ANTIBACTERIAL ACTIVITY 555 



(1927) and a ratio of 2.4 by Geiger (1946). Thus the effect of adding a methyl 

 group to either p-benzoquinone or 1,4-naphthoquinone cannot be character- 

 ized in terms of a consistent change in the potency. 



The following structure-activity generalizations may be made but should 

 be considered as provisional only. 



(A) The progressive substitution of jj-benzoquinone with methyl groups 

 leads at first to an increased potency and then a decreased potency. Geiger 

 (1946) finds the relative potencies for jj-QiCHg-p-QidiCHg-p-QitriCHg-p-Q 

 to be 1:2.3:3.0:0.86 for four bacteria, but additions of a fourth methyl 

 group to form duroquinone brings about a marked divergence, in that 

 gram-positive organisms are quite susceptible (bacteriostatic concentration 

 0.03 mM) while gram-negative organisms are resistant (bacteriostatic 

 concentration > 6.1 milf ). This might be interpreted to indicate that the 

 inhibition of gram-negative bacteria involves reaction with SH groups, 

 whereas this is not so in the case of gram-positive bacteria; on the other 

 hand, it might also indicate the importance of the semiquinone form for 

 the inhibition of gram- positive bacteria. 



(B ) The progressive substitution of js-benzoquinone with chlorine atoms 

 also seems to augment the activity at first but later the potency falls. 

 The relative activities of the series p-Q:diCl-2)-Q:triCl-p-Q:tetraCl-p-Q are 

 1:1.71:0.74: < 0.37 from the results of Geiger (1946). Chloranil is rather 

 inactive on both gram-positives and gram-negatives. 



(C) Methoxy groups apparently increase the activity in the p-benzoqui- 

 none series — e. g., diCHgO-p-Q's are invariably more potent than p-Q 

 by factors of 1.6 to 30 (mean 7.3) — but decrease the activity when in- 

 troduced into toluquinone — e. g., the potency ratio for 3,5-diCH30-TQ:TQ 

 averages 0.30 for six bacteria, and only in S. aureus is the methoxylated 

 derivative more active, 



(D) Substitution in the 2-position of 1,4-naphthoquinone usually reduces 

 the activity if the groups are hydroxyl, chlorine, or bromine. We have 

 seen that a methyl group, forming menadione, can alter the potency in 

 either direction. Inasmuch as 2-NH2-l,4-NQ is 4.8 times as potent as men- 

 adione on four bacteria (Alcalay, 1947 a), it is likely that the amino group 

 increases the activity. 



(E) The effects of substitutions in the 2- and 3-positions of 1,4-naphtho- 

 quinone are important as evidence for the role of SH reaction in the in- 

 hibitory mechanism. When menadione is substituted at the 3-position 

 with a hydroxy group (to form phthiocol), methyl group, or methoxy group, 

 the activity is diminished. A number of 2,3-disubstituted 1,4-naphthoqui- 

 nones are fairly active, but in all cases there is a halogen atom in the 3-po- 

 sition, and we have seen that this does not interfere with SH reaction, so 

 that the data from this group are not pertinent. 



