Discovery of 2,4,6-trisubstituted Pyrimidine Derivatives as Novel Potent HIV-1 NNRTIs by Exploiting the Tolerant Region II of the NNIBP DOI

Zhenzhen Zhou,

Yanying Sun,

Yanyang Qin

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 277, P. 116708 - 116708

Published: July 27, 2024

Language: Английский

Structure-based discovery of novel diarylpyrimidines as potent and selective Non-Nucleoside reverse transcriptase inhibitors: From CH(CN)-Biphenyl-Diarylpyrimidines to C NNH2-Biphenyl-Diarylpyrimidines DOI
Xiaomei Chen, Christophe Pannecouque, Erik De Clercq

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 285, P. 117271 - 117271

Published: Jan. 12, 2025

Language: Английский

Citations

1
Expanding the Solvent/Protein Region Occupation of the Non-Nucleoside Reverse Transcriptase Inhibitor Binding Pocket for Improved Broad-Spectrum Anti-HIV-1 Efficacy: from Rigid Phenyl-Diarylpyrimidines to Flexible Hydrophilic Piperidine-Diarylpyrimidines DOI
Wenjuan Huang, Christophe Pannecouque, Erik De Clercq

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 19889 - 19904

Published: Nov. 5, 2024

Considering the nonideal antiresistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor

Language: Английский

Citations

3
Recent developments of pyrimidine appended HIV-1 non-nucleoside reverse transcriptase inhibitors DOI

S. Maheen Abdul Rahman,

Gurpreet Singh, Md. Sakirul Islam Khan

et al.

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 157, P. 108273 - 108273

Published: Feb. 17, 2025

Language: Английский

Citations

0
Structure-based Design of Novel 2,4,5-Trisubstituted Pyrimidine Derivatives as Potent HIV-1 NNRTIs by Exploiting the Tolerant Regions in NNTRIs Binding Pocket DOI

Zhenzhen Zhou,

Minghui Xie,

Zongji Zhuo

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117464 - 117464

Published: Feb. 27, 2025

Language: Английский

Citations

0
Deuteration Strategy-Inspired Design of Novel Diarylpyrimidine Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors Featuring Improved Efficacy, Selectivity, and Druggability DOI
Kun Zhang, Tieling Xing, Li Ding

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 5, 2025

Deuteration strategy holds significant importance in the field of drug development. In this study, deuteration was applied to incorporate deuterated methyl groups at metabolic sites where were originally present, with expectation improving anti-HIV activity, safety, and druggability. Among compounds, exemplary compound 5a (ZK-316) exhibited potent broad-spectrum activity against wild-type clinically observed mutant strains, EC50 values ranging from 0.99 75.1 nM, surpassing that hit 3 (EC50 = 1.86-795.76 nM). Moreover, low cytotoxicity by ZK-316 (CC50 > 225 nM), which over 36.8 times lower than 3, high selectivity also shown. Not only there no apparent inhibition cytochrome P450 (CYP) enzymes, but human ether-à-go-go-related gene (hERG) toxicity found. And favorable pharmacokinetic profiles shown as well, a bioavailability 29%, all indicated its promising Additionally, identification metabolites carried out verify stability within liver microsomes. These results offer valuable insights into development non-nucleoside reverse transcriptase inhibitors (NNRTIs) for immunodeficiency virus (HIV) therapy.

Language: Английский

Citations

0
Discovery of 2,4,6-trisubstituted Pyrimidine Derivatives as Novel Potent HIV-1 NNRTIs by Exploiting the Tolerant Region II of the NNIBP DOI

Zhenzhen Zhou,

Yanying Sun,

Yanyang Qin

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 277, P. 116708 - 116708

Published: July 27, 2024

Language: Английский

Citations

2