标题: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
作者:Kang, Dongwei; Zhang, Heng; Wang, Zhao; Zhao, Tong; Ginex, Tiziana; Luque, Francisco Javier; Yang, Yang; Wu, Gaochan; Feng, Da; Wei, 更多
作者机构:[Kang, Dongwei; Zhang, Heng; Wang, Zhao; Zhao, Tong; Wu, Gaochan; Feng, Da; Wei, Fenju; Zhang, Jian; Zhan, Peng; Liu, Xinyong] Shandong Univ, Sch Phar 更多
通讯作者:Zhan, P;Liu, XY
通讯作者地址:[Zhan, P; Liu, XY]Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples 更多
来源:JOURNAL OF MEDICINAL CHEMISTRY
出版年:2019
卷:62
期:3
页码:1484-1501
DOI:10.1021/acs.jmedchem.8b01656
摘要: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.; [GRAPHICS]
收录类别:SCOPUS;SCIE
Scopus被引频次:1
资源类型:期刊论文
原文链接:https://www.scopus.com/inward/record.uri?eid=2-s2.0-85060540067&doi=10.1021%2facs.jmedchem.8b01656&partnerID=40&md5=1f46728b8a8deb1035390a2f9ee2a68c
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