Relationship of structure to fungitoxicity of cycloheximide and related glutarimide derivatives

The effect on biological activity of various group substitutions and stereo-chemical changes in the l-cycloheximide molecule was studied. Compounds were assayed for toxicity to cells of Saccharomyces pastorianus and to a cell-free protein-synthesizing system from this organism. Substitution of the imide hydrogen with a methyl group, esterification of the hydroxyl group with acetate, or conversion of the ketone to an oxime, semicarbazone, or hydroxyl group resulted in greatly diminished or complete loss of activity Stereoisomers which differed from l-cycloheximide in configuration of the trisubstituted cyclohexanone ring were low in activity. An isomer with the same cyclohexanone ring configuration as l-cycloheximide, but with a different orientation of the methyl group at the 4-position, was half as active as l-cycloheximide. A cyclic ketone was not an absolute requirement for biological activity of glutarimide antibiotics because streptimidone which contains an aliphatic ketone was about 30 per cent as active as l-cycloheximide. The principal steric requirement in the cyclic ketone moiety appears to be proper orientation of the carbonyl group in respect to the remainder of the molecule. Substitution data suggest that the keto, hydroxyl, and imide nitrogen groups may be involved in a 3-point attachment of the glutarimide antibiotics to the substrate. Acetoxycycloheximide and streptovitacin-A were less toxic to cells but more toxic to the cell-free protein-synthesizing system than was cycloheximide. No glutarimide derivatives were active against whole cells or a cell-free protein-synthesizing system of the cycloheximide-resistant yeast, S. fragilis.