Folate-Synthesizing Enzyme System as Target for Development of Inhibitors and Inhibitor Combinations against Candida albicansSynthesis and Biological Activity of New 2,4-Diaminopyrimidines and 4‘-Substituted 4-Aminodiphenyl Sulfones

The paper describes the design, synthesis, and testing of inhibitors of folate-synthesizing enzymes and of whole cell cultures of Candida albicans. The target enzymes used were dihydropteroic acid synthase (SYN) and dihydrofolate reductase (DHFR). Several series of new 2,4-diaminopyrimidines were synthesized and tested as inhibitors of DHFR and compared with their activity against DHFR derived from mycobacteria and Escherichia coli. To test for selectivity, also rat DHFR was used. A series of substituted 4-aminodiphenyl sulfones was tested for inhibitory activity against SYN and the I50 values compared to those obtained previously against Plasmodium berghei- and E. coli-derived SYN. Surprisingly, QSAR equations show very similar structural dependencies. To find an explanation for the large difference in the I50 values observed for enzyme inhibition (SYN, DHFR) and for inhibition of cell cultures of Candida, mutant strains with overexpressed efflux pumps and strains in which such pumps are deleted were inc...