期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 18, 页码 13604-13621出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00987
关键词
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资金
- National Natural Science Foundation of China [81973181, 81903453]
- Key Project of NSFC for International Cooperation [81420108027]
- National Key Projects of New Drugs RD [2019ZX09301-126]
- Key research and development project of Shandong Province [2017CXGC1401, 2019JZZY021011]
- Science Foundation for Outstanding Young Scholars of Shandong Province [ZR2020JQ31]
- Taishan Scholar Program at Shandong Province, Foreign cultural and educational experts Project [GXL20200015001]
- Spanish Ministerio de Economia y Competitividad [SAF2017-88107-R, MDM-2017-0767]
- AEI/FEDER UE
- Generalitat de Catalunya [2017SGR1746]
- Consorci de Serveis Universitaris de Catalunya (Molecular Recognition project)
- KU Leuven [GOA 10/014]
Two series of new pyridyl-bearing fused bicyclic analogues were synthesized to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket and evaluated for their anti-HIV activities. Several compounds showed potent inhibitory effects against HIV-1 strains at low nanomolar levels. Detailed structure-activity relationships and metabolic stability profiles were obtained, providing insights for further structural optimization of HIV-1 inhibitors.
Two series of new pyridyl-bearing fused bicyclic analogues designed to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket were synthesized and evaluated for their anti-HIV activities. Several compounds, such as 6, 14, 15, 21, 30, and 33, were found to be potent inhibitors against the wild-type (WT) HIV-1 strain or multiple NNRTI-resistant strains at low nanomolar levels. Detailed structure-activity relationships were obtained by utilizing the variation of moieties within the corresponding pharmacophores. In vitro metabolic stability profiles and some drug-like properties of selected compounds were assessed, furnishing the preliminary structure-metabolic stability relationships. Furthermore, molecular modeling studies elucidated the binding modes of compounds 6, 15, 21, and 30 in the binding pocket of WT, E138K, K103N, or Y181C HIV-1 RTs. These promising compounds can be used as lead compounds and warrant further structural optimization to yield more active HIV-1 inhibitors.
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