Discovery of Novel Amino Acids (Analogues)-Substituted Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Design, Synthesis, and Biological Evaluation.
Int J Mol Sci
; 25(16)2024 Aug 20.
Article
en En
| MEDLINE
| ID: mdl-39201714
ABSTRACT
Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC50 values ranging from 0.042 µM to 7.530 µM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC50 values of 0.031 µM and 0.094 µM, being about 4.3-fold superior to EFV (EC50 = 0.132 µM) and 1.9-fold superior to NVP (EC50 = 0.181 µM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC50 = 27.9 µM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure-activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Tiofenos
/
Diseño de Fármacos
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VIH-1
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Inhibidores de la Transcriptasa Inversa
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Fármacos Anti-VIH
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Transcriptasa Inversa del VIH
/
Aminoácidos
Límite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2024
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Suiza