Kokatla, Hari PrasadSil, DipteshMalladi, Subbalakshmi S.Balakrishna, RajalakshmiHermanson, Alec R.Fox, Lauren M.Wang, XinkunDixit, AnshumanDavid, Sunil A.2017-04-062017-04-062013-09-12Kokatla, H. P., Sil, D., Malladi, S. S., Balakrishna, R., Hermanson, A. R., Fox, L. M., … David, S. A. (2013). Exquisite Selectivity For Human Toll-like Receptor 8 in Substituted Furo[2,3-c]quinolines. Journal of Medicinal Chemistry, 56(17), 6871–6885. http://doi.org/10.1021/jm400694dhttps://hdl.handle.net/1808/23592Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We synthesized and evaluated hitherto unexplored furo[2,3-c]quinolines and its regioisomeric furo[3,2-c]quinolines, derived via a tandem, one-pot Sonogashira coupling and intramolecular 5 endo-dig cyclization strategy, in a panel of primary screens. We observed a pure TLR8 agonistic activity profile in select furo[2,3-c]quinolines, with maximal potency conferred by a C2-butyl group (EC50: 1.6 µM); shorter, longer, or substituted homologues, as well as compounds bearing C1 substitutions were inactive, which was rationalized by docking studies using the recently-described crystal structure of human TLR8. The best-in-class compound displayed prominent proinflammatory cytokine induction (including interleukin-12 and interleukin-18), but was bereft of interferon-α inducing properties, confirming its high selectivity for human TLR8.This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm400694d.TLR8TLR8 agonistsVaccine adjuvantsInnate immunityFuroquinolinesSonogashira couplingArticle10.1021/jm400694dhttps://orcid.org/0000-0001-6457-0545 https://orcid.org/0000-0003-1377-0509openAccess