Synthesis and classical pathway Complement inhibitory activity of C7-functionalized filifolinol derivatives, inspired in K-76 COOH

A series of carboxylic acids carrying various functionalization on C-7 of their common 3H-spiro[benzofuran-2,1′-cyclohexane] skeleton were synthesized from filifolinol, as analogs of the natural Complement inhibitor K-76 COOH. In order to probe the relevance of the C-7 functionalization on their bioactivity, the ability of the analogs to inhibit Complement activation through the classical pathway was determined. The observed results suggest that functionalization of C-7 can modulate the inhibitory activity of the tested compounds. The 7-trifluoromethyl derivative was the compound with the lowest IC50 value among the tested analogs (IC50 = 100 μM), being more potent than K-76 COOH (IC50 = 570 μM).

Graphical abstractThe synthesis and classical Complement pathway inhibition activity of new filifolinol derivatives carrying C-7 substituents, as analogs of K-76 COOH, are reported. The IC50 of the 7-trifluoromethyl derivatives 23 (IC50 = 100 μM) is lower than that of K-76 COOH (IC50 = 570 μM), being the most potent of the series.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► New filifolinol derivatives inspired in natural Complement inhibitor K-76 are bioactive. ► Functionalization of C-7 of filifolinol modulates bioactivity in the classical Complement pathway inhibition assay. ► Compound 23 (R7 = CF3) resulted the most potent analog 23 (IC50 = 100 μM; IC50 of K-76 COOH = 570 μM).