Chemical structure and biological activity 



The 3-chloromethyl-derivative proved to be very toxic, probably because 

 of too high a chemical reactivity, as Cl^ was liberated in the medium. The 

 3-hydroxymethyl-derivative is inactive, which is more or less to be 

 expected, as introduction of hydrophilic substituents in the lipophilic 

 part of the molecule is not generally compatible with activity. 



If substituents larger than CH3 or CI are introduced in one of the o-positions 

 only, some activity is retained, which may be enhanced by a 3-substituent, 

 as for example in 2-ethyl-3-chlorobenzoic acid (II) and 2-iodo-3-chloro- 

 benzoic acid (III) (cf. Veldstra, 1955). 



Though these compounds are only weakly active, they are interesting in 

 that they illustrate the sensitivity of the COOH group as to inhibition of 

 conjugation and masking from interaction. In the latter respect it should be 

 noted that 2-wopropyl-3-chlorobenzoic acid (IV) is inactive again. 



(a) Figure 2. Pea test. 



[a) I: 200, 150. lOO.lO-^ mol/1. 

 {b) VI: 25, 10, 4.10-5 mol/1. 



{b) 



Thimann (1952) considered a free 5-position in 2:3:6-substituted benzoic 

 acids to possess an activating influence with respect to the physiological 

 activity. Although the arguments given in Thimann's paper were already 

 unacceptable from a theoretical chemical point of view, the fact that we 

 found 2:3:5:6-tetramethylbenzoic acid (VI) to be slightly more active than 

 2:3:6-trimethylbenzoic acid (V) in the pea test at 25 and 10.10"'' mol/1., also 

 demonstrates that a free 5-position is not essential. (For activity of VI 

 cf Figure 2.) 



However, this proved to be the case until now with respect to the 4-position, 

 all 4-substituted benzoic acids being inactive or in some cases, as with 

 4-chloro-3-nitrobenzoic acid, possessing antagonistic activity (Minarik et al., 

 1951). 



This latter fact, in particular, suggested to us that a free 4-position implies 

 the absence of a hindrance to the 'active' interaction, rather than the presence 

 of an active binding spot, as, quite generally, introduction of a steric hindrance 

 to the normal interaction results in the appearance of antagonistic activity 

 (cf. the wobutyric acid derivatives (Burstrom, 1951) and the acids with a 

 bulky a-substituent (Veldstra and Aberg, 1953)). In order to verify this 

 view, 2 : 3 : 6-trichloro-4-fluorobenzoic acid (VII) was synthesized. This acid 

 and also an intermediate in its synthesis, viz. 2:6-dichloro-3-nitro-4-fluoro- 

 benzoic acid (VIII) proved to be distinctly active, both in the pea test and 



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