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Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs
In this report, a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2. The n...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280082/ https://www.ncbi.nlm.nih.gov/pubmed/32528834 http://dx.doi.org/10.1016/j.apsb.2019.08.013 |
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author | Kang, Dongwei Feng, Da Ginex, Tiziana Zou, Jinmi Wei, Fenju Zhao, Tong Huang, Boshi Sun, Yanying Desta, Samuel De Clercq, Erik Pannecouque, Christophe Zhan, Peng Liu, Xinyong |
author_facet | Kang, Dongwei Feng, Da Ginex, Tiziana Zou, Jinmi Wei, Fenju Zhao, Tong Huang, Boshi Sun, Yanying Desta, Samuel De Clercq, Erik Pannecouque, Christophe Zhan, Peng Liu, Xinyong |
author_sort | Kang, Dongwei |
collection | PubMed |
description | In this report, a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC(50) ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure–activity relationship and molecular docking were also investigated. Furthermore, 26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection. |
format | Online Article Text |
id | pubmed-7280082 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-72800822020-06-10 Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs Kang, Dongwei Feng, Da Ginex, Tiziana Zou, Jinmi Wei, Fenju Zhao, Tong Huang, Boshi Sun, Yanying Desta, Samuel De Clercq, Erik Pannecouque, Christophe Zhan, Peng Liu, Xinyong Acta Pharm Sin B Original Article In this report, a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC(50) ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure–activity relationship and molecular docking were also investigated. Furthermore, 26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection. Elsevier 2020-05 2019-09-14 /pmc/articles/PMC7280082/ /pubmed/32528834 http://dx.doi.org/10.1016/j.apsb.2019.08.013 Text en © 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Kang, Dongwei Feng, Da Ginex, Tiziana Zou, Jinmi Wei, Fenju Zhao, Tong Huang, Boshi Sun, Yanying Desta, Samuel De Clercq, Erik Pannecouque, Christophe Zhan, Peng Liu, Xinyong Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs |
title | Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs |
title_full | Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs |
title_fullStr | Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs |
title_full_unstemmed | Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs |
title_short | Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs |
title_sort | exploring the hydrophobic channel of nnibp leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent hiv-1 nnrtis |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280082/ https://www.ncbi.nlm.nih.gov/pubmed/32528834 http://dx.doi.org/10.1016/j.apsb.2019.08.013 |
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