Cyclization-Inspired Structural Optimization: Designing Potent Non-nucleoside Reverse Transcriptase Inhibitors with Enhanced Safety and Selectivity

To improve the safety and selectivity of etravirine (ETR), cyclization strategy was employed by replacing the pyrimidine ring with a dihydropteridin-6(5<i>H</i>)-one scaffold affording a series of novel bicyclic tetrahydropteridine derivatives. Among them, compound <b>16a</b> demonstrated exceptional potency against both WT HIV-1 (EC₅₀ = 3 nM) and seven mutant strains (EC₅₀ = 14-77 nM), comparable to ETR. Notably, <b>16a</b> showed negligible cytotoxicity (CC₅₀ = 196.46 μM) and high selectivity index (SI = 65,789), greatly surpassing ETR (CC₅₀ > 4.6 μM, SI > 1436) and rilpivirine (RPV) (CC₅₀ > 4.0 μM, SI > 3989). Moreover, <b>16a</b> and its salt forms exhibited remarkably improved aqueous solubility in acid phosphate-buffered saline, compared to ETR and RPV. Additionally, <b>16a</b> displayed minimal sensitivity to CYP enzymes, no inhibition of the hERG potassium channel, and no detectable acute toxicity at an in vivo dose of 2 g/kg. Collectively, these results highlight <b>16a</b> as a highly promising on-nucleoside reverse transcriptase inhibitor candidate.