Discovery of 2-oxopiperazine dengue inhibitors by scaffold morphing of a phenotypic high-throughput screening hit

Cyrille S Kounde; Hui-Quan Yeo; Qing-Yin Wang; Kah Fei Wan; Hongping Dong; Ratna Karuna; Ina Dix; Trixie Wagner; Bin Zou; Oliver Simon; Ghislain M C Bonamy; Bryan K S Yeung; Fumiaki Yokokawa

doi:10.1016/j.bmcl.2017.02.005

Discovery of 2-oxopiperazine dengue inhibitors by scaffold morphing of a phenotypic high-throughput screening hit

Bioorg Med Chem Lett. 2017 Mar 15;27(6):1385-1389. doi: 10.1016/j.bmcl.2017.02.005. Epub 2017 Feb 4.

Authors

Affiliations

¹ Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore. Electronic address: [email protected].
² Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
³ Novartis Institutes for BioMedical Research, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
⁴ Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore. Electronic address: [email protected].

PMID: 28216045
DOI: 10.1016/j.bmcl.2017.02.005

Abstract

A series of 2-oxopiperazine derivatives were designed from the pyrrolopiperazinone cell-based screening hit 4 as a dengue virus inhibitor. Systematic investigation of the structure-activity relationship (SAR) around the piperazinone ring led to the identification of compound (S)-29, which exhibited potent anti-dengue activity in the cell-based assay across all four dengue serotypes with EC₅₀<0.1μM. Cross-resistant analysis confirmed that the virus NS4B protein remained the target of the new oxopiperazine analogs obtained via scaffold morphing from the HTS hit 4.

Keywords: 2-Oxopiperazine; Cell-based screen; Dengue virus; NS4B; Scaffold morphing.

MeSH terms

Antiviral Agents / pharmacology*
Cell Line
Dengue Virus / drug effects*
Drug Discovery
High-Throughput Screening Assays
Humans
Piperazines / pharmacology*
Structure-Activity Relationship

Substances

Antiviral Agents
Piperazines