Tylophorine compounds, phenanthroindolizidines and phenanthroquinolizidines, posses multiple potent biological activities including anti-cancer, anti-inflammation, and anti-coronaviruses. In order to explore more classes of tylophorine derivatives for more drug-like compounds, herein we investigate the role of tylophorine E ring in the biological activities through synthesis of a series of compounds with the modification at the E ring either by increasing the C-number or un-cyclizing the E ring and forming different N-substitutes. We have obtained potent derivatives possessing anti-coronavirus activity in terms of anti-TGEV and anti-MHV replication. In addition, the most potent dibenzoquinoline showed improved solubility, in vivo efficacy, and bioavailability as an orally active agent as well as did not showed significant neurotoxicity. The relations of structure and activity of these N-substitutes were analyzed.
