RESUMEN
Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/química , Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Antituberculosos/química , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Resistencia a Múltiples Medicamentos , Fluoroquinolonas/farmacología , Gatifloxacina , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Conformación Molecular , Mycobacterium bovis/metabolismo , Mycobacterium tuberculosis/metabolismoRESUMEN
Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P(1)' site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P(1)' site. Compounds with MICs of