ISSN 2286-6493
Journal of Asian Association of Schools of Pharmacy

Isoindole-1,3-dione-based α,γ-diketo acid bioisosteres as hepatitis C virus NS5B polymerase inhibitors  Research Paper 

Ravindra Ramesh Deore1, Ajit Dhananjay Jagtap1, Pei-Teh Chang1, WirunyaTrimethasil3 and Ji-Wang Chern1,2
1 School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 1, Section 1, Ren-Ai Road, Taipei 10051, Taiwan.
2 Department of Life Science, College of Life Science, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan, and 3Faculty of Pharmaceutical Science, Khon Kaen University, Khon Kaen, 40002, Thailand.


    Integration of 2-N-hydroxyl- and 2-N-benzoyl-1,3diketo acid moieties into isoindole-1,3-dione led to the development of two series of hepatitis C virus NS5B polymerase inhibitors. Structural optimization to translate enzyme inhibitory activity to cellular cytotoxicity yielded compound 16c, a moderate enzyme inhibitor (IC50 = 27.3 µM) with selective toxicity to hepatitis C virus 1b replicon-containing Ava5 cells (EC50 = 18.0 µM). Binding experiments indicated that 16c (Kd = 1.25 µM) not only competed with fluorescein-labeled GTP for NS5B binding, but also displaced bound GTP from the polymerase active site.  


1 Hepatitis C virus
2 NS5B polymerase
3 &alpha
4 ,&gamma
5 -diketo acid
6 bioisostere
7 isoindole-1,3-dione

Published in

JAASP Volume 1 No. 4
October - December, 2012

Page: 210-225

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