Citation: Li-Min Zhao, Christophe Pannecouque, Erik De Clercq, Shuai Wang, Fen-Er Chen. Structure-directed expansion of biphenyl-pyridone derivatives as potent non-nucleoside reverse transcriptase inhibitors with significantly improved potency and safety[J]. Chinese Chemical Letters, ;2023, 34(12): 108261. doi: 10.1016/j.cclet.2023.108261 shu

Structure-directed expansion of biphenyl-pyridone derivatives as potent non-nucleoside reverse transcriptase inhibitors with significantly improved potency and safety

Li-Min Zhao ^{a, b, c} ,
Christophe Pannecouque ^d ,
Erik De Clercq ^d ,
Shuai Wang ^{a, b, *,} ,
Fen-Er Chen ^{a, b, c, *,}

a.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China
b.
Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China
c.
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanbian University, Yanji 133002, China
d.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, Leuven B-3000, Belgium

^☆

rfchen@fudan.edu.cn

shuaiwang@fudan.edu.cn

Received Date: 10 January 2023
Revised Date: 16 February 2023
Accepted Date: 21 February 2023
Available Online: 1 March 2023

Figures(4)

Following our previous work on human immunodeficiency virus-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel biphenyl-pyridone derivatives were synthesized and evaluated for their anti-HIV-1 activity to expand their structure–activity relationship. Some of them exhibited low nanomolar activity toward wild-type HIV-1 and clinically relevant single/double mutant strains. The most active compound B1 was 231-fold more potent (EC₅₀ = 17 nmol/L) than the lead compound 2 (EC₅₀ = 3.93 µmol/L) against wild-type (WT) HIV-1. This compound was approximately 3.5-fold less cytotoxic (CC₅₀ = 100.58 µmol/L) than compound 2 (CC₅₀ = 28.24 µmol/L), presenting a higher selectivity index (SI) value of 5923. Compared with 2, the antiviral potency of B1 was significantly increased against five single mutant strains (L100I, K103N, E138K, Y181C and Y188L) and two double mutant strains (F227L+V106A and K103N+Y181C). Especially, K103N, Y181C and K103N+Y181C were more sensitive to B1 than both 2 and doravirine. Besides, the enzymatic inhibitory activity of B1 against wild-type HIV-1 reverse transcriptase was approximately 32-fold higher (IC₅₀ = 100 nmol/L) than 2 (IC₅₀ = 3.21 µmol/L). Molecular docking studies and dynamic simulations were conducted to explain their potent activity. Taken together, this research represents an important step toward the discovery of novel biphenyl-pyridone drug candidates for HIV therapy.
- HIV-1,
- NNRTI,
- Doravirine,
- Biphenyl-pyridone,
- Safety
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