RESUMEN
We propose HydraScreen, a deep-learning framework for safe and robust accelerated drug discovery. HydraScreen utilizes a state-of-the-art 3D convolutional neural network designed for the effective representation of molecular structures and interactions in protein-ligand binding. We designed an end-to-end pipeline for high-throughput screening and lead optimization, targeting applications in structure-based drug design. We assessed our approach using established public benchmarks based on the CASF-2016 core set, achieving top-tier results in affinity and pose prediction (Pearson's r = 0.86, RMSE = 1.15, Top-1 = 0.95). We introduced a novel approach for interaction profiling, aimed at detecting potential biases within both the model and data sets. This approach not only enhanced interpretability but also reinforced the impartiality of our methodology. Finally, we demonstrated HydraScreen's ability to generalize effectively across novel proteins and ligands through a temporal split. We also provide insights into potential avenues for future development aimed at enhancing the robustness of machine learning scoring functions. HydraScreen (accessible at http://hydrascreen.ro5.ai/paper) provides a user-friendly GUI and a public API, facilitating the easy-access assessment of protein-ligand complexes.
Asunto(s)
Aprendizaje Profundo , Descubrimiento de Drogas , Descubrimiento de Drogas/métodos , Ligandos , Proteínas/química , Proteínas/metabolismo , Unión Proteica , Redes Neurales de la Computación , Diseño de FármacosRESUMEN
The in vivo antimalarial efficacies of two phosphatidylinositol 4-kinase (PI4K) inhibitors, a 3,5-diaryl-2-aminopyrazine sulfoxide and its corresponding sulfone metabolite, were evaluated in the NOD-scid IL2Rγnull (NSG) murine malaria disease model of Plasmodium falciparum infection. We hypothesized that the sulfoxide would serve as a more soluble prodrug for the sulfone, which would lead to improved drug exposure with oral dosing. Both compounds had similar efficacy (90% effective dose [ED90], 0.1 mg kg-1 of body weight) across a quadruple-dose regimen. Pharmacokinetic profiling revealed rapid sulfoxide clearance via conversion to sulfone, with sulfone identified as the major active metabolite. When the sulfoxide was dosed, the exposure of the sulfone achieved was as much as 2.9-fold higher than when the sulfone was directly dosed, thereby demonstrating that the sulfoxide served as an effective prodrug for the treatment of malaria.
Asunto(s)
Antimaláricos/farmacología , Malaria Falciparum/tratamiento farmacológico , Parasitemia/tratamiento farmacológico , Profármacos/farmacología , Pirazinas/farmacología , Sulfonas/farmacología , Sulfóxidos/farmacología , 1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , 1-Fosfatidilinositol 4-Quinasa/genética , 1-Fosfatidilinositol 4-Quinasa/metabolismo , Animales , Antimaláricos/sangre , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Biotransformación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Eritrocitos/parasitología , Expresión Génica , Humanos , Malaria Falciparum/metabolismo , Malaria Falciparum/parasitología , Malaria Falciparum/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Parasitemia/patología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Plasmodium falciparum/crecimiento & desarrollo , Profármacos/síntesis química , Profármacos/farmacocinética , Pirazinas/sangre , Pirazinas/síntesis química , Pirazinas/farmacocinética , Sulfonas/sangre , Sulfonas/síntesis química , Sulfonas/farmacocinética , Sulfóxidos/sangre , Sulfóxidos/síntesis química , Sulfóxidos/farmacocinética , Resultado del TratamientoRESUMEN
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
Structure-activity relationship (SAR) studies around a previously reported antimalarial aminomethylthiazole pyrazole carboxamide 1 are reported. Several analogues were synthesised and profiled for in vitro antiplasmodial activity against the drug-sensitive Plasmodium falciparum malaria parasite strain, NF54. Although all the reported analogues exhibited inferior in vitro antiplasmodial activity (IC50 = 0.125-173 µM) relative to compound 1 (IC50 = 0.0203 µM), one analogue, compound 5a, retained submicromolar activity (IC50 = 0.125 µM).
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Animales , Ratones , Plasmodium falciparum/fisiología , Relación Estructura-ActividadRESUMEN
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
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
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
The biosynthesis of the essential metabolic cofactor coenzyme A (CoA) has been receiving increasing attention as a new target that shows potential to counter the rising resistance to established antimicrobials. In particular, phosphopantothenoylcysteine synthetase (PPCS)-the second CoA biosynthesis enzyme that is found as part of the bifunctional CoaBC protein in bacteria, but is monofunctional in eukaryotes-has been validated as a target through extensive genetic knockdown studies in Mycobacterium tuberculosis. Moreover, it has been identified as the molecular target of the fungal natural product CJ-15,801 that shows selective activity against Staphylococcus aureus and the malaria parasite Plasmodium falciparum. As such, CJ-15,801 and 4'-phospho-CJ-15,801 (its metabolically active form) are excellent tool compounds for use in the development of new antimicrobial PPCS inhibitors. Unfortunately, further study and analysis of CJ-15,801 is currently being hampered by several unique challenges posed by its synthesis. In this study we describe how these challenges were overcome by using a robust palladium-catalyzed coupling to form the key N-acyl vinylogous carbamate moiety with retention of stereochemistry, and by extensive investigation of protecting groups suited to the labile functional group combinations contained in this molecule. We also demonstrate that using TBAF for deprotection causes undesired off-target effects related to the presence of residual tertiary ammonium salts. Finally, we provide a new method for the chemoenzymatic preparation of 4'-phospho-CJ-15,801 on multi-milligram scale, after showing that chemical synthesis of the molecule is not practical. Taken together, the results of this study advances our pursuit to discover new antimicrobials that specifically target CoA biosynthesis and/or utilization.
RESUMEN
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
A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure-activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite Plasmodium falciparum. In the humanized P. falciparum mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg-1. In vitro mode-of-action studies revealed Plasmodium falciparum phosphatidylinositol-4-kinase as the target.
Asunto(s)
1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , Malaria/tratamiento farmacológico , Naftiridinas/química , Naftiridinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , 1-Fosfatidilinositol 4-Quinasa/química , Animales , Antimaláricos/química , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Modelos Animales de Enfermedad , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Ratones , Modelos Moleculares , Naftiridinas/farmacocinética , Naftiridinas/uso terapéutico , Plasmodium falciparum/fisiología , Conformación Proteica , 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 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.