Tough Road to Agrochemicals

Many pitfalls lie on the path from a lead compound to a commercial product. At the American Chemical Society national meeting in Philadelphia last month, chemists from a number of agrochemical companies discussed some of the reasons that promising pesticide candidates fail to reach the marketplace.

"It is currently very difficult to predict which among a number of agrochemical leads is going to eventually lead to a successful project," said George Theodoridis, a director of pipeline development at FMC Corp. He noted that, of the hundreds of thousands of compounds screened by agrochemical companies each year, only a small percentage make it to greenhouse tests. Of those, only a handful are deemed promising enough to be tested in the field. Fewer still pass the grueling battery of toxicological and environmental tests that follow.

"A good deal of valuable scientific information and lessons can be derived from open discussion of projects that never made it to the marketplace," said John W. Lyga, a research fellow at FMC. So Lyga and Theodoridis organized a pair of symposia at the ACS meeting: "Translation of Pesticidal Activity from Lab to Greenhouse to Field" and "Synthesis of Agrochemicals: Good Ideas that Never Made It to Products," both sponsored by the Division of Agrochemicals. "We thought it would be a good idea to provide a forum where the driving force for discussion was something other than commercial success," Theodoridis noted.

Many agrochemical leads fail because they can't stand up to bright sunlight. And when their structures are modified to deal with that problem, the change can lead to other problems. For example, Scott D. Crawford described how he and his colleagues at FMC attempted to improve the photostability of a promising lead compound identified from screening the company's corporate library for molecules that kill cotton aphids. However, the compound, an N-substituted benzimidazole, was not only unstable in light but also toxic to aquatic life. By modifying the substituent on nitrogen, they enhanced photostability and reduced toxicity. But the resulting optimized lead, an N-aminobenzimidazole, wasn't potent enough against cotton aphids to continue the project, Crawford reported.

Sometimes, agrochemical candidates that show excellent activity in the lab don't retain that activity when they reach the greenhouse. Along these lines, Patrick J. Crowley of Syngenta described his company's efforts to turn a novel natural product into a commercial fungicide. Produced by a type of bacteria, crocacins A and D kill fungi that are pathogenic to plants by blocking the electron-transport chain the fungi rely on to produce energy.

The crocacin structure features multiple double bonds, which make the molecules vulnerable to light and air, and several tough-to-synthesize chiral centers. Aiming to improve stability and simplify synthesis, Crowley's team set about replacing the double bonds and removing the chiral centers. Structure-activity relationship studies showed that the Z-enamide moiety is crucial to activity but that the rest of the molecule could be replaced with an easy-to-make benzylphenyl group. Sadly, none of the derivatives Crowley's team prepared showed sufficient greenhouse activity to graduate to field tests.

Crowley attributed the failure at least in part to the assay used to assess these compounds' fungicidal activity. Because little is known about the electron-transport enzymes in fungi, his team assessed compounds' ability to inhibit the corresponding cow enzymes, which have been well studied and are easily isolated. That's a widely used tactic in agrochemical screening, he pointed out, but it's not necessarily a reliable one.

A COMPOUND might also be discarded simply because it cannot be produced cheaply enough. Such was the story for S-3085, an iminothiazoline cotton herbicide discovered by Yuzuru Sanemitsu of Japan's Sumitomo Chemical. The iminothiazolines kill weeds by blocking the biosynthesis of carotenoid pigments that the weeds require for photosynthesis. Unfortunately, in greenhouse tests Sanemitsu's team found that the amount of herbicide required to kill all weeds was enough to injure the cotton, too. But the nail in the herbicide's coffin was its cost. Installing a difluoroacetyl group proved particularly problematic. Even when Sumitomo managed to come up with an efficient method to do so, the overall cost remained too high for commercialization, Sanemitso reported.

Potential agrochemicals never make it to market for a host of other reasons. Some tend to be transformed into inactive forms by insects or plants. Others are simply not taken up by the target organisms. But problems like these are not always the kiss of death. In a departure from the theme of unsuccessful candidates, Thomas P. Selby described how he and his colleagues at DuPont overcame a number of hurdles--including poor photostability--to develop a commercial agrochemical. DuPont is in the last stages of developing proquinazid, an extremely potent agent against powdery mildew. Powdery mildew is a fungus that affects cereals, grapes, and a variety of vegetables. Because resistance to current agents is a growing problem, products with unique modes of action are of great interest. Like a handful of other commercial fungicides, proquinazid prevents the fungus from penetrating the leaf surface of plants. But proquinazid prevents penetration via a different mechanism, Selby said.

Selby chronicled how proquinazid evolved from a series of promising pyridopyrimidinone lead compounds. Although a number of highly active halogenated pyridopyrimidinones passed greenhouse tests with flying colors, they failed miserably in field tests. Guessing that the failure might be a result of insufficient photostability, Selby's team investigated a closely related but more photostable ring system with a similar pattern of substituents. The best of the compounds they prepared, proquinazid, demonstrated excellent activity both in greenhouse and field tests with cereals, grapes, apples, and squash. Proquinazid is slated to hit the market in 2006.