Design, synthesis and evaluation of 2,2-dimethyl-1,3-dioxolane derivatives as human rhinovirus 3C protease inhibitors

Qiyan Zhang; Ruiyuan Cao; An Liu; Shihai Lei; Yuexiang Li; Jingjing Yang; Song Li; Junhai Xiao

doi:10.1016/j.bmcl.2017.07.049

Design, synthesis and evaluation of 2,2-dimethyl-1,3-dioxolane derivatives as human rhinovirus 3C protease inhibitors

Bioorg Med Chem Lett. 2017 Sep 1;27(17):4061-4065. doi: 10.1016/j.bmcl.2017.07.049. Epub 2017 Jul 25.

Authors

Qiyan Zhang¹, Ruiyuan Cao², An Liu³, Shihai Lei⁴, Yuexiang Li⁵, Jingjing Yang⁶, Song Li⁷, Junhai Xiao⁸

Affiliations

¹ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China; Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].
² Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].
³ Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].
⁴ Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].
⁵ Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].
⁶ Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].
⁷ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China; Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].
⁸ Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].

PMID: 28778471
DOI: 10.1016/j.bmcl.2017.07.049

Abstract

The human rhinovirus (HRV) is the most significant cause of the common cold all over the world. The maturation and replication of this virus entirely depend on the activity of a virus-encoded 3C protease. Due to the high conservation among different serotypes and the minimal homology existing between 3C protease and known mammalian enzymes, 3C protease has been regarded as an attractive target for the treatment of HRV infections. In this study, we identified a novel (4R,5R)-N⁴-(2-((3-methoxyphenyl)amino)ethyl)-2,2-dimethyl-N⁵-(naphthalen-2-yl)-1,3-dioxolane-4,5-dicarboxamide (7a) to be a HRV 3C protease inhibitor via virtual screening. Further research has been focused on the design, synthesis and in vitro biological evaluation of 7a derivatives. The studies revealed that compound 7d has an IC₅₀ value of 2.50±0.7µM against HRV 3C protease, and it thus could serve as a promising compound for the development of novel anti-rhinoviral medicines.

Keywords: 2,2-Dimethyl-1, 3-dioxolane derivatives; 3C protease inhibitors; HRV; Virtual screening.

MeSH terms

3C Viral Proteases
Cysteine Endopeptidases / metabolism
Dioxolanes / chemical synthesis
Dioxolanes / chemistry
Dioxolanes / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Structure
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Rhinovirus / enzymology*
Structure-Activity Relationship
Viral Proteins / antagonists & inhibitors*
Viral Proteins / metabolism

Substances

Dioxolanes
Protease Inhibitors
Viral Proteins
Cysteine Endopeptidases
3C Viral Proteases
formal glycol