CoMFA and CoMSIA Analysis

The results of CoMFA and CoMSIA analysis are summarized in Table 7.1. The CoMFA PLS analysis yielded a high cross-validated correlation coeflftcient (f of 0.872 with standard error of prediction SEP of 0.383. The non-cross-validated PLS analysis gave a conventional of 0.974 with SE of 0.172. These values indicated a good statistical correlation and reasonable predictability of the CoMFA model. 

The steric field descriptors explained 42.7 % of the variance, while the electrostatic descriptors explained 57.3 %. 

The CoMSIA analysis using steric, electrostatic, and lipophilic fields as descriptors gave a model with (f of 0.873 and of 0.954. The CoMSIA steric, electrostatic, and lipophilic fields explained the variance of 8.8, 40.9 and 50.2 %, respectively. This indicated that the hydrophobic interaction was a major factor to explain the field properties of the alkylphosphonates lo. Further attempts to combine the hydrogen bond fields with the standard steric, electrostatic, and lipophilic fields did not lead to any significant improvement = 0.869, = 0.952). Indeed, 

The steric contribution contour maps of CoMFA and CoMSIA are plotted in Figs. 7 2a and 7.3a, respectively. To aid visualization, the most herbicidally active compound IH-18 is displayed in the maps. The CoMSIA approach provided more contiguous contour diagrams, which allowed physicochemical properties relevant 

3- methyl. Therefore the 2-position and 4-position are the most essential sites for substitution, and compounds even with the disfavorable electropositive methyl group at the 2-position stiU have higher activity, which suggests the contribution of the steric effect of the 2-position substituent for enhancing herbicidal activity is more significant than that of the electronic effect. 

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On the basis of CoMFA and CoMSIA analysis, three conformation-ally restricted selective D3 ligands were successfully constructed and synthesized. One of them is rfs-7H,9flH-7- 2-(2-benzo[fc]thienyl)carbo-nylamino]ethyl -2-(2,3-dichlorophenyl)perhydropyrido[l,2-fl]pyrazine (06BMC5898). 

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