Cropsolution has discovered greenhouse active fungicides with commercial level of activity and novel mode of action herbicides.  Cropsolution is currently seeking companies interested in commercializing these leads.

Fungicidal Leads
During the screening of pools of intermediates prepared by solution phase combinatorial synthesis, fungicidal activity was detected in one of our microtiter plate fungal assays at around 50µM concentration. Deconvolution of the active pool quickly led to the identification of the fungicidal hit. Since the hit was very amenable to structural modification, an intensive optimization effort was initiated. Nearly 1,000 compounds were subsequently prepared and evaluated.

From this effort, five structurally distinct classes of broad spectrum, fungicidally active compounds have been identified. Activity increases of 10e3-10e4 in several of our fungal plate screens and commercial level activity in planta have been realized.  The activity profiles of representatives from four of the classes in microtiter plate screens are shown in Table 2. Pathogens included in this primary screen were Botrytis cinerea, Phytophthora infestans, and Septoria nodorum. Many of these compounds are especially

Active on S. nodorum, as shown in a dose response evaluation in Plate 3 (µM concentration). The most active compound, CS-M, controls S. nodorum at a three-fold lower dose than commercial fungicide azoxystrobin.

The broadspectrum activity of these compounds was evident from in planta evaluation, as exemplified for compound CS-A in Table 3. Pathogens in these screens included powdery mildew on wheat (ERYSGH, Erysiphe graminis), grey mold (BOTRCI, Botrytis cinerea), glume blotch (LEPTNO, Septoria nodorum), early blight (ALTESCO, Alternaria solani), brown rust (PUCCRT, Puccinia recondita), rice blast (PYRIOR, Pyricularia oryzae), late blight (PHYTIN, Phytophthora infestans), powdery mildew on squash (SPHFFU, Sphaerotheca fuliginea), and leaf blotch (SEPTTR, Septoria tritici).

As a group, compounds from these classes showed excellent broad spectrum control of  diseases in the most important markets: cereals (Septoria nodorum, glume blotch; Erysiphe graminis, powdery mildew; Puccinia recondita, brown rust), fruit and vegetables (Monilinia fructicola, brown rot; Sphaerotheca fuliginea, powdery mildew; Rhizoctonia solani, root and stem rot; Sclerotinia sclerotiorum, soft rot or stem rot) and turf (Sclerotinia homoeocarpa,  dollar spot; Rhizoctonia spp., brown patch ) in vitro and/or in planta. Greenhouse evaluation of these leads confirmed their potent activity on powdery mildew, as shown in Figure 3. Field testing of several of the leading candidates is planned for 2005.

Figure 3. Control of powdery mildew (Erysiphe graminis) on barley in the greenhouse.

The mode of action of these new experimental fungicides is presently unknown, but investigations to date suggest that inhibition of the ergosterol biosynthetic pathway may be involved. Moreover, there appear to be differences between classes. A yeast genetics analysis of our leading candidates indicate that more than one step in the sterol biosynthetic pathway may be affected.

Novel Bleaching Herbicides
A class of compounds with herbicidal activity has been identified based on hits from a 28,800-compound library prepared by solid phase techniques. Chemical deconvolution of a 720-compound pool gave several subpools that contained the herbicidally active compounds (subpools 19 and 21, Plate 1, 10-15 beads per well), as evidenced by the bleached Arabidopsis.

Synthesis of the discrete components of these pools resulted in a number of hits (e.g., CS-D and CS-E, Plate 2) with herbicidal activity as low as 30nM concentration in the Arabidopsis thaliana microtiter plate assay. In addition to growth inhibition, pronounced bleaching symptomology for these hits was noted.

Several of the compounds were further evaluated in greenhouse testing. Compounds CS-D and CS-E both showed moderate herbicidal activity in postemergence application (Figures 1 and 2) at 1 kg/ha. Bleaching symptomology similar to that of norflurazon was
again noted. Results from two different tests are summarized in Table 1. The broadleaf weeds included in these tests were mustard (BRSSP), velvetleaf (ABUTH), ivy leaf morning glory (IPOHE). Grassy weeds included green foxtail (SETVI), giant foxtail (SETFA), wild oats (AVEFA), blackgrass (ALOMY), barnyardgrass (ECHCG), and yellow nutsedge  (CYPES). The postemergence herbicidal activity of these compounds is greater on broadleaf weeds than on grasses. Their preemergence activity is minimal, unlike norflurazon.

From in vitro mode of action investigations, phytoene desaturase (PDS), zeta-carotene desaturase (ZDS), 4-hydroxyphenylpyruvate dioxygensae (HPPD) were excluded as potential sites of action.  These results, coupled with the novel structure of the bleaching herbicides suggest that they may have a new mode of action, and that an optimization program could lead to herbicides with significant commercial potential.