Tuberculosis Plasmodium falciparum

Enzymes that are addressed by major drugs have been studied in particular detail. Thus, well above one hundred stmctures have been reported for dihydrofolate reductases from a variety of organisms, including major pathogens such as Mycobacterium tuberculosis, which is the causative agent of tuberculosis, and of Plasmodium falciparum, which is the most important of the Plasmodium spp. that causes malaria. The interaction of mammalian dihydrofolate reductases with inhibitors that are used as cytostatic agents and/or immunosuppressants is also documented extensively by X-ray stmctures. 

Phomoxanthones A and B (1080 and 1081, Fig. 13.34) were isolated from the endophytic fungus, Phomopsis sp., when an extract from this species was found to exhibit in vitro antimalarial activity (688). Phomoxanthone A is a symmetrical homodimer with a 4,4 - (para-para)-]mkage, while phomoxanthmie B has a 2,4 -(ortho-para)-lmkage, as seen with the eumitrins. These structures are similar to those of the ergochromes, however, the carboxymethyl substituents at C-lOa (C-lOa ) have been replaced with acetoxymethyl substituents, and the C-6 (C-6a) hydroxy group moieties are acetylated. The relative configuration of both phomoxanthones A and B was determined by NMR experiments. The compounds proved to be inhibitory in vitro for Plasmodium falciparum, Mycobacterium tuberculosis, and several cancer cell lines (Fig. 13.35). 

Tasdemir, D., Topaloglu, B., Perozzo, R., Brun, R., O Neill, R., Carballeira, N.M., Zhang, X., Tonge, P.J., Linden, A., and Rtiedi, P. (2007) Marine natural products from the Turkish sponge Agdas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis, and Escherichia coli. Bioorg. Med. Chem., 15, 6834-6845. 

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