Quantitative structure activity relationship [QSAR] of polyxygenated xanthoses and benzophenones antifungal agents as griseofulvin analogues

A set of polyoxygenated xanthones, as griseofulvin analogues, and their precursors benzophenones, were tested in vitro for antifungal activity against different strains of Aspergulosis and Dermatophytes. Some of the tested compounds showed higher potency than the reference drug, griseofulvin, [e.g IId, IIi vs. A. niger and IIIb, IIIc and IIIf vs. A. alternata]. Other compounds [IIId, IIIe and IIIj] were equipotent as griseofulvin vs. A. alternata. QSAR was studied using free Wilson and linear free energy models. Computer-assisted regression analysis was used for the optimization of the results obtained from QSAR analysis. Some structural features including substitution pattern [indicator variables] and physicochemical parameters [13C-NMR chemical shifts and Rm values, as lipophilic regressor] were involved as variables in the correlations. The resulting QSAR revealed that the contribution of single parameter [Rm, 13C-NMR or indicator variables] to the antifungal activities was nonsignificant except for indicator variable [P1] in case of polymethoxyxanthones vs. A. niger, [r = 0.939]. Combination of the electronic descriptors, 13C-NMR and either of the other variables proved to be necessary for correlating the activity to the structural features. In some cases, maximum antifungal activity was observed, through downfield shift of C-1 and C-4 of polymethoxyxanthones [IIa-i] and C-3 of polyhydroxyxanthones [IIIa-j]

Synthesis, hydrolysis kinetics and physicochemical properties of ester prodrugs of bucetin

Three amino acid esters and two alkyl esters of bucetin have been synthesized. The prepared esters possess different properties including aqueous solubility and lipophilicity. The non-enzymatic hydrolysis was studied in buffers of constant ionic strength at different pH values for the different compounds. The enzymatic hydrolysis in fresh rabbit plasma was studied for the two most promising compounds. Bucetin-4-morpholinoacetate and bucetin acetate revealed a reasonable hydrolysis pattern in plasma and could be considered the prodrugs of choice of bucetin in this study