Chagas' disease. During a typical screening with new compounds, we observed the potential of a new synthetic nitrobenzoylcoumarin (1) as trypanocidal against Trypanosoma cruzi epimastigotas. Then, we decided to prepare and evaluate a set of analogues from 1 to check the major structural requirements for trypanocidal activity. The structural variations were conducted in six different sites on the original compound and the best derivative (3) presented activity (IC50 28 ± 3 µM) similar to that of benznidazole (IC50 25 ± 10 µM). The enhancement of trypanocidal activity was conditioned to a change in the side chain at C6 (allyl to n-propyl group) and the preservation of coumarin nucleus and the nitrobenzoyl group at C3. Exposure of 3 to H9C2 cells showed low toxicity (CC50 > 200 µM) and its activity on T. cruzi amastigotes (IC50 13 ± 0.3 µM) encouraged us to perform an evaluation of its potential when given orally to mice infected with trypomastigote forms. Derivative 3 was able to reduce parasitemia when compared to the group of untreated animals. Taken together, these results show the potential therapeutic application of the synthetic coumarins.
Asunto(s)
Cumarinas/química , Tripanocidas/química , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/veterinaria , Cumarinas/síntesis química , Cumarinas/farmacología , Cumarinas/uso terapéutico , Femenino , Ratones , Nitroimidazoles/farmacología , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/farmacología , Tripanocidas/uso terapéutico , Trypanosoma cruzi/efectos de los fármacosRESUMEN
BACKGROUND: Benznidazole is recommended for treatment of Chagas infection. Effects of combination therapy with benznidazole and posaconazole have not been tested in Trypanosoma cruzi carriers. OBJECTIVES: The purpose of this study was to determine whether posaconazole alone or combined with benznidazole were superior to benznidazole monotherapy in eliminating T. cruzi parasites measured by real time polymerase chain reaction (RT-PCR) in asymptomatic Chagas carriers. METHODS: A prospective, multicenter randomized placebo-controlled study was conducted in 120 subjects from Latin America and Spain who were randomized to 4 groups: posaconazole 400 mg twice a day (b.i.d.); benznidazole 200 mg + placebo b.i.d.; benznidazole 200 mg b.i.d. + posaconazole 400 mg b.i.d.; or placebo 10 mg b.i.d. T. cruzi deoxyribonucleic acid was detected by RT-PCR at 30, 60, 90, 120, 150, 180, and 360 days. The primary efficacy outcome is the proportion of subjects with persistent negative RT-PCR by day 180; the secondary outcome was negative RT-PCR at 360 days. RESULTS: Only 13.3% of those receiving posaconazole and 10% receiving placebo achieved the primary outcome, compared with 80% receiving benznidazole + posaconazole and 86.7% receiving benznidazole monotherapy (p < 0.0001 vs. posaconazole/placebo). Posaconazole monotherapy or posaconazole combined with benznidazole achieved high RT-PCR conversion rates during treatment (30 days; 93.3% and 88.9% and 60 days; 90%, and 92.3%) that were similar to benznidazole (89.7% and 89.3%); all were superior to placebo or posaconazole (10% and 16.7%, p < 0.0001). This was not observed at 360 days; benznidazole + posaconazole and benznidazole monotherapy (both 96%) versus placebo (17%) and posaconazole (16%, p < 0.0001). Serious adverse events were rare (6 patients) and were observed in the benznidazole-treated patients. Permanent discontinuation was reported in 19 patients (31.7%) receiving either benznidazole monotherapy or combined with posaconazole. CONCLUSIONS: Posaconazole demonstrated trypanostatic activity during treatment, but it is ineffective long-term in asymptomatic T. cruzi carriers. Benznidazole monotherapy is superior to posaconazole, with high RT-PCR conversion rates sustained at 1 year. Side effects lead to therapy discontinuation in 32%. No advantages were observed with combined therapy versus benznidazole monotherapy. (A Study of the Use of Oral Posaconazole [POS] in the Treatment of Asymptomatic Chronic Chagas Disease [P05267] [STOP CHAGAS]: NCT01377480).
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Nitroimidazoles/uso terapéutico , Triazoles/uso terapéutico , Tripanocidas/uso terapéutico , Trypanosoma cruzi , Administración Oral , Adulto , Enfermedad Crónica , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Método Simple CiegoRESUMEN
The initial infection of Chagas disease is typically asymptomatic, but approximately 30% of people will progress to a chronic cardiac form, and others develop the gastrointestinal form. Death is often sudden due to arrhythmias or progressive heart failure. Prevention through vector control programs and blood bank screening, along with strengthened surveillance systems and rapid information sharing, are key to decreasing disease burden globally. The epidemiology, diagnostic evaluation, diagnosis, and treatment of acute and chronic Chagas cardiac disease are discussed with focus on educating the primary care professionals and general cardiologists in nonendemic areas who have limited experience treating this disease.
Asunto(s)
Cardiomiopatía Chagásica , Manejo de la Enfermedad , Américas/epidemiología , Cardiomiopatía Chagásica/diagnóstico , Cardiomiopatía Chagásica/epidemiología , Cardiomiopatía Chagásica/terapia , Humanos , Morbilidad/tendenciasRESUMEN
Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[h][1,6]naphthyridines, pyrrolo[3,2-c]quinolines, azepino[3,2-c]quinolines, and pyrano[3,2-c]quinolines through 2-4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei, T. cruzi, and Leishmania infantum, as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC50 values of 1.5 µM, 6.1 µM and 29.2 µM against T. brucei, L. infantum and T. cruzi, respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC50 > 30 µM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells.
Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Leishmania infantum/efectos de los fármacos , Quinolinas/síntesis química , Quinolinas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Animales , Antiprotozoarios/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Relación Dosis-Respuesta a Droga , Electrophorus , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Quinolinas/química , Ratas , Relación Estructura-Actividad , Trypanosoma brucei brucei/enzimología , Trypanosoma cruzi/enzimologíaRESUMEN
Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.