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 inh ibitor K-76 (9-14) and some of their bioisosteres (19,20) have been sy nthesized and evaluated for the inhibition of classical pathway activa tion of human complement and their intrinsic lytic activity. The in vi tro assay results of the inhibition of complement-mediated hemolysis o f these analogs indicate that the bioisosteric tetrazole ring signific antly improves the human complement inhibitory potency. Additionally, most of this series of analogs do not exhibit lytic activity.