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1.
Nat Commun ; 13(1): 5992, 2022 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-36220877

RESUMEN

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.


Asunto(s)
Lisina-ARNt Ligasa , Mycobacterium tuberculosis , Tuberculosis , Animales , Lisina-ARNt Ligasa/química , Lisina-ARNt Ligasa/genética , Lisina-ARNt Ligasa/farmacología , Ratones , Mycobacterium tuberculosis/genética , Tuberculosis/tratamiento farmacológico
2.
J Med Chem ; 65(1): 409-423, 2022 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-34910486

RESUMEN

With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.


Asunto(s)
Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Benzofuranos/farmacología , Palmitoil-CoA Hidrolasa/antagonistas & inhibidores , Piperidinas/farmacología , Sintasas Poliquetidas/antagonistas & inhibidores , Benzofuranos/síntesis química , Cardiotoxicidad , Descubrimiento de Drogas , Canal de Potasio ERG1 , Corazón/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Mycobacterium tuberculosis/efectos de los fármacos , Piperidinas/síntesis química , Relación Estructura-Actividad
3.
Tuberculosis (Edinb) ; 121: 101918, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32279874

RESUMEN

The sensitivity of in vivo low-dose high-resolution micro-computed tomography imaging enables monitoring the lung damage caused by tuberculosis. Here, we propose a radiological score integrated in the experimental workflow that enables longitudinal monitoring for prospective efficacy studies in drug development programs. The score is based on an automatic measurement of total unaffected lung volume in vivo normalized for inter-subject comparison. It was validated on well-characterized progression of chronic tuberculosis in Erdman and H37Rv strains in C3HeB/FeJ-based models. We demonstrated that a decrease in the score value indicates increasing adverse effects and vice versa. The colony-forming units count confirmed the variability in the host response suggested by the score values. The correlation between changes in the mice's weight and the score is consistent with disease progression. The classification of disease extent by k-means clustering of the score values provided the definition of the lung damage severity according to the bacillus strain. The proposed score will reduce sources of bias and improve the statistical robustness of studies by the attrition of non-infected subjects or subjects with a weak immune response. Readily available quantifications allow for a fast assessment of the therapeutic potential in drug-resistant tuberculosis strains.


Asunto(s)
Pulmón/diagnóstico por imagen , Tuberculosis Pulmonar/diagnóstico por imagen , Microtomografía por Rayos X , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Interacciones Huésped-Patógeno , Pulmón/microbiología , Ratones Endogámicos C3H , Mycobacterium tuberculosis/patogenicidad , Valor Predictivo de las Pruebas , Interpretación de Imagen Radiográfica Asistida por Computador , Reproducibilidad de los Resultados , Factores de Tiempo , Tuberculosis Pulmonar/microbiología
4.
J Med Chem ; 63(9): 4732-4748, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32275415

RESUMEN

Screening of a GSK-proprietary library against intracellular Mycobacterium tuberculosis identified 1, a thioalkylbenzoxazole hit. Biological profiling and mutant analysis revealed that this compound is a prodrug that is bioactivated by the mycobacterial enzyme MymA. A hit-expansion program including design, synthesis, and profiling of a defined set of analogues with optimized drug-like properties led to the identification of an emerging lead compound, displaying potency against intracellular bacteria in the low micromolar range, high in vitro solubility and permeability, and excellent microsomal stability.


Asunto(s)
Antituberculosos/farmacología , Proteínas Bacterianas/metabolismo , Benzoxazoles/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Oxigenasas/metabolismo , Profármacos/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/metabolismo , Benzoxazoles/síntesis química , Benzoxazoles/metabolismo , Línea Celular Tumoral , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Profármacos/síntesis química , Profármacos/metabolismo , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 28(22): 3529-3533, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30316633

RESUMEN

Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection.


Asunto(s)
Antituberculosos/química , Proteínas Bacterianas/antagonistas & inhibidores , Cumarinas/química , Animales , Antituberculosos/metabolismo , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Proteínas Bacterianas/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/metabolismo , Quinolinas/química , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología
6.
J Med Chem ; 58(11): 4573-80, 2015 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-25906200

RESUMEN

Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.


Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Bencimidazoles/química , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Amidas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Antimaláricos/farmacocinética , Benzamidas/farmacocinética , Bencimidazoles/farmacocinética , Células Cultivadas , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Femenino , Humanos , Malaria Falciparum , Ratones Endogámicos NOD , Ratones SCID , Modelos Moleculares , Estructura Molecular , Plasmodium falciparum , Relación Estructura-Actividad , Distribución Tisular
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