Design, Synthesis, and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles

摘要

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 F2271A-V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27-has lower-cytotcixicity (CC50 > 227 mu M) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101.27 also showed favorable, drug-like pharmacokinetit and safety properties in rats in vivo). Molecular docking studies and the structure activity relationships prOvide important clues for further molecular elaboration.