Selectivity and Toxicity

In some cases the lack of selectivity can be beneficial. For example, the primary use of dinocap (3) is as a fungicide for control of powdery mildews, but it is also acaricidal and is used to suppress the populations of various mites [33], In a similar way fluazinam (4), one of the most selective fungicidal uncouplers, has been shown to control some mites [34]. 

However, in general the lack of selectivity is undesirable and requires careful management. As an example, dinocap has detrimental effects on some beneficial insects, especially predatory mites [35-37]. Phytotoxicity can also be an issue on some crops [38-41] and ornamentals [42]. 

Several toxic effects of fungicidal uncouplers have been observed, but it is not clear whether these are directly related to the uncoupling mode of action or to other, compound-specific mechanisms. Some uncouplers have a very high acute toxicity, which is almost certainly a result of the mode of action. This has been exploited in the case of bromethalin (6), which is used as a rodenticide. Another toxic effect that has been observed for several distinct structural types of uncoupler, and hence is likely to be a direct result of this mode of action, is oedema of the central nervous system [48]. Direct interaction with the myelin sheath membrane is probably responsible for this toxicity. 

The development of resistance is a major issue for many classes of fungicide, including those that inhibit respiration. However, uncouplers appear to be less susceptible to the onset of resistance than many other fungicides. For example, a study of resistance development in Sphaerotheca Jidiginea in cucumber greenhouses observed no resistance to dinocap, despite it having been used for over 30 years [60]. This was in contrast to other classes of fungicide, such as benzimidazoles, where resistance had developed over a much shorter period. Even under artificial selection pressure, no resistance to dinocap was seen [61]. 

Although little resistance to uncouplers has been observed in fungi, several bacteria are known that have reduced sensitivity to protonophoric uncouplers [78-80]. The likelihood of similar resistance mechanisms developing in fungi is unknown, but is probably small, as no such mutations have yet been observed. 

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B-score Biological profile score based on potency, selectivity, and toxicity of a compound. 

Under in vivo conditions, not only the degree of partitioning but also the dissociation constant of the lipid-drug complex is of importance. It is evident that the accumulation of drug molecules in the various cell membranes can have an enormous influence on the pharmacokinetics of drugs and, in consequence, on effectivity, selectivity, and toxicity. 

The aims of this book are to highlight and summarize for medicinal and pharmaceutical chemists some important properties of phospholipid bilayers to explain, using examples, analytical tools for determining thermotropic and dynamic membrane properties and the possible effects of drugs on such membrane properties and, finally, to discuss examples of the importance of drag-membrane interactions for drug pharmacokinetics (absorption, distribution, accumulation) as well as drag efficacy, selectivity, and toxicity. 

An optimization step, that deals with the improvement of the lead structure. The optimization process takes primarily into account the increase in potency, selectivity and toxicity. Its characteristics are the establishment and analysis of structure-activity relationships, in an ideal context to enable the understanding of the molecular mode of action. However, an assessment of the pharmacokinetic parameters such as absorption, distribution, metabolism, excretion and oral bioavailability is almost systematically practised at an early stage of the development in order to eliminate unsatisfactory candidates. 

By methodically changing the side chains and possibly the polymeric backbone, it should be feasible to adjust the antimicrobial selectivity and toxicity of the polymers in a method analogous to the production of AMP and P-oligomers [59]. 

A series of anileridlne derivatives bearing substituents with potential alkylating ability was made in order to investigate the possibility of locating analgesic receptors by specific alkyla on. The fumaryl derivative (IX) caused apparent inactivation which could be prevented by naloxone pretreatment. Other analogs of IX were non-selective and toxic. 

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