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Quinoxalinylethylpyridylthioureas (QXPTs) as Potent Non-Nucleoside HIV-1 Reverse Transcriptase (RT) Inhibitors. Further SAR Studies and Identification of a Novel Orally Bioavailable Hydrazine-Based Antiviral Agent
- Source :
- Journal of Medicinal Chemistry. 44:305-315
- Publication Year :
- 2001
- Publisher :
- American Chemical Society (ACS), 2001.
-
Abstract
- Quinoxalinylethylpyridylthioureas (QXPTs) represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 6-FQXPT (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis of novel heteroarylethylpyridylthioureas which were tested as anti-HIV agents. Several compounds proved to be potent broad-spectrum enzyme inhibitors and significantly inhibited HIV-1 replication in vitro. Their potency depends on the substituents and the nature of the heterocyclic skeleton linked to the ethyl spacer, and structure-activity relationships are discussed in terms of the possible interaction with the RT binding site. Although the new QXPTs analogues show potent antiviral activity, none of the compounds tested overcome the pharmacokinetic disadvantages inherent to ethylpyridylthioureidic antiviral agents, which in general have very low oral bioavailability. Through an integrated effort involving synthesis, docking studies, and biological and pharmacokinetic evaluation, we investigated the structural dependence of the poor bioavailability and rapid clearance within the thioureidic series of antivirals. Replacing the ethylthioureidic moiety with a hydrazine linker led to a new antiviral lead, offering promising pharmacological and pharmacokinetic properties in terms of antiviral activity and oral bioavailability.
- Subjects :
- Models, Molecular
Anti-HIV Agents
Pyridines
Biological Availability
Cell Line
Mice
Structure-Activity Relationship
Zidovudine
Quinoxalines
Drug Discovery
medicine
Animals
Humans
Settore BIO/10
biology
Chemistry
Thiourea
HIV
Drug Synergism
Stereoisomerism
Drug interaction
Nucleotidyltransferase
antiviral
HIV Reverse Transcriptase
Reverse transcriptase
Bioavailability
Didanosine
HIV, antiviral
Biochemistry
Docking (molecular)
Enzyme inhibitor
HIV-1
biology.protein
Reverse Transcriptase Inhibitors
Molecular Medicine
Nucleoside
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 44
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....5af85449b10fe4777f4999fe47e60784