Design and optimization of piperidine-substituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles

HIV-1 reverse transcriptase (RT) has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome (AIDS), but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors (NNRTIs). This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drug-resistance profiles, reduced toxicity, and excellent druggability. A series of diarylpyrimidine (DAPY) derivatives were prepared <i>via</i> structural modifications of the leads K-5a2 and <b>25a</b>. Among them, <b>15a</b> with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel, being 1.6-fold (WT, EC₅₀ = 1.75 nmol/L), 3.0-fold (L100I, EC₅₀ = 2.84 nmol/L), 2.4-fold (K103N, EC₅₀ = 1.27 nmol/L), 3.3-fold (Y181C, EC₅₀ = 5.38 nmol/L), 2.9-fold (Y188L, EC₅₀ = 7.96 nmol/L), 2.5-fold (E138K, EC₅₀ = 4.28 nmol/L), 4.8-fold (F227L/V106A, EC₅₀ = 3.76 nmol/L) and 5.3-fold (RES056, EC₅₀ = 15.8 nmol/L) more effective than that of the marketed drug ETR. Molecular docking results illustrated the detailed interactions formed by compound <b>15a</b> and WT, F227L/V106A, and RES056 RT. Moreover, <b>15a</b>·HCl carried outstanding pharmacokinetic (<i>t</i> _1/2 = 1.32 h, <i>F</i> = 40.8%) and safety profiles (LD₅₀ > 2000 mg/kg), which demonstrated that <b>15a</b> HCl is a potential anti-HIV-1 drug candidate.