The title reaction has been studied in dioxane/water in a large (0.1-14.9) pS+ range, evidencing, together with an uncatalyzed process at intermediate (3.5-8.0) pS+ values, the occurrence of a catalyzed pathway both in the acidic (pS+ 0.1-3.5) and in the basic region (pS+ 8.0-14.9): specific-acid catalysis and general-base catalysis, respectively, have been found to take place by means of kinetic investigations at different buffer concentrations. Mechanisms for the three pathways have been advanced on the grounds of structural features. In a comparison with previous data particular attention has been paid to the acid-catalyzed pathway, herein observed for the first time in an azole-to-azole interconversion. The mechanistic hypotheses seem well supported by ab initio calculations.

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The reversal of multidrug resistance by 22 molecules [8-aryl-8-hydroxy-5-R'-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (1a-i) and 8-aryl-8-alkoxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (2a-m)] related to myocardial-calcium-channel-modulator diltiazem was studied in multidrug resistant A2780/DX3 and their sensitive counterpart A2780 cells. MTT, cytofluorimetry assays, and fluorescence microscopy analyses were used to define activity and accumulation of doxorubicin with or without the diltiazem-like modulators. Of the 22 molecules, 1a, 2f, 2g, and 2m were able to overcome the established criteria for the selection in A2780/DX3 cells (IC(50) reduction > or = 25%), but only 2f, 2g, and 2m caused a significant increase of intracellular accumulation of doxorubicin. In conclusion, experiments lead to the identification of three diltiazem-like molecules able to increase the intracellular accumulation of doxorubicin by inhibiting the MDR1 function, thus potentiating its antiproliferative activity in multidrug resistant A2780/DX3 cells.