Abstract
We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single-digit) nanomolar EC50 values toward a panel of wild-type (WT), single-mutant, and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its antiviral efficacy was 3-fold greater against WT, 5-7-fold greater against Y181C, Y188L, E138K, and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 > 227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure-activity relationships provide important clues for further molecular elaboration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / chemistry*
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Anti-HIV Agents / pharmacokinetics
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Anti-HIV Agents / pharmacology
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Cell Line, Tumor
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Drug Resistance, Viral
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV-1 / enzymology*
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HIV-1 / genetics
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Heterocyclic Compounds, 2-Ring / chemical synthesis
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Heterocyclic Compounds, 2-Ring / chemistry*
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Heterocyclic Compounds, 2-Ring / pharmacokinetics
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Heterocyclic Compounds, 2-Ring / pharmacology
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Humans
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Male
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Mice
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Molecular Docking Simulation
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Mutation
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rats, Sprague-Dawley
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Reverse Transcriptase Inhibitors / chemical synthesis
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Reverse Transcriptase Inhibitors / chemistry*
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Reverse Transcriptase Inhibitors / pharmacokinetics
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Reverse Transcriptase Inhibitors / pharmacology
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Thiophenes / chemical synthesis
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Thiophenes / chemistry*
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Thiophenes / pharmacokinetics
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Thiophenes / pharmacology
Substances
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4-((4-((4-(4-cyano-2,6-dimethylphenoxy)thieno(3,2-d)pyrimidin-2-yl)amino)piperidin-1-yl)methyl)benzenesulfonamide
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Anti-HIV Agents
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Heterocyclic Compounds, 2-Ring
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Pyrimidines
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Reverse Transcriptase Inhibitors
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Sulfonamides
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Thiophenes
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HIV Reverse Transcriptase