Chemical space exploration around indolylarylsulfone scaffold led to a novel class of highly active HIV-1 NNRTIs with spiro structural features

Eur J Med Chem. 2022 Aug 5:238:114471. doi: 10.1016/j.ejmech.2022.114471.

Shenghua Gao ¹, Yusen Cheng ¹, Shu Song ¹, Letian Song ¹, Fabao Zhao ¹, Shujing Xu ¹, Dongwei Kang ², Lin Sun ¹, Ping Gao ¹, Erik De Clercq ³, Christophe Pannecouque ⁴, Xinyong Liu ⁵, Peng Zhan ⁶

Affiliations

1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.
2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Ji'nan, 250012, China.
3 Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium.
4 Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium. Electronic address: christophe.pannecouque@kuleuven.be.
5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Ji'nan, 250012, China. Electronic address: xinyongl@sdu.edu.cn.
6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Ji'nan, 250012, China. Electronic address: zhanpeng1982@sdu.edu.cn.

PMID: 35640327 DOI: 10.1016/j.ejmech.2022.114471

Abstract

To thoroughly investigate the uncharted chemical space around the entrance channel of HIV-1 Reverse Transcriptase (RT) and to improve the physicochemical properties, we introduced different spiro ring structures with high Fsp³ values as linkers at indole-2-carboxamide, attaching to various terminal substituents to enhance the interactions with the entrance channel. All the newly designed and synthesized indolylarylsulfone (IAS) derivatives exhibited moderate to excellent potency against wild-type HIV-1 with EC₅₀ values ranging from 0.0053 to 0.19 μM. Among them, compounds SO-7g (EC₅₀ = 0.0053 μM) and SO-7h (EC₅₀ = 0.009 μM, SI > 21552) were identified as the most two potent compounds, which displayed 30- and 16-fold improvement than nevirapine and zidovudine and comparable potency to efavirenz and etravirine. Moreover, SO-7g maintained the promising activity against a variety of mutant strains, especially for L100I (EC₅₀ = 0.047 μM), K103 N (EC₅₀ = 0.056 μM), and E138K (EC₅₀ = 0.040 μM). Notably, the introduction of spiro rings could effectively reduce the cytotoxicity (CC₅₀) and greatly improve the selectivity index compared to lead compound, exemplified by SO-7h (CC₅₀ > 214.4 μM, SI > 21552) and SO-7a (CC₅₀ > 233.2 μM, SI > 20933). Additionally, the preliminary SARs based on Antiviral activity and molecular simulation perspective were analyzed with a detailed description, which could point out the direction for further structural optimization.

Keywords

Drug design; Fsp(3); HIV-1; Indolylarylsulfone; NNRTIs; Spiro ring.

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