Short communication Bicyclic octahydrocyclohepta[b]pyrrol-4(1H)one derivatives as novel selective anti-hepatitis C virus agents Neerja Kaushik-Basu a, **, 2 , Nina K. Ratmanova b, 1 , Dinesh Manvar a, 1 , Dmitry S. Belov b, c , Ozge Cevik a , Amartya Basu a , Mark M. Yerukhimovich d , Evgeny R. Lukyanenko b, c , Ivan A. Andreev b, c , Grigory M. Belov b, c , Giuseppe Manfroni e , Violetta Cecchetti e , David N. Frick d , Alexander V. Kurkin b, *** , Andrea Altieri c, **** , Maria Letizia Barreca e, * a Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, NJ 07103, USA b Chemistry Department of Lomonosov Moscow State University, Moscow 119991, GSP-2, Leninskie gory,1/3, Russia c EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo, CH, Italy d Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer St., Milwaukee, WI 53211, USA e Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy article info Article history: Received 4 March 2016 Received in revised form 1 June 2016 Accepted 21 June 2016 Available online 23 June 2016 Keywords: Hepatitis C virus Anti-HCV agents Octahydrocyclohepta[b]pyrrol-4(1H)one derivatives HCV inhibitors Aza-CopeeMannich reaction abstract We report the discovery of the bicyclic octahydrocyclohepta[b]pyrrol-4(1H)-one scaffold as a new che- motype with anti-HCV activity on genotype 1b and 2a subgenomic replicons. The most potent compound 34 displayed EC 50 values of 1.8 mM and 4.5 mM in genotype 1b and 2a, respectively, coupled with the absence of any antimetabolic effect (gt 1b SI ¼ 112.4; gt 2a SI ¼ 44.2) in a cell-based assay. Compound 34 did not target HCV NS5B, IRES, NS3 helicase, or selected host factors, and thus future work will involve the unique mechanism of action of these new antiviral compounds. © 2016 Published by Elsevier Masson SAS. 1. Introduction The hepatitis C virus (HCV) was discovered in 1989 as the etiological agent causing non-A non-B hepatitis [1,2]. HCV is now understood to be a diverse genus of positive sense single-stranded RNA viruses, which is part of the Flaviviridae family. There are presently eleven known HCV genotypes (gt1-gt11) whose RNA se- quences differ by up to 30e50% [3]. Within the HCV genotypes, there are also several subtypes (designated as 1a, 1b, 1c, etc.) [4]. HCV infection typically causes few symptoms, but about 85% of patients develop chronic infection, which leads to progressive liver damage, fibrosis, cirrhosis, hepatocellular carcinoma, and ulti- mately liver failure. Presently, 130e170 million people are chroni- cally infected with HCV [5], about 35,000 of whom die each year [6]. Fortunately, unlike other chronic viral diseases like AIDS, antiviral therapy can eliminate detectable HCV in patients. Such a sustained virologic response (SVR) also prevents cirrhosis, hepatocellular carcinoma and related HCV-induced mortality. Early HCV therapies relied on agents that modulate the host antiviral response like interferon-alpha (IFN-a) and ribavirin (RBV) [7]. INF-a/RBV therapy results in an overall 50%e75% SVR (depending on HCV genotype and numerous other factors), but the therapy is poorly tolerated. INF-a-based therapy has therefore been * Corresponding author. ** Corresponding author. *** Corresponding author. **** Corresponding author. E-mail addresses: neerja.kaushik-basu@nih.gov (N. Kaushik-Basu), kurkin@ direction.chem.msu.ru (A.V. Kurkin), aaltieri@edasascientific.com (A. Altieri), maria.barreca@unipg.it (M.L. Barreca). 1 Equal contribution. 2 Disclaimer: This work was prepared while Dr. Neerja Kaushik-Basu was employed at New Jersey Medical School, Rutgers University. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2016.06.041 0223-5234/© 2016 Published by Elsevier Masson SAS. European Journal of Medicinal Chemistry 122 (2016) 319e325