Open AccessIdentification of Dihydrofuro[3,4-d]pyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Promising Antiviral Activities and Desirable Physicochemical Properties
Author(s) -
Dongwei Kang,
Heng Zhang,
Zhao Wang,
Tong Zhao,
Tiziana Ginex,
F. Javier Luque,
Yang Yang,
Gaochan Wu,
Du Feng,
Fenju Wei,
Jian Zhang,
Erik De Clercq,
Christophe Pannecouque,
Chin Ho Chen,
KuoHsiung Lee,
N. Murugan,
Thomas A. Steitz,
Peng Zhan,
Xinyong Liu
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.8b01656
Subject(s) - chemistry , reverse transcriptase , nucleoside , pyrimidine , human immunodeficiency virus (hiv) , nucleoside reverse transcriptase inhibitor , nucleotidyltransferase , stereochemistry , combinatorial chemistry , virology , biochemistry , rna , biology , gene
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 (EC 50 = 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.