Title: Synthetic strategy and antiviral evaluation of diamide containing heterocycles targeting dengue and yellow fever virus
Authors: Saudi, Milind
Zmurko, Joanna
Kaptein, Suzanne
Rozenski, Jef
Gadakh, Bharat
Chaltin, Patrick
Marchand, Arnaud
Neyts, Johan
Van Aerschot, Arthur # ×
Issue Date: Oct-2016
Series Title: European Journal of Medicinal Chemistry vol:121 pages:158-168
Article number: S0223-5234(16)30441-X
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.
ISSN: 0223-5234
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
Medicinal Chemistry (Rega Institute)
Intellectual Property
× corresponding author
# (joint) last author

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