Structure Optimisation

In collaboration with Hoechst, Anke and Steglich had initially in mind to develop a strobUurin derivative as an antimycotic for application in humans. Since the activity observed in assay systems was however far below standard antimycotics in the market, the project was dropped, and the corresponding patents were later abandoned. While operating a crop protection business, Hoechst had not noticed the fungicidal potential of this novel structural dass. In 1982 however, Zeneca (at that time stiU part of ICI, now Syngenta) started to work on oude-mansin. 

In 1977, Steglich had already begun with structural variations to improve the fungicidal activity of strobUurin A, though the resulting series of compounds turned out to be even inferior when tested against Penicillium notatum (Fig. 8.17). 

Nevertheless, some interesting structure-activity relationship could be derived from this series The first compound came from an incorrect structure elucidation of the natural product, which was initially believed to possess the ( )-con-figuration at the 9-position. It seemed therefore logical to simplify the structure and prepare (9 )-norstrobUurin A. For the second and third compound, the double bonds were then stepwise cut back. Compound four provided information on the impact of the stereochemistry of the double bond in the acrylate system. The fifth one showed that substituents on the aromatic ring are permitted, and the sixth that carbon atoms in the acrylate moiety may be replaced by heteroatoms. 

While searching for new active compounds, it is necessary to achieve a reasonable affinity for the target enzyme, but this is by no means a sufficient requirement. Of crucial importance are also resorption and transport within the plant, metabolism, and elimination ofthe parent compound and its metabolites, as well as the environmental impact of the plant protection agent. Such a data 

The analysis of structure-activity relationships needs to take into account the following properties in particular  

---

These catalysts were first tested as resin-bound derivatives via HTS, first with metals and then without. Three libraries of chiral molecules, based on three different enantiomerically pure diamines, bulky salicylidene moities and optically active ii-amino acids were used for structure optimisation (Scheme 37 TBSCN = fBuMe2SiCN) [152]. 

V.P. Zhukov, V.E. Mizonov, et al., Mathematical modelling and structural optimisation of complex milling circuits, Theor. Found. Chem. Eng. 32 (1998) 288-293 (Russian). 

Figure 24 The structure of thymine used for 170 NMR calculations, cut from the experimental structure. Since the positions of hydrogen bonds were not reported in the literature, [ref. 101] the partial structural optimisations were carried out by the ONIOM method. This figure was kindly provided by Prof. Nakajima.27...

From the foregoing it can be seen that the cathode is once again the more difficult electrode structure. Optimisation is proceeding, in parallel with initial operating experience. 

Fig. 6. Schematic of the optimum NO adsorption geometry on NiO(lOO) determined from PhD [65,66]. The geometrical parameters varied during the structural optimisation are displayed. For the adsorbate, the darker shaded circle is nitrogen, and the lighter oxygen.

J. Butter, H. P. Luthi, and M. Parrinello (1994) Electronic Structure Optimisation in Plane-Wave-Based Density Functional Calculations by Direct Inversion in the Iterative Subspace. Comput. Mat. Sci. 2, p. 244... 

Ab initio calculations have been performed on the 1,4-dihydropyridazine nucleus which indicate considerable enamine character for this system <83JHC855>, and MO calculations have been carried out for different geometries of 1,2-dihydropyridazine at the 6-3IG level using structures optimised at the 4-31G level <89JST(60)17>. 

More efficient is a generic tree representation of the separations based on tasks. The sequencing can be formulated as a structural optimisation problem where standard techniques based on Mixed Integer Linear Programming (MILP) apply. The tasks consist of simple distillation columns, as well as of hybrids for complex column arrangements, modelled by appropriate shortcut or semi-rigorous methods. Details can be found in Doherty and Malone (2001). 

Therefore, in the first place the process synthesis should solve a structural problem, the configuration of the optimal reactor system. Then detailed design and refinement can follow. If there are several candidates close to optimum, these could be assembled in a superstructure and submitted to structural optimisation. 

Taylor M B, G D Barrera, N L Allan, T H K Barron and W C Mackrodt 1998. Shell A Code for Lattice Dynarmcs and Structure Optimisation of Ionic Crystals. Computer Physics Communications 109 135-143. 

The antifungal nitropyrrole antibiotic pyrrolomyoin shows weak activity and hl toxicity, A pTOgram of synthesis/structure optimisation has led to a related tetrazole, 011-146 (2.) which has been selected for development as a topical antlmyootio,50 The compound is active topically but not systemically in animal models and also has gram-posltive/negative antibacterial properties. 

B3LYP/6-311G(d,p) is chosen in the present work because it has a somewhat larger basis set than the commonly used B3LYP/6-31G(d,p) and it is still accurate for structure optimisation and force constant calculation on the molecules considered in this study. 

The problems of code calibration and structural optimisation are analogous in this sense. If one optimises only part of a design then that does not guarantee an overall optimum. If one calibrates a new code of practice on the basis of only part of the uncertainty, then that does not guarantee equivalent safety. 

Whereas carboxypeptidase A cuts off only one amino acid from the C-termi-nal end, ACE splits off two amino acids. Consequently, Cushman and Ondetti concluded, that a succinoylated amino acid ought to be a good inhibitor for ACE. They selected proline as the proper amino acid, because it forms the C-ter-minus in BPPja. And indeed, N-succinoylproline possesses some weak activity, and served as a starting point for further structure optimisation. 

The Austrian pharmacologist Heribert Konzett (1912-2004) had discovered in 1940 isoprenaUne, which should become the prototype of p-selective sympathomimetics. Due to its bronchodilatory properties, but without causing hyper-tention, it was considered the drug of choice to treat asthmatic attacks. With almost equally strong effect on pj- and p2-receptors, it was of concern, that isoprenaline acts as a very potent cardiac stimulant. Further structural optimisation then led to more selective pj-sympathomimetics, like dobutamine, for the treatment of heart failure and cardiogenic shock, while selective p2-sympathomimetics were aimed at safer therapies of bronchial asthma. 

The one compound results from a systematic development programme, the other is a serendipitous discovery without any structure optimisation. The spectrum of modern plant protection research cannot be broader. 

---