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Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from N -Alkylation to Methyl Hopping on the Pyrimidine Ring.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Apr 22; Vol. 64 (8), pp. 5067-5081. Date of Electronic Publication: 2021 Apr 14. - Publication Year :
- 2021
-
Abstract
- Considering the nonideal metabolic stability of the difluoro-biphenyl-diarylpyrimidine lead compound 4 , a series of novel alkylated difluoro-biphenyl-diarylpyrimidines were designed and synthesized based on their structure. Introducing alkyl or substituted alkyl groups on the linker region to block the potential metabolic sensitive sites generated 22 derivatives. Among them, compound 12a with an N -methyl group displayed excellent anti-HIV-1 activity and selectivity. The methyl group was hopped to the central pyrimidine to occupy the small linker region and maintain the water-mediated hydrogen bond observed in the binding of compound 4 with RT. The resulting compound 16y exhibited an improved anti-HIV-1 activity, much lower cytotoxicity, and nanomolar activity toward multiple mutants. In addition, 16y has a better stability in human liver microsomes than 4 . Moreover, no apparent in vivo acute toxicity was observed in 16y -treated female, especially pregnant mice. This series of alkylated compounds with highly potency and safety represent a promising lead template for future discovery.
- Subjects :
- Alkylation
Animals
Binding Sites
Cell Line
Cell Survival drug effects
Drug Stability
Female
HIV Reverse Transcriptase genetics
HIV Reverse Transcriptase metabolism
Half-Life
Humans
Hydrophobic and Hydrophilic Interactions
Mice
Microsomes, Liver metabolism
Molecular Docking Simulation
Mutation
Pyrimidines metabolism
Pyrimidines pharmacology
Reverse Transcriptase Inhibitors metabolism
Reverse Transcriptase Inhibitors pharmacology
Structure-Activity Relationship
Biphenyl Compounds chemistry
Drug Design
HIV Reverse Transcriptase antagonists & inhibitors
Pyrimidines chemistry
Reverse Transcriptase Inhibitors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33851529
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00128