Lipophilicity effect

Lipophilic constants are frequently used when dealing with a series of analogues in which only the substituents are different. This usage is based on the assumption that the lipophilic effect of the unchanged part of the structure is similar for each of the analogues. 

The lipophilic effect of cyclopropyl explains why abacavir, a nucleoside reverse transcriptase inhibitor, has an improved absorption in the CNS compared to diaminop-urine dioxolane (DAPD) (Figure 20.14). ... 

The Molecular Lipophilicity Potential (MLP) describes the combined lipophilic effect of all fragments in a molecule on its environment and can be calculated at any point in space around the molecule [Audry, Dubost et al., 1986, 1992 Fauchere, Quarendon et al, 1988 Furet, Sele et al., 1988 Audry, Dallet et al., 1989]. It is defined by considering a molecule surrounded by nonpolar or low polarity organic solvent molecules, and assuming that the solvent molecule distribution around the considered molecule depends on the fragmental or atomic contributions to log P and the distances at which the solvent molecules are from the target molecule. Therefore, the molecular lipophilicity potential at each feth grid point is calculated as... 

Several studies on structure-activity relationships of succinate dehydrogenase inhibitors have been published [22-28]. Each of the analyses has focused on specific carboxylic acid moieties of the molecule. The influence of substituents of the carboxylic acid and of the aniline has then been studied based on enzyme inhibition and biological data. Some empirical relationships have been established within each structural subclass. The importance of electron-withdrawing groups on the carboxylic acid and of lipophilic effects on the aniline has been observed. The orientation of the amide bond has also been discussed, suggesting that the cis configuration of the amide bond may be important in molecules with bulky ortho substituents [28]. 

The lipophilic effect of hydrocarbon fragments is evident from the table. When a carbon—carbon double bond is present, it makes a definite (—0.55) contribution to hydrophilicity whereas a C—C triple bond makes a much larger one (—1.42). The aliphatic equivalent to phenyl, as a lipophilic substituent, lies between ethyl and propyl, whereas naphthyl approximates to... 

Figure 20.9 Design concept to explore lipophilicity effect with substituent R and the refined chemical scaffold.

Emulsifiers are classified by the hydrophilic—lipophilic balance (HLB) system. This system indicates whether an emulsifier is more soluble in water or oil, and for which type of emulsion (water-in-oil or oil-in-water) it is best suited. Emulsifiers having alow HLB value are more oil soluble, and are better suited for water-in-oil appHcations such as margarine. Conversely, emulsifiers having a high HLB value are more water soluble, and function more effectively in oil-in-water emulsions such as ice cream (34). The use of this system is somewhat limited because the properties of emulsifiers are modified by the presence of other ingredients and different combinations of emulsifiers are needed to achieve a desired effect. The HLB values of some common emulsifiers are given (35). 

Sediment Toxicity. Because of their low solubiUty ia water and lipophilic nature, phthalates tend to be found ia sediments. Unfortunately httle work has previously been carried out on the toxicity of phthalates to sediment dwelling organisms. Eor this reason ECPI has commissioned some sediment toxicity studies designed to measure the effect of DEHP and DIDP ia a natural river sediment on the emergence of the larvae of the midge, Chironomus riparius. 

The -NH(CH2)3N(CH2)2 amide of teicoplanin factor A2-2, coded MPT. 62,873 [122173-74-4] was also prepared. The combined effect of a moderate basicity and a slightly increased lipophilicity at neutral pH probably led to a better penetration through the cell wall. MDL 62,873 was consistentiy more active than teicoplanin against CNS clinical isolates (119,120). No semisynthetic dalbaheptide is under clinical evaluation at this writing. 

Skin. The skin may become contaminated accidentally or, in some cases, materials may be deHberately appHed. Skin is a principal route of exposure in the industrial environment. Local effects that are produced include acute or chronic inflammation, allergic reactions, and neoplasia. The skin may also act as a significant route for the absorption of systemicaHy toxic materials. Eactors influencing the amount of material absorbed include the site of contamination, integrity of the skin, temperature, formulation of the material, and physicochemical characteristics, including charge, molecular weight, and hydrophilic and lipophilic characteristics. Determinants of percutaneous absorption and toxicity have been reviewed (32—35,42,43,46—49). 

Toxic effects of propranolol are related to its blocking P-adrenoceptor blocking actions. They include cardiac failure, hypotension, hypoglycemia, and bronchospasm. Propranolol is lipophilic and crosses the blood—brain barrier. Complaints of fatigue, lethargy, mental depression, nightmares, hallucinations, and insomnia have been reported. GI side effects include nausea, vomiting, diarrhea, and constipation (1,2). 

For practical appHcation in mixtures of water—organic solvent, only ammonium and phosphonium salts containing 15 or more C atoms are sufficiently lipophilic. In empirical catalyst comparisons crown ethers (hexaoxacyclooctodecanes) (1)—(3) were often as effective as the best onium salts. 

A chemical must have certain physicochemical properties to elicit an endocrine disrupting effect. For example, the ability to enter the body and to cross the cell membrane into the cellular medium requires a degree of lipophilicity. Fipophilic potentials may be compared by reference to the chemical s octanol-water coefficient (usually expressed as log K ). This property, together with molecular size and chemical structure, has an important influence on the bioacciimiilation... 

Landini, Montanari and Rolla ° were able to incorporate cyclohexyl residues in the strands and thereby increase lipophilicity. As with the compounds referred to above, these were effective phase transfer catalysts. 

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