title: Discovery of 2-oxopiperazine dengue inhibitors by scaffold morphing of a phenotypic high-throughput screening hit.
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.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore. Electronic address: cyrille-1.kounde@novartis.com.
authors.forename: Cyrille S
authors.initials: CS
authors.lastname: Kounde
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
authors.forename: Hui-Quan
authors.initials: HQ
authors.lastname: Yeo
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
authors.forename: Qing-Yin
authors.initials: QY
authors.lastname: Wang
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
authors.forename: Kah Fei
authors.initials: KF
authors.lastname: Wan
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
authors.forename: Hongping
authors.initials: H
authors.lastname: Dong
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
authors.forename: Ratna
authors.initials: R
authors.lastname: Karuna
authors.affiliation: Novartis Institutes for BioMedical Research, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Ina
authors.initials: I
authors.lastname: Dix
authors.affiliation: Novartis Institutes for BioMedical Research, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
authors.forename: Bin
authors.initials: B
authors.lastname: Zou
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
authors.forename: Oliver
authors.initials: O
authors.lastname: Simon
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
authors.forename: Ghislain M C
authors.initials: GMC
authors.lastname: Bonamy
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
authors.forename: Bryan K S
authors.initials: BKS
authors.lastname: Yeung
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore. Electronic address: fumiaki.yokokawa@novartis.com.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yokokawa
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003716:Dengue Virus / Q000187:drug effects*; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D010879:Piperazines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D010879:Piperazines
keywords: 2-Oxopiperazine; Cell-based screen; Dengue virus; NS4B; Scaffold morphing