3.3 Molecular modelling

Fig. 1. shows the superimposition of optimized OA and (R)-OA structure generated from X-Ray data, this confirms that CAChe™ system is accurate and promising in predicting OA-like compounds. This X-ray data and that of chlordimeform were utilized as the starting point for building the new structures of target molecules. At first, the geometries of the energy-minimized molecules were checked using the CAChe 3D visualization tools and then reoriented to compare the superimposition of side-chain nitrogen atom and the -atom of phenyl group in each structure (ref. Fig. 1): as these features have been postulated to be important for OA activity [20-22]. Some work in this field can be found in our recent report [23].

Fig. 1. Superimposed X-Ray crystallographic and computer-generated structure of OA*.
OA-Xray picture

*The dimmed structure is energy-optimized from CAChe¬ with MM2 and PM3 force fields. The highlighted one is generated from the X-ray coordinates of (R)-OA hydrochloride. Hydrogens are omitted for clarity.

SBOs and their thiazoline derivatives SBTs possess a phenyl group and a side chain which containes two nitrogen atoms. The distance from the side-chain nitrogen atom to the oxygen in p-OH at phenyl group of OA(Fig.1) was calculated and compared with the corresponding distance between the heterocyclic nitrogen atom to the substituent of phenyl group in SBOs and SBTs. An example of the oxazoline 29 and its thiazoline derivative CIT was built, energy-minimized, and reoriented to give a structure, in which the phenyl and oxazoline or thiazoline rings are held in a nonplanar conformation by an amino nitrogen bridge[24] and could be superimposed with OA at low energy cost (Fig. 2, Table 5). When the nitrogen atoms of OA and oxazoline ring of 29, and oxygen atom of p-OH in OA and m-Cl of 29 are overlaid, the formamidine group of 29 can occupy space similar to the ethylamine group of OA: 29 possesses a similar nitrogen-to-chlorine distance (7.25 ┼, Fig. 3a) to nitrogen-to-oxygen (7.75 ┼, Fig. 3b) of OA. In addition, 29 (Fig. 3a) and OA (Fig. 3b) showed a similar electrostatic potential compared to CIT (Fig. 3c)(ref. to electrostatic potential part for details).

Fig. 2. Superimposed computer-generated fitting structure of a) OA and 29 and b) OA and CIT (Hydrogens are omitted for clarity)



Superimposition of energy-minimized OA and 29 revealed structural and conformational similarities that might account for the high activity of 29. Energy-minimized CIT is not superimposed well with OA (Fig. 2b, Table 5): the nitrogen-to-chlorine distance is 5.41 ┼ (Fig. 3c), apparently different from the distance nitrogen-to-oxygen (7.75 ┼, Fig. 3b) of OA. It's noteworthy that oxazoline and thiazoline's five-membered hetero rings overlay with the side chain of OA in completely different direction: the oxygen of oxazoline 29 is in the same side where the hydroxyl group exits, while the sulfer atom in thiazoline CIT is shown to be at the opposite zone.

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