(+)-Usnic acid is a suitable scaffold to anti-infective leads

Natural products often prove to be poor pharmaceuticals, due to limited stability, poor solubility or bioavailability and sometimes pose serious challenges to development due to intrinsic toxicity.1 Indeed, they represent the active principles in plants used as traditional remedies and, in some cases, they have been found active on so many biological targets to induce to enlarge the investigation of their mechanisms of action. (+)-Usnic acid is a benzofurandione, phloroglucinol like, secondary metabolite from lichens, occurring in Nature up to 26% in species growing in China.2,3 The most reactive portion of the molecule is the triketone moiety of poliketide origin, which is also responsible for activity. But its high lipophilicity due to the strong intramolecular hydrogen bondings, probably also increases its toxicity, rendering the molecule permeable to membranes. Thus (+)-usnic acid is a good candidate to investigate factors involved in its biological behavior: it is easily affordable, it has recognized and proved in vitro activities, but it has limits in exploitation due to in vivo toxicity.4 We have synthesized and tested many derivatives obtained by nucleophilic attack of a number of amines and amino derivatives at the triketone portion. Depending on the type of substituent, new potent antibacterial, antimycobacterial and antiprotozoal hits have been identified, most of them showing a better pharmacological profile than the parent compound. We speculate that decreases in lipophilicity in addition to potent chelating factors are involved in the maintenance (sometimes increasing) of the activity.