RESUMO
A series of novel pyrazinones designed as non-nucleoside reverse transcriptase inhibitors (NNRTIs) was synthesized and their anti-HIV structure-activity relationship (SAR) was studied.
Assuntos
Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/metabolismo , Pirazinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , HIV-1/efeitos dos fármacos , HIV-1/genética , Modelos Moleculares , Mutação , Pirazinas/química , Pirazinas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
Human immunodeficiency virus type-1 integrase is an essential enzyme for effective viral replication and hence a valid target for the design of inhibitors. We report here on the design and synthesis of a novel series of phthalimide analogues as integrase inhibitors. The short synthetic pathway enabled us to synthesize a series of analogues with a defined structure diversity. The presence of a single carbonyl-hydroxy-aromatic nitrogen motif was shown to be essential for the enzymatic activity and this was confirmed by molecular docking studies. The enzymatically most active compound from this series is 7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo[3,4-g]quinoxaline-6,8-dione (15l) with an IC(50) value of 112 nM on the HIV-1 integrase enzyme, while ((7-(4-chlorobenzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione (15k)) showed an EC(50) of 270 nM against HIV-1 in a cell-based assay.
Assuntos
Fármacos Anti-HIV/síntese química , Inibidores de Integrase de HIV/síntese química , Integrase de HIV/metabolismo , Compostos Heterocíclicos com 3 Anéis/síntese química , Ftalimidas/síntese química , Pirróis/síntese química , Quinoxalinas/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Linhagem Celular , Integrase de HIV/química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Modelos Moleculares , Ftalimidas/química , Ftalimidas/farmacologia , Ligação Proteica , Pirróis/química , Pirróis/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-AtividadeRESUMO
This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
Assuntos
Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Pirimidinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/toxicidade , Linhagem Celular , Farmacorresistência Viral , Transcriptase Reversa do HIV/genética , HIV-1/genética , Humanos , Mutação , Pirimidinas/farmacologia , Pirimidinas/toxicidade , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/toxicidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We have developed a fast and robust computational method for prediction of antiviral activity in automated de novo design of HIV-1 reverse transcriptase inhibitors. This is a structure-based approach that uses a linear relation between activity and interaction energy with discrete orientation sampling and with localized interaction energy terms. The localization allows for the analysis of mutations of the protein target and for the separation of inhibition and a specific binding to the enzyme. We apply the method to the prediction of pIC(50) of HIV-1 reverse transcriptase inhibitors. The model predicts the activity of an arbitrary compound with a q(2) of 0.681 and an average absolute error of 0.66 log value, and it is fast enough to be used in high-throughput computational applications.
