RESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Pirimidinas/farmacología , Quinolonas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/síntesis química , Sitios de Unión , Línea Celular , Diseño de Fármacos , Células Precursoras de Granulocitos/efectos de los fármacos , Células Precursoras de Granulocitos/patología , Células Precursoras de Granulocitos/virología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/enzimología , VIH-1/crecimiento & desarrollo , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Pirimidinas/síntesis química , Quinolonas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Relación Estructura-Actividad , Acetato de Tetradecanoilforbol/farmacología , Latencia del Virus/efectos de los fármacosRESUMEN
A novel series of etravirine-VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50=0.24 , SI>1225), was more potent than delavirdine (EC50=0.66 µM, SI>67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Inhibidores de la Transcriptasa Inversa/química , Acetanilidas/química , Fármacos Anti-VIH/síntesis química , Línea Celular , Técnicas de Química Sintética , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Humanos , Simulación de Dinámica Molecular , Nitrilos , Piridazinas/química , Pirimidinas , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
Based on molecular simulation, the etravirine-VRX-480773 hybrids previously disclosed by our group were optimized to yield novel pyrimidine sulfonylacetanilides 8 with improved activity against a panel of seven clinically relevant single and double mutant strains of HIV-1. The improvement in potency in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits the reverse transcriptase (RT), and represents a remarkable step forward in the development of anti-HIV drugs.
Asunto(s)
Acetanilidas/síntesis química , Acetanilidas/farmacología , Fármacos Anti-VIH/farmacología , Secuencia Conservada/efectos de los fármacos , VIH-1/efectos de los fármacos , VIH-1/genética , Mutación , Pirimidinas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Acetanilidas/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , VIH-1/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Células Tumorales CultivadasRESUMEN
A novel series of piperidin-4-yl-aminopyrimidine derivatives were designed fusing the pharmacophore templates of etravirine-VRX-480773 hybrids our group previously described and piperidine-linked aminopyrimidines. Most compounds displayed significantly improved activity against wild-type HIV-1 with EC50 values in single-digit nanomolar concentrations compared to etravirine-VRX-480773 hybrids. Selected compounds were also evaluated for activity against reverse transcriptase, and had lower IC50 values than that of nevirapine. The improved potency observed in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits reverse transcriptase, and represents a remarkable step forward in the development of AIDS therapeutics.