The paper describes the design, synthesis, and testing of inhibitors of folate-synthesizing enzymes and of whole cell cultures of Candida albicans. The target enzymes used were dihydropteroic acid synthase (SYN) and dihydrofolate reductase (DHFR). Several series of new 2,4-diaminopyrimidines were synthesized and tested as inhibitors of DHFR and compared with their activity against DHFR derived from mycobacteria and Escherichia coli. To test for selectivity, also rat DHFR was used. A series of substituted 4-aminodiphenyl sulfones was tested for inhibitory activity against SYN and the I(50) values compared to those obtained previously against Plasmodium berghei- and E. coli-derived SYN. Surprisingly, QSAR equations show very similar structural dependencies. To find an explanation for the large difference in the I(50) values observed for enzyme inhibition (SYN, DHFR) and for inhibition of cell cultures of Candida, mutant strains with overexpressed efflux pumps and strains in which such pumps are deleted were included in the study and the MICs compared. Efflux pumps were responsible for the low activity of some of the tested derivatives, others showed no increase in activity after pumps were knocked out. In this case it may be speculated that these derivatives are not able to enter the cells.

Solubility data of 787 organic liquids (electrolytes and nonelectrolytes) with diverse structures has been quantitatively described by physicochemical property descriptors. Special effects like intra-and intermolecular hydrogen bonds have been shown to be very important for water solubility. It is found that an important part of the solutesolvent interaction is neglected in all correlations of logS with (only) logP, as in this case the solute H-bond donor effect is not considered. As expected intramolecular hydrogen bonds lead to reduced solubility, whereas intermolecular hydrogen bonds (both HB donors and acceptors) of solutes result in higher solubility. An exception to the latter rule are carboxylic acids which due to intermolecular HB-induced dimerization in the pure liquid phase of acids show a three times lower solubility as expected on the basis of their molecular properties. A volume-related term (molecular polarizability a) was found to have an essential negative contribution to solubility. For the first time the solubility increasing effect of partial ionization of weak acids and bases in saturated aqueous solutions has been quantitatively considered for sets of compounds by exact calculation of the pH determined by the solutes aqueous solubility and pKa value(s).

The importance of the interaction of drug molecules with membranes is discussed. The first two examples use the interaction of benzylpyrimidines with membranes of sensitive and resistant E. coli. This leads to a partial inactivation due to binding and to a change in mechanism of action, respectively. Another example deals with the interaction of amphiphilic benzylamines with artificial bilayers which lead to a change in conformation. The neuroleptic activity of Flupirtin derivatives could be described by the degree of interaction with bilayers quantified by NMR technique and a newly developed HPLC technique. Finally the interaction of amphiphilic drugs with membranes, possibly responsible for reversal of multidrug resistance in tumor and malaria therapy, is discussed.

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The number of genes coding for various enzymes have been determined in Ciona intestinalis (Tunicata) in comparison with Branchiostoma lanceolatum (Cephalochordata) using electrophoretic methods. Both species, generally, have identical gene numbers for homologous proteins. This finding does not support the hypothesis that Branchiostoma represents an anciently polyploid step relative to Ciona. High levels of allozymic variation were observed in the two species. The data are discussed in view of the neutral mutation hypothesis.