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Synthesis and biological evaluation of dihydroquinazoline-2-amines as potent non-nucleoside reverse transcriptase inhibitors of wild-type and mutant HIV-1 strains.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2019 Aug 15; Vol. 176, pp. 11-20. Date of Electronic Publication: 2019 May 10. - Publication Year :
- 2019
-
Abstract
- A novel series of dihydroquinazolin-2-amine derivatives were synthesized and evaluated for their anti-HIV-1 activity in MT-4 cell cultures. All of the molecules were active against wild-type HIV-1 with EC <subscript>50</subscript> values ranging from 0.61 μM to 0.84 nM. The most potent inhibitor, compound 4b, had an EC <subscript>50</subscript> value of 0.84 nM against HIV-1 strain IIIB, and thus was more active than the reference drugs efavirenz and etravirine. Moreover, most of the compounds maintained high activity (low-micromolar EC <subscript>50</subscript> values) against strains bearing the reverse transcriptase (RT) E138K mutation. Compound 4b had EC <subscript>50</subscript> values of 3.5 nM and 66 nM against non-nucleoside reverse transcriptase inhibitor-resistant strains bearing the RT E138K and RES056 mutations. In enzyme activity assays, compound 4b exhibited an IC <subscript>50</subscript> value of 10 nM against HIV-1 RT. Preliminary SARs and molecular docking studies provide valuable insights for further optimization.<br /> (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Amines chemical synthesis
Amines metabolism
Amines toxicity
Anti-HIV Agents chemical synthesis
Anti-HIV Agents metabolism
Anti-HIV Agents toxicity
Binding Sites
Cell Line, Tumor
HIV Reverse Transcriptase chemistry
HIV Reverse Transcriptase metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Protein Binding
Quinazolines chemical synthesis
Quinazolines metabolism
Quinazolines toxicity
Reverse Transcriptase Inhibitors chemical synthesis
Reverse Transcriptase Inhibitors metabolism
Reverse Transcriptase Inhibitors toxicity
Structure-Activity Relationship
Amines pharmacology
Anti-HIV Agents pharmacology
HIV Reverse Transcriptase antagonists & inhibitors
HIV-1 enzymology
Quinazolines pharmacology
Reverse Transcriptase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 176
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31091477
- Full Text :
- https://doi.org/10.1016/j.ejmech.2019.05.011