Electrophilically active substances

The electrophilically active substances have as toxophoric constituent an electrophilic group which is responsible for the antimicrobial effect, because it enables these active substances to react with specific nucleophilic entities of the microbial cell (Paulus, 1993) Examples of this class are aldehydes [II, 2.], e.g. Glutaraldehyde, compounds with activated halogen atoms [II, 17.], e.g. Bronopol, and microbiocides with an activated S-N-bond [II, 15.], for example Isothiazolinones. Since Isothiazolinones represent a major class of bactericides for industrial preservation, much research has been performed in this area. 

Microbicides of this kind are electrophilic active substances having at their disposal an activated halogen atom in the a-position and/or in the vinyl position to an electronegative group E (Figure 20). The antimicrobial activity of these substances arises from the fact that nucleophilic entities (H-Nu) of the microbial cell react with the carbon atom boasting an electron hole. It is apparent that a variety of modifications of both the electronegative... 

Deprotonation. Various uses of BuLi as a base continue to be reported. Its deprotonation of allene gives a species which acts as a propargyl group transfer agent. Dehydrofluorination by BuLi is a step toward formation of useful compounds such as CFj=C(NMe)2 and CF2=CF(SnMej). The former substance shows both nucleophilic and electrophilic activities. 

The presence of mefhoxy groups in the poly(oxyethyloie phosphate)s predetermines two possible ways for immobilization through an ionic bond of amine-containing biologically active substances (i) alkylation reaction, (ii) dealkylation reaction. Both of them are due to the reactivity of the a-carbon atom of the methoxy group, which acts as an electrophilic center. 

The ambient medium impairs the effectiveness of microbicides also if its constituents include those capable of interacting with a microbicide in competition with the constituents of the microbe cell. This is true of electrophilically active microbicides in general as far as the ambient medium contains nucleophilically active constituents with which the microbicide can react in competition with the corresponding cell constituents. It is also true, however, of membrane-active microbicides if adsorption of the microbicide on organic matter competes with the adsorptive processes on the cytoplasmic membrane or if such microbicides, e.g. phenol derivatives, become incorporated in micelles that are formed in certain media at levels above the critical micelle concentration with the result that the incorporated active substance molecules are no longer available for the antimicrobial effect (see III. 16, Fig. 34). 

The effectiveness and efficiency of microbicides result from the interplay of the chemicophysical properties of the active substance molecule, which are determined by the molecule s constitution. Solubility, polarity, ionicity and reactivity are examples of properties that influence effectiveness. Taking the N-trihalo-methylthio derivative as examples, Paulus Kiihle (1986) drew attention to an important principle that evidently applies to electrophilically active microbicides in general, namely that the relationship shown in Fig. 11 exists between the antimicrobial effectiveness and reactivity of microbicide molecules. As the reactivity increases, so, too, does the effectiveness—until it peaks at a moderately high reactivity level. Thereafter the antimicrobial activity decreases as the reactivity continues to rise because at this stage competition reactions — interactions of the reactive microbicide molecules with constituents of the surrounding medium — predominate. 

Active substances. Target specificity is a non-desired property of a technical microbicidal active molecule. The applied molecules are either classified as membrane-active substances or as reactive electrophiles. Some molecules can not be clearly assigned to one of the two categories while showing both modes of actions. See chapter 2. 

The effect of different types of condensation of the pyrrole and indole rings on the specific features of electrophilic substitution was of defirrite interest. Firrthermoro, the study of the above reactions was also of practical importance, since some of the pyrroloindole derivatives themselves possess physiological activity or can be used in the syntheses of other physiologically active substances. 

It is noteworthy that the compounds which have been shown to undergo extensive acetoxylation or side-chain nitration, viz. those discussed above and hemimellitene and pseudocumene (table 5.4), are all substances which have an alkylated ring position activated towards electrophilic attack by other substituents. 

The assay can be performed using mutagenic substances that react directly with DNA or, where metabolic activation is necessary, with pre-mutagen in the presence of rat liver homogenate that is enriched in mixed function oxidases (termed S9). Metabolic oxidation (if that is what is required) results in ultimate or penultimate mutagenic forms, which act as electrophiles towards S. typhimurium. 

Certain substances may need special consideration, such as highly electrophilic substances, which give positive results in vitro, particularly in the absence of metabolic activation. Although these substances may react with proteins and water in vivo and thus be rendered inactive toward many tissues, they may be able to express their mutagenic potential at the first site of contact with the body. Consequently, the use of test methods that can be applied to the respiratory tract, upper gastrointestinal tract, and skin may be appropriate. 

Formation of the electrophilic halogen species leads to the potential for rapid reaction with compounds containing strongly activating groups, such as activated aryl compounds. Particularly, substances containing aromatic ring structures that have... 

---