Amanda Zattar Calixto1, Ana Cunha1,Laurilyn Rojas de Florez1, Leticia Ramos de Faria Miyahara1, Simon Bernhard Cämmerer1*, Nicole Gregório2,Dima Garaibeh3, Glenn Gomba3, Tara Kenny3, Cary Retterer3, Rouzbeh Zamani3, Veronica Soloveva 3, Sina Bavari3
1Instituto de Química, Universidade Estadual de Campinas (UNICAMP), Rua Josué de Castro 336, 126 – Cidade Universitaria Zeferino Vaz, Barão Geraldo, CEP 13083-861, Campinas, São Paulo, Brasil.
2Faculdade de Ciências Farmacêuticas, Pontifícia Universidade Católica de Campinas (PUCC) – Avenida John Boyd Dunlop, S/N, Jardim Ipaussurama, CEP: 13060-803, Campinas, São Paulo, Brasil.
3U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, 1425 Porter Street, Frederick, Maryland 21702, USA.
A B S T R A C T
In this study, a library of 30 selected N-aryl-7-chloro-4-aminochloroquines was prepared by chemical synthesis from 4,7-dichloroquinoline and substituted anilines. The library was screened for biological activity against Ebola (Makona) virus in a phenotypic assay utilizing HeLa and HFF host cell lines. Most compounds exhibited high biological activity against Ebola (Makona) virus infection. The most potent compound, N-[(4´-benzyloxy)-phenyl]-4-amino-7-chloroquinoline, exhibited high anti-filoviral activity with EC 50 = 1.55 M (HFF cells), resp. EC50 = 3.73 M (HeLa cells), and a selectivity of S.I. = 7.34 (HFF cells) resp. S.I. = 8.19 (HeLa cells). Various compounds showed high activity against Ebola (Makona) virus and moderate toxicity against the host cell system (5 < S.I.-index < 10). Some compounds exhibited higher cytotoxicity against the host cell system (S.I.-Index < 5). Preliminary structure-activity relationships (SAR) revealed that N-aryl-4-amino-7-chloroquinolines with a polar o-, m-, p-substituent (R = OH, OBn) or polar side chain (R=-OCH2CH2OH,-OCH2CH2CH2OH) connected to the N-phenyl-substituent favored higher anti-filoviral activity and lower cytotoxicity, whereas N-aryl-4-chloro-7-chloroquinolines with EWG-substituted N-aryl-substituents (except 2-fluorophenyl) exhibited a higher cytotoxicity and low selectivity towards the filovirus. This finding is of great importance for tropical medicine and biodefense research.
Keywords: N-Aryl-4-aminoquinolines, Antivirals, Filoviruses, Ebola virus, Infection Assay, SAR-Study