Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, BEARING BRIDGEHEAD NITROGEN, NNRTI BINDING POCKET, ENTRANCE CHANNEL, BIOLOGICAL EVALUATION, ENHANCED SOLUBILITY, COLORIMETRIC ASSAY, CRYSTAL-STRUCTURES, ETRAVIRINE TMC125, PRELIMINARY SAR, MUTANT VIRUSES, Animals, Anti-HIV Agents, Cell Line, Tumor, Drug Resistance, Viral, HIV Reverse Transcriptase, HIV-1, Heterocyclic Compounds, 2-Ring, Humans, Male, Mice, Molecular Docking Simulation, Mutation, Pyrimidines, Rats, Sprague-Dawley, Reverse Transcriptase Inhibitors, Structure-Activity Relationship, Sulfonamides, Thiophenes, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

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.