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1.
Bioorg Med Chem Lett ; 43: 128089, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33964438

RESUMEN

Several boron-containing small molecules have been approved by the US FDA to treat human diseases. We explored potential applications of boron-containing compounds in modern agriculture by pursuing multiple research and development programs. Here, we report a novel series of multi-substitution benzoxaboroles (1-36), a compound class that we recently reported as targeting geranylgeranyl transferase I (GGTase I) and thereby inhibiting protein prenylation (Kim et al., 2020). These compounds were designed, synthesized, and tested against the agriculturally important fungal pathogens Mycosphaerella fijiensis and Colletotrichum sublineolum in a structure-activity relationship (SAR) study. Compounds 13, 28, 30, 34 and 36 were identified as active leads with excellent antifungal MIC95 values in the range of 1.56-3.13 ppm against M. fijiensis and 0.78-3.13 ppm against C. sublineolum.


Asunto(s)
Antifúngicos/farmacología , Ascomicetos/efectos de los fármacos , Compuestos de Boro/farmacología , Colletotrichum/efectos de los fármacos , Fungicidas Industriales/farmacología , Agricultura , Transferasas Alquil y Aril/antagonistas & inhibidores , Transferasas Alquil y Aril/metabolismo , Antifúngicos/síntesis química , Antifúngicos/química , Ascomicetos/metabolismo , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Colletotrichum/metabolismo , Relación Dosis-Respuesta a Droga , Fungicidas Industriales/síntesis química , Fungicidas Industriales/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad
2.
ACS Chem Biol ; 15(7): 1930-1941, 2020 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-32573189

RESUMEN

Fungal pathogens pose an increasing threat to global food security through devastating effects on staple crops and contamination of food supplies with carcinogenic toxins. Widespread deployment of agricultural fungicides has increased crop yields but is driving increasingly frequent resistance to available agents and creating environmental reservoirs of drug-resistant fungi that can also infect susceptible human populations. To uncover non-cross-resistant modes of antifungal action, we leveraged the unique chemical properties of boron chemistry to synthesize novel 6-thiocarbamate benzoxaboroles with broad spectrum activity against diverse fungal plant pathogens. Through whole genome sequencing of Saccharomyces cerevisiae isolates selected for stable resistance to these compounds, we identified mutations in the protein prenylation-related genes, CDC43 and ERG20. Allele-swapping experiments confirmed that point mutations in CDC43, which encodes an essential catalytic subunit within geranylgeranyl transferase I (GGTase I) complex, were sufficient to confer resistance to the benzoxaboroles. Mutations in ERG20, which encodes an upstream farnesyl pyrophosphate synthase in the geranylgeranylation pathway, also conferred resistance. Consistent with impairment of protein prenylation, the compounds disrupted membrane localization of the classical geranylgeranylation substrate Cdc42. Guided by molecular docking predictions, which favored Cdc43 as the most likely direct target, we overexpressed and purified functional GGTase I complex to demonstrate direct binding of benzoxaboroles to it and concentration-dependent inhibition of its transferase activity. Further development of the boron-containing scaffold described here offers a promising path to the development of GGTase I inhibitors as a mechanistically distinct broad spectrum fungicide class with reduced potential for cross-resistance to antifungals in current use.


Asunto(s)
Antifúngicos/farmacología , Compuestos de Boro/farmacología , Prenilación de Proteína/efectos de los fármacos , Proteínas de Saccharomyces cerevisiae/metabolismo , Tiocarbamatos/farmacología , Transferasas Alquil y Aril/antagonistas & inhibidores , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Antifúngicos/síntesis química , Antifúngicos/metabolismo , Compuestos de Boro/síntesis química , Compuestos de Boro/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Membrana Celular/efectos de los fármacos , Dimetilaliltranstransferasa/genética , Dimetilaliltranstransferasa/metabolismo , Farmacorresistencia Fúngica/genética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Hongos/efectos de los fármacos , Hongos/genética , Simulación del Acoplamiento Molecular , Mutación Puntual , Unión Proteica , Proteínas de Saccharomyces cerevisiae/genética , Tiocarbamatos/síntesis química , Tiocarbamatos/metabolismo , Proteína de Unión al GTP cdc42 de Saccharomyces cerevisiae/metabolismo
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