Structure-based design of diarylpyrimidines and triarylpyrimidines as potent HIV-1 NNRTIs with improved metabolic stability and drug resistance profiles
© 2024 Wiley Periodicals LLC..
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component of anti-acquired immunodeficiency syndrome treatment regimen. In the present work, with the previously reported compound K-16c as lead, a series of novel 2,4,5-trisubstituted pyrimidine derivatives were designed based on the cocrystal structure of K-16c/RT, with the aim to improve the anti-human immunodeficiency virus type-1 (HIV-1) activities and metabolic stability properties. Compound 11b1 exhibited the most potent antiviral activity against wild-type (WT) and a panel of single mutant HIV-1 strains (EC50 = 2.4-12.4 nM), being superior to or comparable to those of the approved drug etravirine. Meanwhile, 11b1 exhibited moderate cytotoxicity (CC50 = 4.96 μM) and high selectivity index (SI = 1189) toward HIV-1 WT strain. As for HIV-1 RT inhibition test, 11b1 possessed excellent inhibitory potency (IC50 = 0.04 μM) and confirmed its target was RT. Moreover, the molecular dynamics simulation was performed to elucidate the improved drug resistance profiles. Moreover, 11b1 was demonstrated with favorable safety profiles and pharmacokinetic properties in vivo, indicating that 11b1 is a potential anti-HIV-1 drug candidate worthy of further development.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:96 |
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| Enthalten in: |
Journal of medical virology - 96(2024), 3 vom: 01. März, Seite e29502 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xie, Minghui [VerfasserIn] |
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| Links: |
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| Themen: |
2,4,5-trisubstituted pyrimidines |
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| Anmerkungen: |
Date Completed 08.03.2024 Date Revised 08.03.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1002/jmv.29502 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369405803 |
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| 520 | |a Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component of anti-acquired immunodeficiency syndrome treatment regimen. In the present work, with the previously reported compound K-16c as lead, a series of novel 2,4,5-trisubstituted pyrimidine derivatives were designed based on the cocrystal structure of K-16c/RT, with the aim to improve the anti-human immunodeficiency virus type-1 (HIV-1) activities and metabolic stability properties. Compound 11b1 exhibited the most potent antiviral activity against wild-type (WT) and a panel of single mutant HIV-1 strains (EC50 = 2.4-12.4 nM), being superior to or comparable to those of the approved drug etravirine. Meanwhile, 11b1 exhibited moderate cytotoxicity (CC50 = 4.96 μM) and high selectivity index (SI = 1189) toward HIV-1 WT strain. As for HIV-1 RT inhibition test, 11b1 possessed excellent inhibitory potency (IC50 = 0.04 μM) and confirmed its target was RT. Moreover, the molecular dynamics simulation was performed to elucidate the improved drug resistance profiles. Moreover, 11b1 was demonstrated with favorable safety profiles and pharmacokinetic properties in vivo, indicating that 11b1 is a potential anti-HIV-1 drug candidate worthy of further development | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 2,4,5-trisubstituted pyrimidines | |
| 650 | 4 | |a HIV-1 | |
| 650 | 4 | |a NNRTIs | |
| 650 | 4 | |a RT | |
| 650 | 4 | |a drug design | |
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| 700 | 1 | |a Wang, Zhao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Fabao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ye |e verfasserin |4 aut | |
| 700 | 1 | |a Zhuo, Zongji |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a De Clercq, Erik |e verfasserin |4 aut | |
| 700 | 1 | |a Pannecouque, Christophe |e verfasserin |4 aut | |
| 700 | 1 | |a Zhan, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xinyong |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Dongwei |e verfasserin |4 aut | |
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