ANALOGUES 



A series of four imidazolidone aliphatic acids were synthesised by 

 Dittmer et al. ; *® these differed from desthiobiotin and its homologues 

 in the absence of the methyl group. These compounds inhibited S. 

 cerevisiae and L. helveticus and the effect was counteracted by biotin.*''^^ 

 Imidazolidone-M-hexoic acid was the most potent, with a molar inhibi- 

 tion ratio of 126,000 for L. helveticus and 760,000 for yeast ; it also 

 inhibited types II and III pneimiococci and E. colt. It was much more 

 effective with desthiobiotin as the growth stimulant so that it prob- 

 ably functions by competing with desthiobiotin for an enzyme system 

 that synthesises biotin. The antibacterial index for the competitive 

 inhibition of desthiobiotin by imidazolidone-caproic acid was increased 

 from 100 to 300 by exogenous a-ketoglutaric acid. The significance 

 of this observation has already been discussed (page 443). 



Two other potent anti-biotins were y-(3 : 4-ureylene cyclohexyl)- 

 butyric acid andy-(2 : 3-ureylene cyclohexyl) -butyric acid, which have 

 a formal resemblance to biotin : 



NH 



rH } NH ! I 



\co/\/^(CH2)3 . COOH \co/\j^ 



(CH2)3 . COOH 



Rather surprisingly the former inhibited L. helveticus, but not S. 

 cerevisiae, whereas the latter inhibited S. cerevisiae but not L. helveti- 

 cus.*^ 



y-(3 : 4-Ureylene cyclohexyl)-butyric acid and also biotin sulphone 

 were more potent antagonists of f^/-oxybiotin with L. arabinosus than 

 of ^-biotin, for at certain levels the action of oxybiotin was com- 

 pletely counteracted, whereas that of i^-biotin was scarcely affected. ^° 



The following homologues of biotin and their derivatives were 

 found to be antagonistic to biotin both for S. cerevisiae 139 and for 

 L. helveticus : ^Z-norbiotin, i/-homobiotin, ^/-bishomobiotin and 

 ^/-tris-homobiotin ; iZ-homobiotin sulphone, ^/-bis-homobiotin sul- 

 phone and ^/-tris-homobiotin sulphone. ^^ Of these, homobiotin was 

 the most potent, being probably the most potent anti-biotin known 

 for both micro-organisms. 



Some but not all of these compounds also inhibited L. arabinosus. 

 With oxybiotin as growth factor, the homologues of biotin were more 

 effective than the sulphones in inhibiting L. helveticus and S. cerevisiae, 

 but the sulphones were more effective with L. arabinosus. ^^ Homo- 

 logues of oxybiotin containing 2, 3, 5 and 6 methylene groups in the 

 side-chain were prepared, and tested as antagonists of biotin and 



453 



