New benzylpyrimidines: inhibition of DHFR from various species. QSAR, CoMFA and PC analysis

Summary To further analyze the structural requirements responsible for the enhanced activity of the newly developed, highly active benzylpyrimidine K-130, a series of trimethoprim analogues with various 4-anilinoalkoxy moieties has been synthesized and tested against dihydrofolate reductase (DHFR) derived from various species (Mycobacterium lufu, Escherichia coli, Candida albicans and rats). The importance of the secondary amino group for binding affinity could be shown by varying the substituent in the para position to the sec-amino moiety. This finding could be supported by multiple linear regression and comparative molecular field analysis (CoMFA). The polarized SO2 group, which was thought to be responsible for the increased activity of K-130, seems not to be the only group important for receptor binding. Additionally, a high selectivity of the new compounds for DHFR derived from the various bacteria and C albicans compared with DHFR derived from rat liver is shown by PC analysis.