RESUMO
A series of novel diarylpyrimidine analogues featuring a hydroxyiminomethyl group between the pyrimidine scaffold and the aryl wing I have been synthesized and tested in MT-4 cells culture as non-nucleoside reverse transcriptase inhibitors against human immunodeficiency virus (HIV). Most of these new congeners exhibited moderate to excellent activity against wild-type virus with an EC(50) value ranging from 0.569microM to 0.005microM. 4-(4-((Hydroxyimino) (3-methoxyphenyl)methyl)pyrimidin-2-ylamino)benzonitrile (12n) was identified as the most active compound of this new series (EC(50)=0.025microM, SI >1223) associated with moderate activity against HIV-1 double mutant strains (K103N+Y181C) (EC(50)=8.72microM) in addition to its anti-HIV-2 activity with an EC(50) value of 8.31microM. Preliminary structure-activity relationship (SAR) among the newly synthesized DAPYs was also investigated.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Linhagem Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Molecular hybridization of the known anti-HIV-1 template DPC083 and etravirine based on docking model overlay has been generated a novel series of diarylbenzopyrimidine analogues (DABPs) (5a-z). These new hybrids were assessed for their activity against HIV in MT-4 cell cultures. Most of these compounds showed good activity against wild-type HIV-1 and mutant viruses. In particular, compound 5r showed the most potent activity against wild-type HIV-1 with an EC50 value of 1.8 nM, and with a selectivity index up to 111,954. It also proved more active against mutant L100I, K103N, Y188L, and K103N+Y181C RT HIV-1 strains than efavirenz.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/química , Humanos , Modelos Moleculares , Nitrilas , Ligação Proteica , Piridazinas/química , Piridazinas/farmacologia , Pirimidinas , Quinazolinas/química , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Nine newly 6-cyano-2-naphthyl substituted diarylpyrimidines (DAPY) were synthesized as non-nucleoside reverse transcriptase inhibitors on the basis of our previous work. The antiviral and cytotoxicity evaluation indicated that these compounds displayed strong activity against wild-type HIV-1 at nanomolar concentrations with selectivity index SI greater than 23 779. The most active compounds 3c and 3e exhibited activity against the double mutant (103N+181C) strains at an EC50 of 0.16 and 0.15 µM, and were more activity than that of efavirenz.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Naftóis/química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Alcinos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/toxicidade , Benzoxazinas/farmacologia , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Ciclopropanos , Transcriptase Reversa do HIV/metabolismo , Humanos , Naftóis/síntese química , Naftóis/toxicidade , Pirimidinas/síntese química , Pirimidinas/toxicidade , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/toxicidadeRESUMO
A novel series of diarylpyrimidine analogues (DAPYs) featuring a naphthyl moiety at the C4 position were designed, with all compounds exhibiting strong activity against wild-type HIV-1.A novel series of diarylpyrimidine analogues (DAPYs) featuring a naphthyl moiety at the C4 position were synthesized and evaluated for their in vitro activity against HIV in MT-4 cells. All compounds exhibited strong activity against wild-type HIV-1. The most active compound showed activity against wild-type HIV-1 with an EC(50) value of 2.35 nM and against the double mutant strain (K103N+Y181C) with an EC(50) value of 6.6 microM, with a selectivity index greater than 60 000 against wild-type HIV-1. Additionally, some compounds also showed activity against HIV-2 (EC(50)=5.82 microM).
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A series of 38 2-naphthyl-substituted diarylpyrimidine (DAPY) analogues, characterized by various substitution patterns on the pyrimidine and naphthalene rings, was synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of the HIV-1 wild-type and double mutant (K103N+Y181C) strains. Most of the compounds displayed strong activity against wild-type HIV-1. The most active compound, with a cyano group at position C6 on the naphthalene ring, exhibited activity against wild-type HIV-1 with an EC50 value of 0.002 microM and against the double mutant strain with an EC50 value of 0.24 microM; the selectivity index (SI) against wild-type is >180 000, the highest SI value among DAPY analogues. The structure-activity relationship (SAR) of the newly synthesized DAPYs is presented herein.