A perspective on the role of quantitative structure-activity and structure-property relationships in herbicide discovery

BACKGROUND: For the last 15 years the agrochemical industry has focused on using genetic modification to put genes that confer resistance to existing commercial herbicides into crop plants rather than on discovering new herbicides with novel modes of action. The widespread appearance of weeds resistant to those herbicides is now causing the industry to revive their herbicide discovery programs. RESULTS: Elucidation of quantitative structure–activity relationships (QSARs) played a major role in the discovery and development of existing commercial herbicides, but the advent of genetically modified crops has caused published work (at least) in the area to drift from the industrial arena into academic studies. The focus has also turned inward, to refining models for established herbicide targets instead of elucidating new ones. CONCLUSION: This perspective highlights the importance of QSARs and quantitative structure–property relationships (QSPRs) to herbicide discovery in an historical context and provides some guidance as to how they might profitably be applied going forward. Copyright © 2011 Society of Chemical Industry     

Structure-activity relationships of triazinone herbicides on resistant weeds and resistant Chlamydomonas reinhardtii

Weeds resistant to the s-triazine herbicide atrazine also show resistance to the triazinone herbicide metribuzin. However, with highly lipophilic triazinones, thylakoids isolated from atrazine-resistant Amaranthus retroflexus (mutation at position Ser₂₆₄ of the photosystem II D-1 reaction centre protein) in general show a higher pI₅₀ value in photosystem II electron transport than those from the wild type (i.e. negative cross-resistance; ‘supersensitivity’). A quantitative structure–activity relationship (QSAR) can be established, wherein the lipophilicity of the compound plays a major role. In in-vivo experiments, it was found that the triazinone DRW2698 killed resistant Amaranthus retroflexus and Chenopodium album whereas the wild type was almost unaffected. Triazinones were further investigated in five different mutants of Chlamydomonas rheinhardtii (mutations in the D-1 protein at positions Ser₂₆₄, Ala₂₅₁, Leu₂₇₅, Phe₂₅₅, and Val²¹⁹). Inhibitory activity of all triazinones was generally enhanced in the Phe₂₅₅ mutant but decreased in the Val₂₁₉ mutant. In the other mutants, biological activity was decreased when position 3 of the triazinone was substituted by CH₃, OCH₃, SCH₃, NHCH₃ or N(CH₃)₂. However, negative cross-resistance was again observed when this position was occupied by free thiol. It is therefore suggested that these two groups of triazinones orient themselves differently within the herbicide binding niche of the photosystem II D-1 protein.     

Insecticide resistance in cotton aphid Aphis gossypii (Glov.) in the Sudan Gezira

The resistance to insecticides of three Sudanese strains of A. gossypii (Glov.) collected from cotton fields in the Sudan Gezira Scheme over three seasons (1988, 1989, 1990) and that of two French strains was studied in the laboratory. When compared with a known susceptible strain, the aphids were found to be resistant-to the eight insecticides tested. Evolution of resistance in Sudanese strains during the three crop seasons was observed. Assay of aphid homogcnate for carboxytesterase activity towards the substrates α-naphthyl acetate and β-naphthyl acetate showed that there was no enhancement of this class of enzyme and thus it was not a cause of resistance in this species. A study of interaction between the acetylcholinesterase (AchE) and pirimicarb established the kinetics of the inhibition process. I₅₀ values were found to be much higher for the Sudanese strains than for the susceptible strain. First-order inhibition kinetics revealed that resistance towards pirimicarb in Sudanese-strains was caused by a modified AchE which had a reduced affinity (higher K_a value) and poor carbamylation ability (lower K₂ value) for pirimicarb. The resistance mechanisms for the other insecticides remain to be studied.     

Glutathione transferase activities toward herbicides used selectively in soybean

Using extracts from suspension-cultured cells of soybean (Glycine max cv. Mandarin) as a source of active enzymes, the activities of glutathione transferases (GSTs) catalysing the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) and selective herbicides were determined to be in the order CDNB≫ fomesafen>metolachlor=acifluorfen>chlorimuron-ethyl. GST activities showed a thiol dependence in a substrate-specific manner. Thus, GST activities toward acifluorfen and fomesafen were greater when homoglutathione (hGSH), the endogenously occurring thiol in soybean, was used as the co-substrate rather than glutathione (GSH). Compared with GSH, hGSH addition either reduced or had no effect on GST activities toward other substrates. In the absence of enzyme, the rates of hGSH conjugation with acifluorfen, chlorimuron-ethyl and fomesafen were negligible, suggesting that rapid hGSH conjugation in soybean must be catalysed by GSTs. GST activities were subsequently determined in 14-day-old plants of soybean and a number of annual grass and broadleaf weeds. GST activities of the plants were then related to observed sensitivities to post-emergence applications of the four herbicides. When enzyme activity was expressed on a mg^-1 protein basis, all grass weeds and Abutilon theophrasticontained considerably higher GST activity toward CDNB than soybean. With fomesafen as the substrate, GST activities were determined to be in the order soybean≫Echinochloa crus-galli>Digitaria sanguinalis>Sorghum halepense=Setaria faberi with none of the broadleaf weeds showing any activity. This order related well to the observed selectivity of fomesafen, with the exception of A. theophrasti, which was partially tolerant to the herbicide. Using metolachlor as the substrate the order of the GST activities was soybean>A. theophrasti≫S. halepense>Amaranthus retroflexus>Ipomoea hederacea, with the remaining species showing no activity. GST activities toward metolachlor correlated well with the selectivity of the herbicide toward the broadleaf weeds but not toward the grass weeds. Acifluorfen and chlorimuron-ethyl were selectively active on these species, but GST activities toward these herbicides could not be detected in crude extracts from whole plants. © 1997 SCI     

Environmental fate of mineral,vegetable and transesterified vegetable oils

Vegetable oils, synthetic esters (including transesterified oils) and mineral oils are the main classes of oil used in pesticide formulations. Biodegradation is a major route for the removal of oils from soil systems. Most of the oils used in pesticide formulations are degraded substantially in the laboratory tests that are used to assess aquatic biodegradability. The susceptibility of different oils to biodegradation can be explained in terms of the metabolic capacity of common microorganisms. Fewer soil biodegradability tests have been carried out with oils, but the available data suggest that the mode of degradation is not very different from that in aquatic systems. Supplements of inorganic nutrients (in particular nitrogen) are needed to stimulate microbial activity in soils containing the high concentrations of oil that can be encountered in the event of a spill. However, oils are applied at such low rates in pesticide form illations (maximum of 5g oil m^? soil) that nutrient availability is unlikely to affect the rate of biodegradation in the field.     

Does sand content in spawning substrate result in early larval emergence? Evidence from a lithophilic cyprinid fish

The spawning success of lithophilic salmonids is strongly influenced by the fine sediment content (“fines”) of spawning substrates, yet knowledge on the impacts of fines on the spawning of non‐salmonid lithophiles remains limited, despite their ecological and socio‐economic importance in European rivers. Consequently, the aim here was to use an ex‐situ experiment to investigate the impact of sand content on egg survival and timing of larval emergence of the surface‐spawning cyprinid European barbel Barbus barbus. Thirty incubator boxes within a recirculating system were filled with one of five experimental sediment mixtures (0%–40% sand by mass) that each contained 300 fertilised eggs at a depth of 50 mm. Emerged, free‐swimming larvae were captured and counted daily to assess grain‐size effects on larval survival and emergence. Specifically, total proportion of emerged larvae, cumulative daily proportion of emerged larvae and time required to reach 50% emergence were measured during the study. Whilst the proportion of sand in the sediments did not have a significant impact on egg‐to‐emergence survival (mean survival per treatment 75%–79%), it significantly affected the timing of larval emergence to the water column; early emergence was detected in treatments with elevated sand content (on average, 50% emergence after 12–13 days versus 19 days in the control). Similar to findings from salmonid studies, these results suggest high sand content in spawning gravels can influence timing of larval emergence and potentially cyprinid lithophilic fish survival.     

The effect of introgressions of wheat D-genome chromosomes into 'Presto' triticale

Hexaploid triticale (X Triticosecale Wittmack) (2n= 6x= 42, AABBRR) and wheat (Triticum aestivum L.) (2n= 6x= 42, AABBDD) differ in their R and D-genomes. This produces differences in both agronomic and end-use quality characteristics. Our objective was to determine how introgressions of individual chromosomes from the D-genome of wheat affect these characteristics of a winter triticale 'Presto'. We studied the effects of 18 D-genome chromosome substitution lines, 15 sib-lines as controls, and five check cultivars at Lincoln, NE in 1996, using a randomized complete block design with two replications. The experiment was repeated at Lincoln and Mead, NE in 1997 and 1998 with 15 substitution lines that survived the first winter in Lincoln, along with their 12 control sibs and five check cultivars. Few D-genome chromosomes had positive effects. Chromosomes 2D, 4D, and 6D significantly reduced plant height when substituted for 2R, 4B, and 6R, respectively. No grain yield increases were associated with any of the D-genome chromosomes tested, but three substitutions decreased the grain yield. Depending on the allele of the hardness gene present, chromosome 5D increased or decreased kernel hardness when substituted for 5R or 5A, respectively. Introgressions of chromosomes 1D and 6D improved end-use quality characteristics of Presto. These results suggest that apart from beneficial effects of individual loci located on the D-genome chromosomes, no major benefit can be expected from D-genome chromosome substitutions.