2. Academic Validation
  3. Cyclization-Inspired Structural Optimization: Designing Potent Non-nucleoside Reverse Transcriptase Inhibitors with Enhanced Safety and Selectivity

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

  • J Med Chem. 2026 Jan 22;69(2):1199-1217. doi: 10.1021/acs.jmedchem.5c02556.
Yin-Xiang Zhang 1,  Christophe Pannecouque 2,  Erik De Clercq 2,  Enzo Tramontano 3,  Angela Corona 3,  Laura Dettori 3,  Phuong-Thao Tran 4,  Xu-Dong Li 5,  Shuo Su 6,  Shuai Wang 1,  Fen-Er Chen 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Shanghai Engineering Research Center of Industrial Asymmetric Catalysis of Chiral Drugs, State Key Laboratory of Green Chemical Synthesis and Conversion, Fudan University, Shanghai 200433, China.
  • 2 Rega Institute for Medical Research, KU Leuven, Herestraat 49, Leuven B-3000, Belgium.
  • 3 Dept Appl Sci Biosyst, University of Cagliari, Monserrato I-09042, Italy.
  • 4 Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Cua Nam, Hanoi 10000, Vietnam.
  • 5 School of Data Science, Shanghai, Fudan University, Shanghai 200433, China.
  • 6 Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai 200032, China.
PMID: 41511861 DOI: 10.1021/acs.jmedchem.5c02556
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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