Design, synthesis and evaluation of C/D-ring analogs of the fungal metabolite K-76 as potential complement inhibitors

A series of the C/D-ring analogs of the natural product complement inhibitor K-76 (9–14) and some of their bioisosteres (19–20) have been synthesized and evaluated for the inhibition of classical pathway activation of human complement and their intrinsic lytic activity. The in vitro assay results of the inhibition of complement-mediated hemolysis of these analogs indicate that the bioisosteric tetrazole ring significantly improves the human complement inhibitory potency. Additionally, most of this series of analogs do not exhibit lytic activity.