Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 3, Pages 1484-1501Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01656
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Funding
- Key Project of NSFC for International Cooperation [81420108027]
- National Natural Science Foundation of China (NSFC) [81273354, 81573347]
- Young Scholars Program of Shandong University (YSPSDU) [2016WLJH32]
- Key Research and Development Project of Shandong Province [2017CXGC1401]
- KU Leuven [GOA 10/014]
- National Institutes of Health [AI033066]
- Spanish Ministerio de Economia y Competitividad [SAF2017-88107-R]
- Generalitat de Catalunya [2017SGR1746]
- Barcelona Supercomputing Center [BCV-2018-2-0006]
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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]
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