Protox inhibitors

Figure 2. A Agrophore model derived from 318 Protox inhibitors.

Figure 3. Statistics derived from a comparative molecular similarity indices analysis (CoMSIA) [26] for the agrophore model shown in Figure 2A. The graph depicts the predictive power of a leave-one-out cross-validation procedure for 318 Protox inhibitors (SDEP = standard errorof prediction).

Figure 4. Sterically favorable volume derived from a 3-D QSAR study for Protox inhibitors. Molecules totally enclosed by the volume are, with respect to this particular property, more active (left) than derivatives with protruding residues (right).

A reasonable result is shown for the BASF Protox inhibitor BPI (Figure 7). In this solution, the acid function of INH is mimicked by the nitrogen atom of the benzothiazole moiety of BPI forming the crucial hydrogen bond to arginine. This facilitates a good match for the trifluoromethyl-pyrazol of INH and the trifluoromethyl-pyrimidinedione of BPI. 

Fig. 3.2. Chemical structures of three early examples of Protox inhibitors.

Another breakthrough discovery was the boost in biological activity caused by the replacement of chlorine by fluorine at the 2-phenyl position. In 1976, DuPont introduced the first example of a 2-fluoro-4-chlorophenyl tetrahydrophthalimide Protox inhibitor (11) [44] (Fig. 3.4). The dramatic increase in biological activity caused by the fluorine in the 2 position of the phenyl ring would, in the next decade, the 1980s, influence work in the Protox area, such as the discovery of the 4-chloro-2-fluorophenyltetrahydrophthalimide herbicide S-23142 (12) [45]. 

A class of Protox inhibitors that redefined the accepted SARs and QSARs of the aromatic 4 position was the substituted benzyloxyphenyl heteroaryl area. As discussed earlier, SAR and QSAR studies of the phenyl ring of Protox herbicides demonstrated the need for halogens in the 2- and 4 positions of the phenyl ring, with the exception of the 4-chlorobenzyloxy group such as that of 4-chlorobenzyloxyphenyl tetrahydrophthalimide outlier 55 (Fig. 3.15) and reported by Ohta and coworkers in 1980 [79]. Chlorine at the para position of the benzy-loxy was reported to provide optimum biological activity. 

As discussed earlier, extensive studies of the 2, 4, and 5 positions of the phenyl ring of Protox inhibitors revealed very specific electronic, lipophilic, and steric requirements for chemical groups at these positions. Thus, it was rather surprising when it was discovered that it was possible to obtain highly active molecules by linking the 4 and 5 or the 5 and 6 positions of the phenyl ring to yield a wide variety of benzoheterocycles, such as those in Figs. 3.16 and 3.17. 

Fig. 3.16. Benzoheterocycles resulting from linking aromatic positions 4 and 5 of phenyl heterocyclic Protox inhibitors.

In terms of recent patent activity related to Protox inhibitors, a series of N-substituted phenyl isothiazolone Protox herbicides were prepared to investigate the potential of the isothiazolone heterocycle ring to act as a bioisostere for comparable tetrahydrophthalimides such as compound 80 [93] (Fig. 3.21). The 2-(4-chloro-3-isopropoxycarbonyl)phenyl isothiazole-1,1-dioxide 83 was the most active... 

Fig. 3.20. Protox inhibitor 4-bromo-3-(5-carboxy-4-chloro-2-fluorophenyl)-l-methyl-5-trifluoromethylpyrazole (79) used in protoporphyrinogen IX oxidase binding studies.

Fig. 3.22. Phenyl pyrazole and phenyl pyrrole Protox inhibitors.

Fig. 3.25. Chemical structure of a 2-fluoro-4-chloro-5-alkoxy phenyl imidazolidine triketone Protox inhibitor.

Isagro Ricerca claimed good pre-emergence and post-emergence weed control at rates as low as 15 g-a.i. ha for several Protox inhibitors with a wide variety of groups in the 5 aromatic position of 2,4-dihalo-5-substituted uracils, such as... 

Fig. 3.28. Protox inhibitors with diverse groups at the aromatic meta position (see text for details).

Bencarbazone (114) [115] is a recent Protox inhibitor triazolinone herbicide from Arvesta for the post-emergence control of broadleaf weeds in cereals and com. It provides good control of bedstraw, velvetleaf, redroot pigweed, common lambsquarter, and speedwell at rates of appUcation of20-30 g-a.i. ha . Bencarba-... 

In addition to Protox herbicide activity reported in the patent literature, there is continued interest in understanding the structure-activity relationships of Protox inhibitors [118-120]. Research efforts continue to be devoted to the development of Protox inhibitor-resistant crops [121]. In 1999, Syngenta announced its discovery of a novel gene technology, under the trademark Acuron, that provides crops with tolerance to Protox inhibitors. 

When pyrazolynate (pyrazolate) (6, Fig. 4.4.3) was launched in 1980 by Sankyo Co., Ltd in Japan the world s first HPPD compound entered the herbicide market even though at that time the target site was unknown. Two years earlier, Sankyo had presented its activity on this area at the Fourth International Congress of Pesticide Chemistry in Zurich, Switzerland [2] but had already patented the main compounds in 1974 [3]. Interestingly, this all happened without the knowledge of the precise mode of action. Pyrazolynate and two analogues were previously classified as Protox inhibitors [4]. Pyrazolynate is not new and modern but it is included in this review as it is relatively unknown outside of Japan. 

Fig. 34.2. Superposition of a pyridinedione-type Protox inhibitor on a calculated protoporphyrinogen-like template (cyan). For clarity, the corresponding ring systems are indicated and hydrogen atoms are omitted. Atoms are color coded as carbon, greyj nitrogen, blue oxygen, red sulfur, yellow and chlorine, green.

Fig. 34.3. Common interaction pattern of potent Protox inhibitors from uracil- (left) and pyridine-type. Each molecule consists of two ring systems and electron-rich functions on both sides of the linked rings (blue and red).

Fig. 34.4. Pharmacophore model of 318 Protox inhibitors (color code as indicated in Fig. 34.2).

Fig. 34.6. Contour map derived by a 3D-QSAR study. Clouds indicate favorable space to be occupied by potent Protox inhibitors. While the highly active imidazolinone derivative (left) fits almost perfectly, the ethylcarboxylate residue of the weaker ligand protrudes from the preferred region (right).

Studies of the structure-activity relationship (SAR) of uracile derivatives as protox inhibitor showed that presence of a polyfluorinated alkyl group at position 6 of the uracil ring critical. Alkyl groups such as methyl at position 6 of the uracil ring resulted in compounds with low or no biological activity [263]. 

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