Edward J. Modest

DISCUSSION PAPER: SYNTHESIS AND BIOLOGICAL ACTIVITY OF TRICYCLIC ANTIFOLATE COMPOUNDS WITH FIXED GEOMETRY*

The outstanding antifolate properties and clinical interest of pyrimethamine and related 2,4-diamino-5-aryl-6-alkylpyrimidine derivatives prompted us several years ago to initiate a broad synthetic program whose dual aim was to enlarge our understanding of the relationship between molecular geometry and biological activity in these compounds, and at the same time to generate new structural analogues possessing a more favorable chemotherapeutic index or a qualitatively altered spectrum of activity. In this paper, we should like to summarize the underlying rationale of this program, to review its chemical progress, and to report preliminary bioassay data for selected members of each new class of compounds. More detailed accounts of some of the work will appear elsewhere at a later date.