Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs
Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and...
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MDPI AG
2020-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/7/1581 |
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| author | Ting-Ting Li Christophe Pannecouque Erik De Clercq Chun-Lin Zhuang Fen-Er Chen |
| author_facet | Ting-Ting Li Christophe Pannecouque Erik De Clercq Chun-Lin Zhuang Fen-Er Chen |
| author_sort | Ting-Ting Li |
| collection | DOAJ |
| description | Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds <b>B4</b> (EC<sub>50</sub> = 6 nM) and <b>B6</b> (EC<sub>50</sub> = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC<sub>50</sub> values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC<sub>50</sub> = 0.08 μM). The preliminary structure–activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues. |
| first_indexed | 2024-03-10T20:47:37Z |
| format | Article |
| id | doaj.art-23c81b6dca6f4d79ad0136e9d37a98b0 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T20:47:37Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-23c81b6dca6f4d79ad0136e9d37a98b02023-11-19T20:09:48ZengMDPI AGMolecules1420-30492020-03-01257158110.3390/molecules25071581Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYsTing-Ting Li0Christophe Pannecouque1Erik De Clercq2Chun-Lin Zhuang3Fen-Er Chen4Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, ChinaRega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, BelgiumRega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, BelgiumDepartment of Chemistry, Fudan University, Shanghai 200433, ChinaInstitute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, ChinaScaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds <b>B4</b> (EC<sub>50</sub> = 6 nM) and <b>B6</b> (EC<sub>50</sub> = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC<sub>50</sub> values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC<sub>50</sub> = 0.08 μM). The preliminary structure–activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues.https://www.mdpi.com/1420-3049/25/7/1581CH(CN)-DAPYsHIV-1NNRTIscaffold hoppingstrucutral optimization |
| spellingShingle | Ting-Ting Li Christophe Pannecouque Erik De Clercq Chun-Lin Zhuang Fen-Er Chen Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs Molecules CH(CN)-DAPYs HIV-1 NNRTI scaffold hopping strucutral optimization |
| title | Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs |
| title_full | Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs |
| title_fullStr | Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs |
| title_full_unstemmed | Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs |
| title_short | Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs |
| title_sort | scaffold hopping in discovery of hiv 1 non nucleoside reverse transcriptase inhibitors from ch cn dabos to ch cn dapys |
| topic | CH(CN)-DAPYs HIV-1 NNRTI scaffold hopping strucutral optimization |
| url | https://www.mdpi.com/1420-3049/25/7/1581 |
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