RESUMEN
Earlier we reported the identification of diarylpyrimidine-quinolone hybrids as a new class of HIV-1 NNRTIs. A few of these hybrids displayed moderate inhibitory activity against wt HIV-1 replication at submicromolar level, however, all of them lacked inhibitory activity against the double mutant virus (K103N/Y181C), which is the most prevalent NNRTI resistant-associated double mutant observed in the clinic. In the present study, we designed and synthesized a new series of diarylpyrimidine-quinolone hybrids featuring a halogen group at C-6' position of quinolone ring. The biological results indicated that most of these hybrids could inhibit wt HIV-1 replication at nanomolar level ranging from 0.088 to 0.0096 µM. The most promising hybrid 5c displayed a significant EC50 value of 0.0096 µM against HIV-1 IIIB and of 0.98 µM against K103N/Y181C. Further docking studies revealed that these hybrids could be well located in the hydrophobic NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid scaffold in the molecules. These promising results suggested a high potential to further develop these hybrids as next-generation NNRTIs with improved antiviral efficacy and resistance profile.
Asunto(s)
Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH/efectos de los fármacos , Pirimidinas/farmacología , Quinolonas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Pirimidinas/química , Quinolonas/química , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28±0.07µM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules.