460 CHEMICAL AGENTS 



apparently because such factors as solubility are of more predictive 

 value for gross biological action than are specific reactive groupings. 

 The dichotomy does not seem justified either on theoretical or experi- 

 mental grounds. Separation in theory of physical and chemical activi- 

 ties of molecules is artificial; the covalent bond and, for example, van 

 der Waals' forces may both be involved in the reactivity of the same 

 molecule. Experimentally, it is found that such narcotics as urethane, 

 chloral hydrate, and ethyl ether have specific measurable effects on 

 some cell activities at concentrations which do not affect other activities 

 (138, 193, 194, 207, 261, 285). It has been proposed (190, 261) that the 

 ultimate action of structurally non-specific poisons is the denaturation 

 of one or more proteins of the cell. As Danielli (79) points out, this is 

 not in conflict with the more general theory that these poisons act by 

 virtue of their concentration in or on a lipoid phase or non-polar struc- 

 ture of the cell. 



The distinguishing feature of the structurally non-specific poisons 

 from a chemical viewpoint is that they must form weak bonds with re- 

 ceptors of the cell. This follows from the fact that inhibition is, within 

 limits, easily reversible by dilution alone. This also explains why ac- 

 tivity is associated with chemical potential — a relatively high propor- 

 tional concentration is necessary if such weak bonds are to occupy re- 

 ceptor sites enough of the time for perceptible inhibition to occur. 



Most fungicides are not narcotics, i.e., structural specificity is the rule. 

 The importance of the narcotics to the problem of structure and activ- 

 ity in the fungitoxic materials is that they may explain the effect of 

 modifications of a basic toxicant molecule. Specifically, and following 

 Horsfall (174), we may theorize that for an effective toxicant two re- 

 quirements must be met. First, there must be one (possibly more) 

 reactive atomic configuration that can combine with and inactivate 

 essential materials of the cell. Second, the total structure of the toxi- 

 cant molecule must allow concentration at the site of action. This 

 second property includes, but emphatically is not restricted to, entrance 

 into the cell. If, for example, the union between an enzyme and the 

 combining region of a toxicant molecule is ionic or partially ionic, the 

 formation of hydrogen or other weak bonds between the rest of the 

 inhibitor and areas on the enzyme protein adjacent to the point of 

 union would tend to stabilize the enzyme-inhibitor complex (6). 



Homologous Series and Fungicidal Action. A selection of recent 

 data on the homologous series effect is embodied in Table 1. Some of 

 these compounds, e.g., the alcohols, are esentially narcotics as described 

 in the previous section. The imidazolines, on the other hand, are prob- 



