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Exploiting the hydrophobic channel of the NNIBP: Discovery of novel diarylpyrimidines as HIV-1 NNRTIs against wild-type and K103N mutant viruses.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2021 Jul 15; Vol. 42, pp. 116239. Date of Electronic Publication: 2021 May 28. - Publication Year :
- 2021
-
Abstract
- To further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), a new series of diarylpyrimidines (DAPYs) were designed and synthesized as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs). The target compounds were evaluated for anti-HIV potency in MT-4 cells. Most of the synthesized DAPYs exhibited moderate to excellent activity against the HIV-1 wild-type (WT) strain with EC <subscript>50</subscript> values ranging from 16 nM to 0.722 µM. Interestingly, few compounds displayed remarkable activity in inhibiting K103N mutant virus with EC <subscript>50</subscript> values ranging from 39 nM to 1.708 µM. Notably, FS2 (EC <subscript>50(IIIB)</subscript>  = 16 nM, EC <subscript>50(K103N)</subscript>  = 39 nM, SI = 294) was identified as the most significant compound, which was considerably more potent than nevirapine, lamivudine, and comparable to zidovudine. Additionally, the HIV-1 RT inhibition assay confirmed their binding target. Preliminary structure-activity relationships (SARs) and molecular modeling studies were also performed, providing significant suggestions for further optimization.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- Anti-HIV Agents chemistry
Dose-Response Relationship, Drug
HIV Reverse Transcriptase metabolism
HIV-1 genetics
Humans
Hydrophobic and Hydrophilic Interactions
Microbial Sensitivity Tests
Molecular Structure
Mutation
Reverse Transcriptase Inhibitors chemistry
Structure-Activity Relationship
Anti-HIV Agents pharmacology
Drug Discovery
HIV Reverse Transcriptase antagonists & inhibitors
HIV-1 drug effects
Reverse Transcriptase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 42
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34090079
- Full Text :
- https://doi.org/10.1016/j.bmc.2021.116239