Toxophores

Propylpiperonyl) (benzyl) ether (VIII) Modification of toxophoric nucleus 26 6 25 1... 

Experimental work carried out in these laboratories during recent years has been based on the theory that insecticides owe their activity to a toxic nucleus—the toxophore—the properties of which may be modified by auxiliary radicals—the auxotoxes. This nomenclature is suggested by the names of analogous functions in dyestuffs, the chromophore and auxochrome groups. 

A striking illustration of the effect of chemical structure on insecticidal properties is provided by the data given in this paper on compounds related to piperonyl butoxide. According to the above theory, the methylenedioxyphenyl nucleus present in this substance is the toxophore. The materials selected for comparison show the reduction in toxicity produced, first, by modifying the toxophore, and, second, by substituting different groups for the auxotox radical. 

Although structurally-diverse as evidenced above, the insecticidal pyrethroids still conform to a unique, operationally-defined, structure-activity relationship based on the physical characteristics and three-dimensional shape of the entire molecule conforming to those originally evidenced in the natural pyrethrins [13]. From this relationship, it becomes apparent that there is no single molecular aspect or reactive moiety that serves as a true toxophore for the pyrethroids and that their actions at target sites are dependent upon the entire stereospecific structure of these insecticides [1]. 

Compounds in which the fluorine atom is very loosely bound are relatively non-toxic. Thus the COF group is not toxophoric... 

Molecular modification can be used to eliminate the potential for toxicity from a candidate drug. This requires knowledge of the chemical mechanisms of toxic action, both direct and indirect (via metabolic activation), so that one may recognize the potential toxophore. 

Currently, the programs available are all able to suggest a great many potential novel ligands to target sites. Unfortunately, many would represent very difficult synthetic challenges Many would contain toxophores, or be unstable structures. A major difficulty still remains in making a selection of... 

Handrick (Ref 3), Pletz (Ref 1) proposed the theory of explosopbores and auxoexploses analogous to the Witt theory of chromophores auxochromes and to the Ehrlich theory of toxophores and autotoxes... 

Deguelin (19),32 in which rings D and E have a chromene, not a benzofuran, structure, is fully as ichthyotoxic and insecticidal as rotenone. It has been suggested33 that the toxophore in rotenoids might be the sequence =CH—CH=CH—O— in rings C and D, which is found both in (13) and in (19). The same sequence is found in... 

Furocoumarins, such as xanthotoxin (20), are also strongly ichthyo-toxic.35 It is not yet possible to deduce the toxophore responsible for these physiological properties. 

In the group of synthetic benzofurans are found nitro derivatives with the nitro group on the benzofuran ring.36-38 It is difficult to attribute these properties to a definite toxophore, isopropyl derivatives being at least as active as nitro derivatives. Nitrobenzofurans are also bactericidal.39,40 A parallel between structure and antibacterial activity has been made in the nitrofuran series.41... 

Although alkylbenzofuran derivatives (e.g., 2-methyl-2,3-dihydro-benzofuran) have no vitamin F activity,88 they seem to show some regulating activity on plant growth.89 The 2,2-dimethyl-2,3-dihydro-benzofuran ring is an effective toxophore.90... 

The real reactive, DNA-cleaving, toxophore is a phenylene-1,4-diyl radical that is formed via a Bergman cyclization. 

A further effort to establish a relationship between explosive properties and structure has been made more recently by Piets [2]. He proposed a theory of ex-plosophores and auxoploses in a way analogous to Witt s suggested chromo-phores and auxochromes in the dyes, and Ehrlich s suggested toxophores and autotoxes in chemotherapeutics. 

Although the effect of the ortho substituents needs further elucidation which requires the synthesis of new compounds, we tentatively draw one conclusion it seems likely that steric interaction of the ortho substituents with the toxophoric NH group does not decrease the activity on the contrary, it may enhance it. 

Figure 2. Representative structures of inhibitors of the cytochrome bci complex (cf section 2). The toxophore moiety has been indicated.

The Qi site inhibitor antimycin contains a 3-formamidosalicylic acid toxophore which is bound via an amide to a complex dilacton moiety (Figure 2). Antimycin is highly specific and binds only to the Qi site of mitochondrial and most bacterial bci complexes but not to the Qi site of the b complex while class 1 Qo inhibitors are much more promiscuous with some of them acting at the Qi site of the b complex or at complex I (NADHrquinone oxidoreductase) [17]. 

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