Biological active compounds steric effects

In a recent puhhcation, an ultrasound-supported procedure for the selective monoacylation of symmetric diamines was presented by Maurya et al. [25j]. The corresponding products are key intermediates in the synthesis of biologically active compounds. However, the selectivity to monoacylated diamines from symmetric diamines remains a major challenge as there are no directing steric or electronic effects. N-Hydroxysuccinimide ester 52 (see Table 6.5) was used as an acylating agent... 

The fundamental assumption of SAR and QSAR (Structure-Activity Relationships and Quantitative Structure-Activity Relationships) is that the activity of a compound is related to its structural and/or physicochemical properties. In a classic article Corwin Hansch formulated Eq. (15) as a linear frcc-cncrgy related model for the biological activity (e.g.. toxicity) of a group of congeneric chemicals [37, in which the inverse of C, the concentration effect of the toxicant, is related to a hy-drophobidty term, FI, an electronic term, a (the Hammett substituent constant). Stcric terms can be added to this equation (typically Taft s steric parameter, E,). 

The alkyl and alkoxy substituents of phosphate or phosphonate esters also affect the phosphorylating abiUty of the compound through steric and inductive effects. A satisfactory correlation has been developed between the quantitative measure of these effects, Tafts s O, and anticholinesterase activity as well as toxicity (33). Thus long-chain and highly branched alkyl and alkoxy groups attached to phosphoms promote high stabiUty and low biological activity. 

Absorption, metaboHsm, and biological activities of organic compounds are influenced by molecular interactions with asymmetric biomolecules. These interactions, which involve hydrophobic, electrostatic, inductive, dipole—dipole, hydrogen bonding, van der Waals forces, steric hindrance, and inclusion complex formation give rise to enantioselective differentiation (1,2). Within a series of similar stmctures, substantial differences in biological effects, molecular mechanism of action, distribution, or metaboHc events may be observed. Eor example, (R)-carvone [6485-40-1] (1) has the odor of spearrnint whereas (5)-carvone [2244-16-8] (2) has the odor of caraway (3,4). 

In a parallel development, structural effects on the chemical reactivity and physical properties of organic compounds were modelled quantitatively by the Hammett equation 8). The topic is well reviewed by Shorter 9>. Hansen 10) attempted to apply the Hammett equation to biological activities, while Zahradnik U) suggested an analogous equation applicable to biological activities. The major step forward is due to the work of Hansch and Fujita12), who showed that a correlation equation which accounted for both electrical and hydrophobic effects could successfully model bioactivities. In later work, steric parameters were included 13). 

Hamor and Lien have analyzed anticonvulsant activities of sulfamoyl-benzoates. For the test of antistrychnine activity, compounds having the same aromatic substituents are used so that no 2o-(X,Y) term appears in Equation 22. They have suggested that the similarity of equations in terms of steric, hydrophobic, and electronic properties of substituents indicates a common anticonvulsant mechanism for the two biological effects of this set of compounds. They have also suggested that the mechanism of action of these drugs was quite different from those of barbiturates and other hypnotics where quite different structure-activity correlations of physicochemical significance have been obtained. 

These possible steric effects have been evaluated by an approach involving partition coefficients. In this way, an estimate of comparative lipophilicity can be made since this property is felt to influence the ease of membrane transport and thus eventual availability to the site of action. A number of psychotomimetic phenylisopropylamines have been studied in an octanol-water partition system, and the correlation of the resulting values, with central activity has provided a relationship that suggests an optimum lipophilicity for maximum biological activity (Barfknecht et al. 1975). These partition values have been correlated to serotonin receptor stimulation capability (Nichols and Dyer 1977) and have recently been extended to a number of phenethylamine compounds (Nichols et al. 1977). 

Quantitative structure-activity relationship (QSAR) dates back to the nineteenth century and is a computer-based tool that attempts to correlate variations in structural or molecular properties of compounds with their biological activities. These physicochemical descriptors, which include parameters to account for hydrophobicity, topology, electronic properties, and steric effects, are determined empirically or, more recently, by computational methods. The premise is that the structure of a chemical determines the physiochemical properties and reactivities that underlie its biological and toxicological properties. Being able to predict potential adverse effects not only aids in the designed development of new chemicals but also reduces the need for animal testing. It may ultimately or potentially lead to better... 

Hansch analysis The investigation of the quantitative relationship between the biological activity of a series of compounds and their physicochemical substituent or global parameters representing hydrophobic, electronic, steric, and other effects using multiple-regression correlation methodology. 

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