Carboxylate antifungals

Although not perfect, Hansch s lipophilicity parameter and log P values are the most widely used parameters in QSAR studies. In addition to their effectiveness in predicting biological activity through target binding (pharmacodynamics), both parameters also affect pharmacokinetics. The pharmacokinetic applications of log P and 7r-values can be seen in Lipinski s rules and a Case Study (Carboxylate Antifungals) later in this chapter. 

The impact of small molecules on the acetylation status of histones has attracted the interest of the medicinal chemistry community for almost a decade now. Nevertheless, the fast and reversible increase in cellular histone acetylation in the presence of -butyrate was already recognized in 1977 by Riggs et al. (Fig. 3) [30]. Two years later, it was proven that n-butyrate, among some related and less active small linear aliphatic carboxylates, was a noncompetitive inhibitor of histone deacetylating enzymes [31-34]. More than ten years after the initial interest in -butyrate, Yoshida et al. showed that trichostatin A (TSA, Fig. 3), originally reported as an antifungal agent [35],... 

Phenanthroline-8-carboxylic acid derivatives have been patented as antibacterials and antifungal agents.295,533-535 1,10-Phenanthroline... 

In another study by Hansch, aliphatic carboxylate salts (12.15) showed antifungal activity. The data are provided in Table 12.6. The activity was found to correlate very well with two parameters log P and its square (Equation 12.23). 

TABLE 12.6 Antifungal activity of aliphatic carboxylic acid salts... 

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