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.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Kang, D; Zhang, H; Wang, Z; Zhao, T; Ginex, T; Luque, FJ; Yang, Y; Wu, G; Feng, D; Wei, F; Zhang, J; De Clercq, E; Pannecouque, C; Chen, CH; Lee, K-H; Murugan, NA; Steitz, TA; Zhan, P; Liu, X

Published Date

  • February 14, 2019

Published In

Volume / Issue

  • 62 / 3

Start / End Page

  • 1484 - 1501

PubMed ID

  • 30624934

Pubmed Central ID

  • PMC7441537

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.8b01656


  • eng

Conference Location

  • United States