Microbiological studies with thioctic acid analogues. I. Inhibitory effects of 6-ethyl-8-mercaptooctanoic acid and related thioctic acid analogues for growth of microorganisms.

Present knowledge of the metabolic role of thioctic acid (lipoic acid) is derived almost exclusively from studies of bacterial enzyme systems, although it may well have similar functions in higher plants and animals. A number of microorganisms are known which have an absolute growth requirement for thioctic acid but higher animals do not seem to require preformed thioctic acid for growth. If effective antagonists of thioctic acid could be prepared, such compounds might be useful in demonstrating more broadly the biochemical role of thioctic acid in diverse organisms. The biological activity of 6, 8-dithiononanoic acid or "8-methylthioctic acid" was reported by Stokstad (1954) who found it to be a true antimetabolite of thioctic acid in a limited number of biological systems; in that its toxic effect could be reversed by thioctic acid. The analogue was not inhibitory for growth of Escherichia coli, Corynebacteriutm bovis, the chick, and the rat. Recently, the synthesis of 6-ethyl-8-mereaptooctanoic acid and some of its homologues was reported from these Laboratories (Brockman and Fabio, 1957). The general structure of these analogues is shown in figure 1 together with certain biologically active forms of thioctic acid. It is apparent from the figure that 6-ethyl-8mercaptooctanoic acid may be regarded as an analogue of 6, 8-dimercaptooctanoic acid in which the 6-mereapto group is replaced by an ethyl group. While the syrnthesis of this series of thioctic acid analogues was in progress, Gunsalus et al. (1956) presented evidence that 6-S-acetyl6,8-dimercaptooctanoic acid (acetyl-6,8-dimercaptooctanoic acid, figure 1) may be the functional form of thioctic acid concerned in acetyl transfer reactions, thus emphasizing the meta-