New inhibitors of the complement system inspired in K76-COOH. A SAR study of filifolinol derivatives through modifications of the C3′ position

A new series of tricyclic carboxylic acids with a 3H-spiro[benzofuran-2,10-cyclohexane] skeleton were synthesized from filifolinol, as analogs of the natural complement inhibitor K76-COOH. Their complement inhibitory activity was determined aiming to probe the importance of structural characteristics of the alicyclic part of K76-COOH. The presence and stereochemistry of O- and N-functionalities on C3′ of the filifolinol derivatives are relevant for biological activity. The IC50 values of the most potent compounds were comparable or surpassed the activity of K76-COOH. The results also suggest that the diol moiety of the natural product may be useful for improving compound solubility.

Graphical abstractThe synthesis of new analogs of K76-COOH, as complement inhibitors, employing filifolinol as staring material suggest that the nature and stereochemistry of the C3′ substituent may be important for the biological activity.Figure optionsDownload full-size imageDownload as PowerPoint slide