Entwicklung neuer Chemotherapeutika fuer klinisch relevante Problemkeime auf der Basis gesicherter Mechanismen und unter Einbeziehung moderner Methoden der rationalen Wirkstoffentwicklung Schlussbericht

In vitro test systems for testing inhibitors of the folate biosynthesis of C.albicans have been developed successfully. Supported by quantitative structure-activity relationship analysis sulfones and sulfonamides have been optimized as inhibitors of pteroate synthase of C.albicans. New benzylpyrimidines have been designed an synthesized as inhibitors of C.albicans dihydrofolate reductase, wich are 380 times more active than trimethoprim (patent pending). The inhibitory activity against whole cell culture is, however, disappointingly low as the compounds are unable to pass sufficiently the membrane of C.albicans. To overcome the multidrug resistance of mycobacteria new potential inhibitors of ribonucleosidediphosphate reductase have been designed and synthesized as partners in combination with rifampicin. The new heterocyclic hydrazones are inhibitors of mycobacteria and show strong synergism when combined with rifampicin. The new compounds cannot yet be used clinically. Therefore rifampicin was combined with thiacetazone which shows also strong synergism. The clinical results are very promising. Patents were received for the new combinations. (orig.)Available from TIB Hannover: F95B687+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman