Problems in the Designing of Antimetabolites †

Historically, the most useful medicinal agents have been obtained by empirical screening or by the chemical modification of compounds of known activity in the hope of making them more effective. To these approaches a new one was added in recent years-antimetabolites. An antimetabolite may be defined as a compound bearing structural resemblance to a metabolite and capable of being attached to the enzyme for which the metabolite serves as the normal substrate. The enzyme-antimetabolite complex, however, is incapable of undergoing the reactions of the enzyme-metabolite complex and, by interfering with the modification of the metabolite, a specific biochemical lesion is created. The best example of truly effective antimetabolites is the sulfonamides, still among our most useful antibacterial agents. Sulfonamides are anti-metabolites of p-aminobenzoic acid, which in turn is used by susceptible bacteria for the synthesis of coenzymes structurally related to pteroyl-glutamic (folic) acid.' The animal host cannot synthesize its own folic acid; most bacteria, on the other hand, cannot utilize preformed folic acid. Here, a clean-cut, qualitative metabolic difference between invading cells and the cells of the host has been exploited with considerable success. After the discovery of the mode of action of the sulfa drugs which, incidentally, were found through screening synthetic dyes, rather than by the application of the principles discussed above, it seemed likely that the exploitation of biochemical differences between host and invading cells (whether bacteria, viruses, or neoplasms) would lead to the synthesis of a large number of potent drugs. This approach, the design of antimetabolites, did lead to the synthesis of large numbers of organic compounds. However, while thousands of potential antimetabolites have been synthesized, the number of useful drugs among them has been disappointingly small. Certainly the most important medicinal agents to be introduced during the last twenty years, the antibiotics,