title: Synthetic strategy and antiviral evaluation of diamide containing heterocycles targeting dengue and yellow fever virus.
abstract: High-throughput screening of a subset of the CD3 chemical library (Centre for Drug Design and Discovery; KU Leuven) provided us with a lead compound 1, displaying low micromolar potency against dengue virus and yellow fever virus. Within a project aimed at discovering new inhibitors of flaviviruses, substitution of its central imidazole ring led to synthesis of variably substituted pyrazine dicarboxylamides and phthalic diamides, which were evaluated in cell-based assays for cytotoxicity and antiviral activity against the dengue virus (DENV) and yellow fever virus (YFV). Fourteen compounds inhibited DENV replication (EC50 ranging between 0.5 and 3.4 μM), with compounds 6b and 6d being the most potent inhibitors (EC50 0.5 μM) with selectivity indices (SI) > 235. Compound 7a likewise exhibited anti-DENV activity with an EC50 of 0.5 μM and an SI of >235. In addition, good antiviral activity of seven compounds in the series was also noted against the YFV with EC50 values ranging between 0.4 and 3.3 μM, with compound 6n being the most potent for this series with an EC50 0.4 μM and a selectivity index of >34. Finally, reversal of one of the central amide bonds as in series 13 proved deleterious to the inhibitory activity.
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Minderbroedersstraat 10, 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, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Joanna
authors.initials: J
authors.lastname: Zmurko
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kaptein
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Bharat
authors.initials: B
authors.lastname: Gadakh
authors.affiliation: CISTIM Leuven vzw, Gaston Geenslaan 2, 3001 Leuven, Belgium; Centre for Drug Design and Discovery (CD3), KU Leuven Research and Development, Waaistraat 6, 3000 Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chaltin
authors.affiliation: CISTIM Leuven vzw, Gaston Geenslaan 2, 3001 Leuven, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Marchand
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: Arthur.Vanaerschot@kuleuven.be.
authors.forename: Arthur
authors.initials: A
authors.lastname: Van Aerschot
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003716:Dengue Virus / Q000187:drug effects*; D003958:Diamide / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects; D015005:Yellow fever virus / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D006571:Heterocyclic Compounds; D003958:Diamide
keywords: Dengue virus; Diamide; Flavivirus inhibitors; Ortho-phtalic acid; Pyrazine dicarboxylic acid