Citation: Da Feng, Fenju Wei, Yanying Sun, Prem Prakash Sharma, Tao Zhang, Hao Lin, Brijesh Rathi, Erik De Clercq, Christophe Pannecouque, Dongwei Kang, Peng Zhan, Xinyong Liu. Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1 NNRTIs: Design, synthesis and biological evaluation[J]. Chinese Chemical Letters, ;2021, 32(12): 4053-4057. doi: 10.1016/j.cclet.2021.02.033 shu

Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1 NNRTIs: Design, synthesis and biological evaluation

Da Feng ^a ,
Fenju Wei ^a ,
Yanying Sun ^a ,
Prem Prakash Sharma ^b ,
Tao Zhang ^a ,
Hao Lin ^a ,
Brijesh Rathi ^b ,
Erik De Clercq ^c ,
Christophe Pannecouque ^c ,
Dongwei Kang ^{a, e, *,} ,
Peng Zhan ^{a, d, *,} ,
Xinyong Liu ^{a, d, *,}

a.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China
b.
Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi 110007, India
c.
Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Leuven B-3000, Belgium
d.
China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Ji'nan 250012, China
e.
Suzhou Research Institute, Shandong University, Suzhou 215123, China

kangdongwei@126.com

zhanpeng1982@sdu.edu.cn

xinyongl@sdu.edu.cn

Received Date: 29 January 2021
Revised Date: 5 February 2021
Accepted Date: 17 February 2021
Available Online: 19 February 2021

Figures(5)

Drug resistance remains to be a serious problem with type I human immunodeficiency virus (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs). A series of novel boronic acid-containing diarylpyrimidine (DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies, taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells. Compound 10j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 IIIB [wild-type (WT) strain], L100I and K103N strains, with 50% effective concentration (EC₅₀) values of 7.19–9.85 nmol/L. Moreover, 10j inhibited the double-mutant strain RES056 with an EC₅₀ value of 77.9 nmol/L, which was 3.3-more potent than that of EFV (EC₅₀ = 260 nmol/L) and comparable to that of ETR (EC₅₀ = 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase (RT) with 50% inhibition concentration (IC₅₀) value of 0.1837 μmol/L. Furthermore, molecular dynamics simulation indicated that 10j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10j could serve as a lead molecule for further modification to address virus-drug resistance.
- HIV-1,
- NNRTIs,
- NNIBP,
- DAPY,
- Boronic acid,
- Molecular dynamics simulation
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沈阳化工大学材料科学与工程学院沈阳 110142