title: Aminopurine and aminoquinazoline scaffolds for development of potential dengue virus inhibitors.
abstract: Previous efforts led to dicarboxamide derivatives like 1.3, comprising either an imidazole, pyrazine or fenyl ring as the central scaffold, with many congeners displaying strong inhibitory effects against dengue virus (DENV) in cell-based assays. Following up on some literature reports, the rationale was borne out to preserve the pending groups, now attached to either a 2,6-diaminopurine or 2,4-diaminoquinazoline scaffold. Synthetic efforts turned out less straightforward than expected, but yielded some new derivatives with low micromolar anti-DENV activity, albeit not devoid of cellular toxicity. The purine 14 proved the most potent compound for this series with an EC50 of 1.9 μM and a selectivity index of 58, while the quinazoline 18a displayed an EC50 of 2.6 μM with SI of only 2.
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Akkaladevi
authors.initials: A
authors.lastname: Venkatesham
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Milind
authors.initials: M
authors.lastname: Saudi
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kaptein
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Mathy
authors.initials: M
authors.lastname: Froeyen
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Arthur.Vanaerschot@rega.kuleuven.be.
authors.forename: Arthur
authors.initials: A
authors.lastname: Van Aerschot
mesh_terms: D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D003716:Dengue Virus / Q000187:drug effects* / Q000201:enzymology; D015195:Drug Design; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; C582223:NS5 protein, dengue virus; D011799:Quinazolines; D017361:Viral Nonstructural Proteins; C013474:2,4-diaminoquinazoline; D015075:2-Aminopurine; C007300:2,6-diaminopurine
keywords: Dengue virus; Diaminopurines; Diaminoquinazolines; Flavivirus inhibitors; NS5 polymerase