Citation: Han Sheng, Lei Yuan, Pannecouque Christophe, De Clercq Erik, Zhuang Chunlin, Chen Fener. Fragment-based discovery of sulfur-containing diarylbenzopyrimidines as novel nonnucleoside reverse transcriptase inhibitors[J]. Chinese Chemical Letters, ;2020, 31(3): 764-768. doi: 10.1016/j.cclet.2019.11.020 shu

Fragment-based discovery of sulfur-containing diarylbenzopyrimidines as novel nonnucleoside reverse transcriptase inhibitors

Han Sheng ^a,b,1 ,
Lei Yuan ^c,1 ,
Pannecouque Christophe ^e ,
De Clercq Erik ^e ,
Zhuang Chunlin ^a,b,*, ,
Chen Fener ^a,b,c,d,*,

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.
Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
d.
Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China
e.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium

zclnathan@163.com

rfchen@fudan.edu.cn

Received Date: 9 October 2019
Revised Date: 11 November 2019
Accepted Date: 12 November 2019
Available Online: 13 November 2019

Figures(4)

Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further oxidation. The best compound 6e with a sulfonyl scaffold displayed EC₅₀ values of 0.0356 μmol/L against WT and 0.0228 μmol/L against HIV K103N mutant strain. More pronounced, it had a lower cytotoxicity (CC₅₀=99.6 μmol/L), higher selectivity index (SI_WT=2799, SI_K103N=4375) and better calculated logarithm of the octanol-water partition coefficient (cLogP) than the lead compound 3. Molecular docking and dynamics provided the binding modes of these compounds with reverse transcriptase, explaining their activity. Collectively, the new compounds could be candidates for anti-HIV drug discovery.
- HIV-1,
- NNRTIs,
- DAPY,
- Sulfur-containing DABPs,
- FBDD
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