RESUMEN
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2Rγ null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.
RESUMEN
Objectives: Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in-depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual-acting antimalarials. Methods: We evaluated compounds against P. falciparum gametocytes using several assay platforms for cross-validation and stringently identified hits that were further profiled for stage specificity, speed of action and ex vivo efficacy. Physicochemical feature extraction and chemogenomic fingerprinting were applied to explore the kinase inhibition susceptibility profile. Results: We identified 34 compounds with submicromolar activity against late stage gametocytes, validated across several assay platforms. Of these, 12 were potent at <100 nM (8 were IMPs and 4 were 2-APs) and were also active against early stage gametocytes and asexual parasites, with >1000-fold selectivity towards the parasite over mammalian cells. Front-runner compounds targeted mature gametocytes within 48 h and blocked transmission to mosquitoes. The resultant chemogenomic fingerprint of parasites treated with the lead compounds revealed the importance of targeting kinases in asexual parasites and gametocytes. Conclusions: This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies.
Asunto(s)
Aminopiridinas/farmacología , Antimaláricos/farmacología , Fosfotransferasas/antagonistas & inhibidores , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Inhibidores de Proteínas Quinasas/farmacología , Aminopiridinas/química , Aminopiridinas/aislamiento & purificación , Antimaláricos/química , Antimaláricos/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/aislamiento & purificaciónRESUMEN
BACKGROUND: Recent whole cell in vitro screening campaigns identified thousands of compounds that are active against asexual blood stages of Plasmodium falciparum at submicromolar concentrations. These hits have been made available to the public, providing many novel chemical starting points for anti-malarial drug discovery programmes. Knowing which of these hits are fast-acting compounds is of great interest. Firstly, a fast action will ensure rapid relief of symptoms for the patient. Secondly, by rapidly reducing the parasitaemia, this could minimize the occurrence of mutations leading to new drug resistance mechanisms.An in vitro assay that provides information about the speed of action of test compounds has been developed by researchers at GlaxoSmithKline (GSK) in Spain. This assay also provides an in vitro measure for the ratio between parasitaemia at the onset of drug treatment and after one intra-erythrocytic cycle (parasite reduction ratio, PRR). Both parameters are needed to determine in vitro killing rates of anti-malarial compounds. A drawback of the killing rate assay is that it takes a month to obtain first results. METHODS: The approach described in the present study is focused only on the speed of action of anti-malarials. This has the advantage that initial results can be achieved within 4-7 working days, which helps to distinguish between fast and slow-acting compounds relatively quickly. It is expected that this new assay can be used as a filter in the early drug discovery phase, which will reduce the number of compounds progressing to secondary, more time-consuming assays like the killing rate assay. RESULTS: The speed of action of a selection of seven anti-malarial compounds was measured with two independent experimental procedures using modifications of the standard [3H]hypoxanthine incorporation assay. Depending on the outcome of both assays, the tested compounds were classified as either fast or non-fast-acting. CONCLUSION: The results obtained for the anti-malarials chloroquine, artesunate, atovaquone, and pyrimethamine are consistent with previous observations, suggesting the methodology is a valid way to rapidly identify fast-acting anti-malarial compounds. Another advantage of the approach is its ability to discriminate between static or cidal compound effects.
Asunto(s)
Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Parasitaria/métodos , Factores de TiempoRESUMEN
Widespread Plasmodium falciparum resistance to first-line antimalarials underscores the vital need to develop compounds with novel modes of action and identify new druggable targets. Here, we profile five compounds that potently inhibit P. falciparum asexual blood stages. Resistance selection studies with three carboxamide-containing compounds, confirmed by gene editing and conditional knockdowns, identify point mutations in the parasite transporter ABCI3 as the primary mediator of resistance. Selection studies with imidazopyridine or quinoline-carboxamide compounds also yield changes in ABCI3, this time through gene amplification. Imidazopyridine mode of action is attributed to inhibition of heme detoxification, as evidenced by cellular accumulation and heme fractionation assays. For the copy-number variation-selecting imidazopyridine and quinoline-carboxamide compounds, we find that resistance, manifesting as a biphasic concentration-response curve, can independently be mediated by mutations in the chloroquine resistance transporter PfCRT. These studies reveal the interconnectedness of P. falciparum transporters in overcoming drug pressure in different parasite strains.
Asunto(s)
Antimaláricos , Antagonistas del Ácido Fólico , Malaria Falciparum , Parásitos , Quinolinas , Transportadoras de Casetes de Unión a ATP/genética , Animales , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Hemo , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Proteínas de Transporte de Membrana/genética , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Quinolinas/farmacologíaRESUMEN
Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.
Asunto(s)
Antimaláricos/uso terapéutico , Descubrimiento de Drogas , Malaria/tratamiento farmacológico , Malaria/transmisión , Pandemias , Aedes/parasitología , Animales , Antimaláricos/química , Antimaláricos/farmacología , Análisis por Conglomerados , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Estadios del Ciclo de Vida/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/parasitología , Malaria/epidemiología , Masculino , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrolloRESUMEN
A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (<50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.
Asunto(s)
Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Compuestos de Espiro/farmacología , Animales , Anopheles/efectos de los fármacos , Antimaláricos/síntesis química , Antimaláricos/metabolismo , Femenino , Células Germinativas/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/metabolismo , Relación Estructura-ActividadRESUMEN
Phenotypic whole-cell screening against Mycobacterium tuberculosis (Mtb) in glycerol-alanine-salts supplemented with Tween 80 and iron (GASTE-Fe) media led to the identification of a 2-aminoquinazolinone hit compound, sulfone 1 which was optimized for solubility by replacing the sulfone moiety with a sulfoxide 2. The synthesis and structure-activity relationship (SAR) studies identified several compounds with potent antimycobacterial activity, which were metabolically stable and noncytotoxic. Compound 2 displayed favorable in vitro properties and was therefore selected for in vivo pharmacokinetic (PK) studies where it was found to be extensively metabolized to the sulfone 1. Both derivatives exhibited promising PK parameters; however, when 2 was evaluated for in vivo efficacy in an acute TB infection mouse model, it was found to be inactive. In order to understand the in vitro and in vivo discrepancy, compound 2 was subsequently retested in vitro using different Mtb strains cultured in different media. This revealed that activity was only observed in media containing glycerol and led to the hypothesis that glycerol was not used as a primary carbon source by Mtb in the mouse lungs, as has previously been observed. Support for this hypothesis was provided by spontaneous-resistant mutant generation and whole genome sequencing studies, which revealed mutations mapping to glycerol metabolizing genes indicating that the 2-aminoquinazolinones kill Mtb in vitro via a glycerol-dependent mechanism of action.
Asunto(s)
Antituberculosos , Mycobacterium tuberculosis , Animales , Antituberculosos/farmacología , Diseño de Fármacos , Ratones , Relación Estructura-ActividadRESUMEN
A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite Plasmodium falciparum. Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multidrug-resistant K1 strain, in vitro cytotoxicity, and cardiotoxicity and were addressed through structure-activity and structure-property relationship studies. Pharmacokinetic properties were assessed in mice for compounds showing desirable in vitro activity, a selectivity window over cytotoxicity, and microsomal metabolic stability. Frontrunner compound 37 showed good exposure in mice combined with good in vitro activity against the malaria parasite, which translated into in vivo efficacy in the P. falciparum NOD-scid IL-2Rγnull (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action.
Asunto(s)
Antimaláricos/química , Hemoproteínas/antagonistas & inhibidores , Imidazoles/química , Plasmodium falciparum/fisiología , Proteínas Protozoarias/antagonistas & inhibidores , Piridinas/química , Animales , Antimaláricos/metabolismo , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Modelos Animales de Enfermedad , Semivida , Hemoproteínas/metabolismo , Imidazoles/metabolismo , Imidazoles/farmacología , Imidazoles/uso terapéutico , Estadios del Ciclo de Vida/efectos de los fármacos , Malaria/tratamiento farmacológico , Malaria/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , Microsomas Hepáticos/metabolismo , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/metabolismo , Piridinas/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2Rγnull mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Imidazoles/química , Imidazoles/farmacología , Plasmodium falciparum/efectos de los fármacos , Piridinas/química , Piridinas/farmacología , Absorción Fisicoquímica , Animales , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Relación Dosis-Respuesta a Droga , Imidazoles/metabolismo , Imidazoles/farmacocinética , Ratones , Piridinas/metabolismo , Piridinas/farmacocinética , Relación Estructura-Actividad , Distribución TisularRESUMEN
Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.
Asunto(s)
Descubrimiento de Drogas , Imidazoles/química , Imidazoles/farmacocinética , Malaria/tratamiento farmacológico , Plasmodium falciparum/fisiología , Piridinas/química , Piridinas/farmacocinética , Animales , Modelos Animales de Enfermedad , Estabilidad de Medicamentos , Canal de Potasio ERG1/metabolismo , Humanos , Imidazoles/metabolismo , Imidazoles/uso terapéutico , Malaria/genética , Malaria/metabolismo , Ratones , Piridinas/metabolismo , Piridinas/uso terapéutico , Solubilidad , Relación Estructura-Actividad , Distribución Tisular , Agua/químicaRESUMEN
As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment.
Asunto(s)
1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , Aminopiridinas/uso terapéutico , Antimaláricos/uso terapéutico , Sulfonas/uso terapéutico , Aminopiridinas/farmacología , Animales , Antimaláricos/farmacología , Femenino , Malaria/tratamiento farmacológico , Malaria/enzimología , Masculino , Ratones , Ratones SCID , Pruebas de Sensibilidad Parasitaria , Plasmodium/efectos de los fármacos , Plasmodium/patogenicidad , Sulfonas/farmacologíaRESUMEN
Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rγnull mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.
Asunto(s)
Antimaláricos/farmacología , Estadios del Ciclo de Vida/efectos de los fármacos , Malaria/tratamiento farmacológico , Enfermedades Parasitarias en Animales/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Pirazinas/farmacología , Animales , Antimaláricos/química , Antimaláricos/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Células Hep G2 , Humanos , Ratones , Ratones SCID , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Enfermedades Parasitarias en Animales/parasitología , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei/crecimiento & desarrollo , Plasmodium falciparum/crecimiento & desarrollo , Pirazinas/química , Pirazinas/metabolismo , Solubilidad , Relación Estructura-Actividad , Agua/químicaRESUMEN
Based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. Improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously reported compounds, and with a slightly improved hERG profile.
Asunto(s)
Antimaláricos/química , Pirimidinas/química , Administración Oral , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Cristalografía por Rayos X , Resistencia a Medicamentos , Canales de Potasio Éter-A-Go-Go/fisiología , Femenino , Humanos , Malaria/tratamiento farmacológico , Malaria/parasitología , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Técnicas de Placa-Clamp , Plasmodium berghei , Plasmodium falciparum/efectos de los fármacos , Conformación Proteica , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Solubilidad , Relación Estructura-ActividadRESUMEN
Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics profiles. The lead compounds also proved to be very potent in the parasite liver and gametocyte stages, which makes them of high interest.
Asunto(s)
Antimaláricos/química , Antimaláricos/uso terapéutico , Malaria/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Pirazoles/química , Pirazoles/uso terapéutico , Piridinas/química , Piridinas/uso terapéutico , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Hígado/parasitología , Malaria/parasitología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Ratones , Pirazoles/farmacocinética , Pirazoles/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
On the basis of our recent results on a novel series of imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po.
Asunto(s)
Antimaláricos/síntesis química , Piridazinas/síntesis química , Sulfonas/síntesis química , Animales , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Resistencia a Múltiples Medicamentos , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Malaria Falciparum/parasitología , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Piridazinas/metabolismo , Piridazinas/farmacología , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad , Sulfonas/metabolismo , Sulfonas/farmacologíaRESUMEN
A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Plasmodium/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/química , Piridazinas/síntesis química , Piridazinas/farmacología , Animales , Antimaláricos/farmacocinética , Disponibilidad Biológica , Diseño de Fármacos , Resistencia a Medicamentos , Estabilidad de Medicamentos , Biblioteca de Genes , Semivida , Ensayos Analíticos de Alto Rendimiento , Malaria/tratamiento farmacológico , Malaria/parasitología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/psicología , Ratones , Ratones SCID , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei , Plasmodium falciparum/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.
Asunto(s)
Antimaláricos/síntesis química , Pirimidinas/síntesis química , Tiofenos/síntesis química , Administración Oral , Animales , Antimaláricos/química , Antimaláricos/farmacología , Línea Celular , Bases de Datos de Compuestos Químicos , Resistencia a Múltiples Medicamentos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Ensayos Analíticos de Alto Rendimiento , Humanos , Malaria/tratamiento farmacológico , Malaria/parasitología , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Plasmodium berghei , Plasmodium falciparum/efectos de los fármacos , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC50 values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei -infected mice, compound 4 was completely curative at an oral dose of 4 × 10 mg/kg.