Details

Autor(en) / Beteiligte

• Kang, Dongwei
• Zhang, Heng
• Wang, Zhao
• Zhao, Tong
• Ginex, Tiziana
• Luque, Francisco Javier
• Yang, Yang
• Wu, Gaochan
• Feng, Da
• Wei, Fenju
• Zhang, Jian
• De Clercq, Erik
• Pannecouque, Christophe
• Chen, Chin Ho
• Lee, Kuo-Hsiung
• Murugan, N. Arul
• Steitz, Thomas A
• Zhan, Peng
• Liu, Xinyong

Titel

Identification of Dihydrofuro[3,4‑d]pyrimidine Derivatives as Novel HIV‑1 Non-Nucleoside Reverse Transcriptase Inhibitors with Promising Antiviral Activities and Desirable Physicochemical Properties

Ist Teil von

• Journal of medicinal chemistry, 2019-02, Vol.62 (3), p.1484-1501

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting “tolerant region I” and “tolerant region II” of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro­[3,4-d]­pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC50 = 0.9–8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance.