A theoretical density functional theory (DFT, B3LYP) investigation has been carried out on the catalytic cycle of the carbonic anhydrase. A model system including the Glu106 and Thr199 residues and the "deep" water molecule has been used. It has been found that the nucleophilic attack of the zinc-bound OH on the CO2 molecule has a negligible barrier (only 1.2 kcal mol -1 ). This small value is due to a hydrogenbond network involving Glu106, Thr199, and the deep water molecule. The two usually proposed mechanisms for the internal bicarbonate rearrangement have been carefully examined. In the presence of the two Glu106 and Thr199 residues, the direct proton transfer (Lipscomb mechanism) is a two-step process, which proceeds via a proton relay network characterized by two activation barriers of 4.4 and 9.0 kcal mol -1 . This pathway can effectively compete with a rotational mechanism (Lindskog mechanism), which has a barrier of 13.2 kcal mol -1 . The fast proton transfer found here is basically due to the effect of the Glu106 residue, which stabilizes an intermediate situation where the Glu106 fragment is protonated. In the absence of Glu106, the barrier for the proton transfer is much larger (32.3 kcal mol -1 ) and the Lindskog mechanism becomes favored.

As an extension of previous investigations (Tetrahedron 1999, 55, 5433-5440; J. Heterocycl. Chem. 2000, 37, 875-878), a series of 21 [1,4]thiazino[3,4-c][1,2,4]oxadiazolones, which has already been synthesized (except for compounds 5a, 5b, 6), was evaluated as calcium entry blockers by functional studies, namely, in isolated guinea-pig left and right atria and K(+)-depolarized aortic strips. With the aim of investigating the effect of a condensed benzene ring on the molecular structure and the influence of substituents on the 8-phenyl ring of 4a, ab initio computations (RHF/3-21G) were performed on compounds 3, 4a-d, 4f, and 4k. The results obtained show that many of the compounds studied are potent and selective negative inotropic agents; in particular, compounds 4e and 4f are about 3- and 2-fold more potent than diltiazem, respectively.

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.

A combined kinetic and theoretical study of the monocyclic rearrangements of heterocycles (MRH) has been carried out. The interconversion of the Z-hydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole into the corresponding triazole has been experimentally investigated in dioxane/water in the pS + range 5.55−13.9. The uncatalyzed region has been examined at the DFT level using a model system formed by the Z-hydrazone of 3-formyl-1,2,4-oxadiazole and one or two water molecules. The environmental effect of the solvent has been emulated using a continuum model (COSMO) approach. The kinetic data suggest a concerted process where the magnitude of the activation barrier is determined by the interplay of two opposite factors, that is, the nucleophilicity of the nitrogen atom and the acidity of the nitrogen-bonded protons. The computations indicate the existence of two multistep reaction pathways. When the solvent environment is taken into account, the preferred path, which involves two water molecules acting as a base, becomes a concerted highly asynchronous path, where the nucleophilic attack and the proton transfer occur not simultaneously but in the same kinetic step.