RESUMEN
The synthesis and preliminary structure-activity relationship of a series of pyrrolidinones are described. These pyrrolidinones have been characterized as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) which are highly potent against wild-type and drug-resistant human immunodeficiency viruses (HIV-1).
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirrolidinonas/química , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
A series of 2-amino-9-aryl-7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized to target focal adhesion kinase (FAK). A number of these pyrrolopyrimides exhibited low micromolar inhibitory activities against focal adhesion kinase, and their preliminary SAR was established via systematic chemical modifications. The 2-amino-9-aryl-7H-pyrrolo[2,3-d]pyrimidines represent a new class of kinase inhibitors.
Asunto(s)
Antineoplásicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Antineoplásicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacología , Humanos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
A series of 2-amino-9-aryl-7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized as focal adhesion kinase (FAK) inhibitors using molecular modeling in conjunction with a co-crystal structure. Chemistry was developed to introduce functionality onto the 9-aryl ring, which resulted in the identification of potent FAK inhibitors. In particular, compound 32 possessed single-digit nanomolar IC(50) and represents one of the most potent FAK inhibitors discovered to date.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/síntesis química , Inhibidores Enzimáticos/farmacología , Estructura Molecular , Pirimidinas/farmacologíaRESUMEN
Screening of our compound collection using Staphylococcus aureus Ni-Peptide deformylase (PDF) afforded a very potent PDF inhibitor with an IC(50) in the low nanomolar range but with poor antibacterial activity (MIC). Three-dimensional structural information obtained from Pseudomonas aeruginosa Ni-PDF complexed with the inhibitor suggested the synthesis of a variety of analogues that would maintain high binding affinity while attempting to improve antibacterial activity. Many of the compounds synthesized proved to be excellent PDF-Ni inhibitors and some showed increased antibacterial activity in selected strains.