RESUMEN
In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole (10alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs Asunto(s)
Antibacterianos/química
, Antibacterianos/farmacología
, Farmacorresistencia Bacteriana
, Carbono/química
, Diseño de Fármacos
, Evaluación Preclínica de Medicamentos
, Resistencia a Múltiples Medicamentos
, Bacterias Gramnegativas/efectos de los fármacos
, Bacterias Grampositivas/efectos de los fármacos
, Haemophilus influenzae/efectos de los fármacos
, Pruebas de Sensibilidad Microbiana
, Moraxella catarrhalis/efectos de los fármacos
, Oxazoles
, Pirazoles
, Relación Estructura-Actividad
RESUMEN
Peptidyl deformylase (PDF) is a metallo protease that catalyzes the removal of a formyl group from the N-termini of prokaryotic prepared polypeptides, an essential step in bacterial protein synthesis. Screening of our compound collection using Staphylococcus aureus PDF afforded a very potent inhibitor with an IC(50) in the low nanomolar range. Unfortunately, the compound that contains a hydroxamic acid did not exhibit antibacterial activity (MIC). In order to address the lack of activity in the MIC assay and to determine what portion of the molecule was responsible for binding to PDF, we prepared several analogues. This paper describes our findings that the hydroxamic acid functionality found in 1 is mainly responsible for the high affinity to PDF. In addition, we identified an alternative class of PDF inhibitors, the N-hydroxy urea 18, which has both PDF and antibacterial activity.
Asunto(s)
Amidohidrolasas , Aminopeptidasas/antagonistas & inhibidores , Antibacterianos/farmacología , Ácidos Hidroxámicos/farmacología , Staphylococcus aureus/efectos de los fármacos , Aminopeptidasas/química , Antibacterianos/síntesis química , Antibacterianos/química , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/química , Metaloendopeptidasas/antagonistas & inhibidores , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Proteica , Staphylococcus aureus/enzimología , Relación Estructura-ActividadRESUMEN
A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based substitution (III). Incorporation of sulfonamide substitution within the dihydropyrone template provided a series of highly potent HIV protease inhibitors, with structure-activity relationships described in this paper. Crystallographic studies provided further information on important binding interactions responsible for high enzymatic binding. These studies culminated in compound VI, which inhibits HIV protease with a Ki value of 8 pM and shows an IC90 value of 100 nM in antiviral cell culture. Clinical trials of this compound (PNU-140690, Tipranavir) for treatment of HIV infection are currently underway.
Asunto(s)
Fármacos Anti-VIH , Inhibidores de la Proteasa del VIH , Proteasa del VIH/metabolismo , Piridinas , Pironas , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacología , Línea Celular , Línea Celular Transformada , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/metabolismo , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Enlace de Hidrógeno , Ratones , Modelos Moleculares , Unión Proteica , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacología , Pironas/química , Pironas/metabolismo , Pironas/farmacología , Estereoisomerismo , Relación Estructura-Actividad , SulfonamidasAsunto(s)
Fármacos Anti-VIH/farmacología , VIH-1 , Piridinas/farmacología , Pirimidinas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Línea Celular , Farmacorresistencia Microbiana , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/enzimología , Masculino , Mutación , Piridinas/síntesis química , Piridinas/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacocinética , EstereoisomerismoRESUMEN
Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.