Steric fit evaluation

Molecular orbital calculations were introduced to estimate the active conformations of azole compounds at an enzyme active site. The computed data were discussed referring to the spectroscopic information and utilized for the steric fit evaluation. 

The steric fit evaluation between the low energy conformers of (I) and that of lanosterol was carried out in such a way that the N4 and C14 methyl carbon atoms locate in close proximity. In the case of (II), the C19 methyl carbon of (-)-kaur-16-ene was used for the evaluation. Based on these results, the conformers of (I) and (II) which well overlapped with the natural substrates were selected. 

The Z-isomer (III) is much less fungitoxic than (I) (J 5 ). The steric fit evaluation between (I) and (III) by computer graphics indicates the similarity of three-dimensional structure, as shown in Figure 10. The tert-butyl moiety of (III) occupies the space where the 1, 2,4-triazo1y1 moiety of (I) locates. It is interesting to compare these results with those of the binding assay. The co-ordination of the tert-butyl group to Fe atom of porphyrin moiety of cytochrome... 

Based on these results, the proposed mode of action of uniconazole (ES pure) is illustrated as an example in Figure 11. Although each of the methods used in this study is already known, the combined application of these methods enables to reduce the number of conceivable active conformations and hence the steric fit evaluation can be performed with high accuracy. The remaining problem is how the azole compounds interact with the non-active sites of enzymes. This is surely related to the difference of biological activity between the optical isomers. 

Figure 10 Steric fit evaluation by computer graphics between (I) (---) and its Z-isomer (III) (----).

Thiazoles readily undergo AT-alkylation by alkyl halides or tosylates (Menshutkin reaction). The sensitivity of this SN2 quaternization reaction to the molecular environment of the nitrogen atom has been used to evaluate, in a quantitative way, steric and electronic effects of ring substituents. The electronic effect of alkyl substituents (unperturbed by any steric effect) may be evaluated from the rate constants for the reaction of 5-alkylthiazoles with methyl iodide (in nitrobenzene at 30 °C) Table 19 shows that introducing a methyl group at the 5-position corresponds to an acceleration of the rate by a factor of 2 but that each addition of a methyl ramification to the 5-alkyl group enhances the rate only by a factor of 1.1. The data in Table 19 fit well with a Hammett-Taft equation (3) ... 

Several recent papers deal with the restricted C—N rotations in monosubstituted, NN -disubstituted, and NNN -trisubstituted thioureas, together with the conformational aspects involved. N-Alkyl-thioureas were found to exist both in the cis- and the trans-form, but N-arylthioureas appeared to exist solely in the intramolecularly hydrogen-bonded form (363). A similar form (364) was found to be predominant in l-alkyl-3-aryl- and 1,3-diaryl-thioureas, whereas both of the isomers (365) and (366), but not the sterically unfavourable form (367), were detectable in the case of l,3-dialkylthioureas. Reeves and his coworkers, by means of a total n.m.r, line-shape fitting, have evaluated the... 

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