To improve the safety and selectivity of etravirine (ETR), cyclization strategy was employed by replacing the pyrimidine ring with a dihydropteridin-6(5H)-one scaffold affording a series of novel bicyclic tetrahydropteridine derivatives. Among them, compound 16a demonstrated exceptional potency against both WT HIV-1 (EC50 = 3 nM) and seven mutant strains (EC50 = 14–77 nM), comparable to ETR. Notably, 16a 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, 16a and its salt forms exhibited remarkably improved aqueous solubility in acid phosphate-buffered saline, compared to ETR and RPV. Additionally, 16a 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 16a as a highly promising on-nucleoside reverse transcriptase inhibitor candidate.
Cyclization-Inspired Structural Optimization: Designing Potent Non-nucleoside Reverse Transcriptase Inhibitors with Enhanced Safety and Selectivity
Tramontano E.;Corona A.;Dettori L.;
2026-01-01
Abstract
To improve the safety and selectivity of etravirine (ETR), cyclization strategy was employed by replacing the pyrimidine ring with a dihydropteridin-6(5H)-one scaffold affording a series of novel bicyclic tetrahydropteridine derivatives. Among them, compound 16a demonstrated exceptional potency against both WT HIV-1 (EC50 = 3 nM) and seven mutant strains (EC50 = 14–77 nM), comparable to ETR. Notably, 16a 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, 16a and its salt forms exhibited remarkably improved aqueous solubility in acid phosphate-buffered saline, compared to ETR and RPV. Additionally, 16a 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 16a as a highly promising on-nucleoside reverse transcriptase inhibitor candidate.
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