ANALOGUES 



that could utilise the pyrimidine and thiazole portions of the aneuri 

 molecule. In other words, the more exacting the organism, the moi 

 sensitive it is to the effect of pyrithiamine — a phenomenon also 

 observed with other growth inhibitors. 



Pyrithiamine and certain derivatives of 6-aminopyrimidine in- 

 hibited the utilisation by Lactobacillus fermenti of aneurine pyro- 

 phosphate more readily than the utilisation of free ameurine.^^ lodo- 

 acetate, malonate, dinitrophenol, fluoride and cyanide also inhibited 

 growth and acid production by this organism in presence of aneurine 

 or its mono- or pyrophosphate. H. P. Sarett and V. H. Cheldelin ^^ 

 suggested that, when aneurine combines with the protein of the enzyme 

 before being phosphorylated, a more stable form of cocarboxylase 

 results than when combination takes place after phosphorylation. 



Drug-fastness has been observed with pyrithiamine, as with most 

 other antibacterial substances. This is a well-known phenomenon in 

 chemotherapy, and means the development of resistance to the 

 inhibitory effect of an antibacterial substance. A strain of Endomyces 

 vernalis resistant to pyrithiamine was developed by D. W. Woolley ^^ 

 by conditioning it to gradually increasing concentrations of inhibitor. 

 This strain was able to tolerate twenty-five times the concentration 

 that inhibited the parent strain. The pyrithiamine-fast strain 

 required either aneurine or the pyrimidine half for growth, but in 

 presence of small amounts of pyrithiamine and in absence of aneurine, 

 it converted a portion of the pyrithiamine into the pyrimidine half. 



Not only did pyrithiamine inhibit the "growth of several species of 

 bacteria, but it also produced symptoms of vitamin B^ deficiency in 

 mice.^® The eifect was cumulative and delayed, and could be cured 

 by the administration of aneurine at a level equal to i/40th that of 

 the pyrithiamine. 



Neopyrithiamine and Oxythiamine 



Neopyrithiamine hydrobromide (page 124) proved to be at least 

 four times as active as pyrithiamine as an antagonist of aneurine 

 hydrochloride in the growth of rats.^^" The index of inhibition was 

 about 10 : I. It produced polynejiritic symptoms in mice, the 

 animals developing complete paralysis of the hind iegs.^^ It pro- 

 tected aneurine from destruction by carp thiaminase (page 25), 

 being preferentially attacked by the enzyme.^^ 



A somewhat less potent antagonist of aneurine is 3-(4'-hydroxy- 

 2'-methyl-pyrimidyl-5'-methyl)-5-iS-hydroxyethyl-4-methyl-thiazoliiun 

 chloride, first prepared by Todd and Bergel,- and given the name 

 oxythiamine by M. Soodak and L. R. Cerecedo,^^ who obtained it by 

 treatment of aneurine with nitrous acid. Oxythiamine had little or 



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