Lead compounds molecular size

Uncharged styryl (methine) disperse dyes were originally introduced to provide greenish yellow colours on cellulose acetate fibres. One such dye still in use is Cl Disperse Yellow 31 (6.226), which is made by condensing 4-(N-butyl-N-chloroethylamino)benzaldehyde with ethyl cyanoacetate. Suitable compounds for polyester usually contain the electron-accepting dicyanovinyl group, introduced with the aid of malononitrile. An increased molecular size leads to improved fastness to sublimation, as in the case of Cl Disperse Yellow 99 (6.227). A novel polymethine-type structure of great interest is present in Cl Disperse Blue 354 (6.228), which is claimed to be the most brilliant blue disperse dye currently available [85]. 

Gryns (1896), Hedin (1897), and especially Overton (1900) looked at the permeability of a wide range of different compounds, particularly non-electrolytes, and showed that rates of penetration of solutes into erythrocytes increased with their lipid solubility. Overton correlated the rate of penetration of the solute with its partition coefficient between water and olive oil, which he took as a model for membrane composition. Some water-soluble molecules, particularly urea, entered erythrocytes faster than could be attributed to their lipid solubility—observations leading to the concept of pores, or discontinuities in the membrane which allowed water-soluble molecules to penetrate. The need to postulate the existence of pores offered the first hint of a mosaic structure for the membrane. Jacobs (1932) and Huber and Orskov (1933) put results from the early permeability studies onto a quantitative basis and concluded molecular size was a factor in the rate of solute translocation. 

An example for the pore pathway is discussed using the example of sulfonamides. For this class of compounds it is generally accepted that the degree of ionization determines the antibacterial activity, the ionized form being more potent then the neutral form. Total ionization, however, leads to decreased activity in whole cells because cell wall permeation becomes the rate-limiting step [99-101]. The possible effect of molecular size on cell wall permeation has been studied on a series of substituted 5-sulfanilamido-l-phenylpyrazoles that show only a small variation in pKa values but a large difference in molecular weight [102]. 

We discuss how the size of a library can he drastically reduced without loss of information or decreases in the chances of finding a lead compound. The approach is based on the use of statistical molecular design (SMD) for the selection oflibrary compounds to synthesise and test, followed by the use of quantitative structure activity relationships (QSARs) for the evaluation of the resulting test data. The use of SMD and QSAR is, in turn, critically dependent on an appropriate translation of the molecular structure to numerical descriptors, the recognition of inhomogeneities (clusters) in both the structural... 

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