Identification of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.
Eur J Med Chem
; 247: 115045, 2023 Feb 05.
Article
em En
| MEDLINE
| ID: mdl-36577216
ABSTRACT
Here, we reported a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP). The anti-HIV-1 activity results demonstrated that compound 9e (EC50 = 2.04-61.1 nM) displayed robust potencies against a panel of HIV-1 NNRTIs-resistant strains, being comparable to that of etravirine (ETR). Moreover, 9e displayed much lower cytotoxicity (CC50 = 59.2 µM) and higher SI values (4605) toward wild-type HIV-1 strain. The HIV-1 RT enzyme inhibitory activity clarified the binding target of 9e was HIV-1 RT (IC50 = 0.019 µM). Furthermore, the molecular modeling study was also investigated to give a reasonable explanation of the preliminary SARs. Further test indicated that 9e possessed significantly improved water solubility under pH 7.0 and 7.4 conditions. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features. Consequently, compound 9e showed the highest activity and low cytotoxicity, which could be used as a lead for further modification to obtain potent HIV-1 NNRTIs.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
HIV-1
/
Fármacos Anti-HIV
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2023
Tipo de documento:
Article