Natural Products as Leads for Pharmaceutically Active Compounds

Abstract: In the search for new pharmaceutically active compounds, it is recognized that Nature produces structurally different compounds in a great variety. By having the compounds or extracts tested in defined systems, new drugs or more often leads (a compound that has an interesting but moderate activity) can be found. When a lead is found, structurally similar compounds with modified functional groups are synthesized to find the structure-activity relationships (SAR:s). The secondary metabolite pterulone, isolated from the basidomycete Pterula species 82168 shows an selective and interesting antifungal activity, inhibiting Complex I in the respiration chain. Methods to synthesize pterulone has been developed and a number of analogues have been synthesized and tested on four different fungi, Mucor meihei, Paecilomyces variotii, Penicillium notatum, and Nematospora coryli. The structure-activity relationships were studied but no more efficient compounds than the natural product pterulone was obtained. Flavones belong to a substance class flavonoids present in virtually all plants. 6-Methylflavone shows a quite high affinity for the benzodiazepine site of the GABAA receptor with a K1 value of 125 nM. A number of flavones have been synthesized and the final product, 5'-bromo-2'-hydoxy-6-methylflavone has 250 times higher affinity for the binding site compared to 6-methylflavone. An existing pharmacophore model has been refined and used in the design of new flavones. The flavones were tested in vitro on rat cortical membranes and the pharmacophore model was confirmed and further refined by the structure-activity relationships observed. The pharmacophore model was also built in the database search program Catalyst™, to find new structural classes of substances, i.e scaffold hopping, that fits the model and may bind to the receptor. Databases from Maybridge, NCI and ACD were used for this purpose and a number of hits were obtained.