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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180830/ https://www.ncbi.nlm.nih.gov/pubmed/32235557 http://dx.doi.org/10.3390/molecules25071581 |
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author | Li, Ting-Ting Pannecouque, Christophe De Clercq, Erik Zhuang, Chun-Lin Chen, Fen-Er |
author_facet | Li, Ting-Ting Pannecouque, Christophe De Clercq, Erik Zhuang, Chun-Lin Chen, Fen-Er |
author_sort | Li, Ting-Ting |
collection | PubMed |
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 B4 (EC(50) = 6 nM) and B6 (EC(50) = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC(50) values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC(50) = 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. |
format | Online Article Text |
id | pubmed-7180830 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-71808302020-05-01 Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs Li, Ting-Ting Pannecouque, Christophe De Clercq, Erik Zhuang, Chun-Lin Chen, Fen-Er Molecules Article 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 B4 (EC(50) = 6 nM) and B6 (EC(50) = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC(50) values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC(50) = 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. MDPI 2020-03-30 /pmc/articles/PMC7180830/ /pubmed/32235557 http://dx.doi.org/10.3390/molecules25071581 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Li, Ting-Ting Pannecouque, Christophe De Clercq, Erik Zhuang, Chun-Lin Chen, Fen-Er Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180830/ https://www.ncbi.nlm.nih.gov/pubmed/32235557 http://dx.doi.org/10.3390/molecules25071581 |
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