Organic chemistry

Small molecules vs plants!

We're combining higher throughput plated based assays with soil-based assays and using Arabidopsis to find the most effective herbicides with a view to testing on agronomically important weed species.

Herbicide discovery

  • In close collaboration with the Stubbs lab and guidance from AHRI, our lab is discovering chemically new herbicides and exploring new possible modes of action.

    The use of herbicides in agriculture has greatly improved crop yields through better weed management while also reducing labour and associated costs. Due to the powerful activity of these chemical molecules, many different herbicides have been developed and this has coincided with a dramatic rise in use. Consequently many different resistance mechanisms have developed (akin to antibiotic resistance) which means many frontline herbicides have waned in usefulness to the agricultural community.

    Collaboration with BASF

    In 2015 dialogue with BASF led to a new collaboration whereby their agrochemical wing in Ludwigshafen am Rhein tested lead compounds emerging from our revelation that many antimalarial drugs are herbicidal (Corral et al. 2017 Sci. Rep.). The first paper to emerge from this collaboration was published in Angewante Chemie with BASF co-authors on the work (Corral et al. 2017 Ange. Chem. Int. Ed.). The second was published soon after (Corral et al. 2018 Pest Manag. Sci.).

    Like the project below with Bayer, this work is being done in close collaboration with Associate Professor Keith Stubbs, an organic chemist in the School of Molecular Sciences. The first compound to be published, MMV006188, showed post-emergence herbicidal activity similar to commercial herbicides and worked not just against Arabidopsis, but also against some common crop weeds. Its physiological profiling suggested it was a photosystem II inhibitor, representing a new scaffold for herbicide development. A second compound, MMV007978 was active against select monocot and dicot weeds and its physiological profiling indicated its mode of action was related to germination and cell division. Interestingly, its physiological profile is currently not found amongst known herbicides, suggesting it might have a new mode of action.

    Collaboration with Bayer

    In 2016 we started a new collaboration with agrochemical Bayer CropScience with an award from their Grants4Targets scheme for a project entitled "Ripping plant plastid DNA replication in two". This work seeks to explore whether plant gyrase is a viable herbicide target and more information may be read about plant DNA gyrease at this UWA blog and our publication in JBC. The initial outcome of the work has been published (Wallace et al. 2018 ChemComm).

    This project is a collaboration with organic chemists from the Stubbs lab and a world authority on gyrase, Prof. Tony Maxwell of the John Innes Centre in the UK. Gyrase is an essential component of the DNA replication machinery in plants and antibiotics that target gyrase also effective at killing plants. A gyrase inhibitor will need to be plant-specific and not affect the related gyrase enzymes in bacteria. Gyrase represents a potential new mode of action which is important. At the recent Global Herbicide Resistance Challenge conference it was said that "no new herbicide mode of action discoveries had been made" and that there are "no new ones coming in the foreseeable future". This problem coupled with decades of over-reliance on the highly effective glyphosate means there has never been a greater need for new, effective and safe herbicides and new modes of action are a top priority.

    Inspired by antimalarials - DHFR inhibition

    The folate synthetic pathway and its key enzyme dihydrofolate reductase (DHFR) is a popular target for antimalarial drugs, but little is known about plant DHFRs. Using genetic knockout lines we confirmed which of the three DHFR genes were essential and we also screened mutated A. thaliana seeds and discovered genetic resistance to antimalarial DHFR-inhibitor drugs pyrimethamine and cycloguanil. Our findings deepen our understanding of plant DHFR enzymes and hint at how a plant-specific DHFR inhibitor might be developed. This characterisation of plant DHFR-TS enzymes has been published (Corral et al. 2018 Plant Journal).

    Gandy-334 herbicide database

    To guide our own herbicide discovery efforts we developed a database that allows users to visualize, build, interrogate, interpret and present the physicochemical properties of herbicides. It overcomes some limitations associated with similar previous compilations of data which are static resources not readily amenable to interrogation by the reader. Some previous studies like this of herbicide hits, leads and products did not include the actual identity of the herbicidal compounds, making the findings irreproducible.

    Our database, published in Gandy et al. in Organic & Biomolecular Chemistry (2015, 13: 5586-5590) included 334 commercially successful herbicides. The 334 herbicides included are listed below. If you spot any missing compounds, please contact Josh Mylne and we will update the Gandy-334 database.

    The accompanying paper may be accessed via PubMed or its DOI. To download the database directly (4.7 MB, .zip file), click here, or alternatively find it as Supplementary Info at RSC's landing page.

    A textual list of the 334 compound names follows: 2,4,5-T; 2,4-D; 2,4-DB; acetochlor; acifluorfen; aclonifen; acrolein; alachlor; allidochlor; alloxydim; ametryne; amicarbazone; amidosulfuron; aminocyclopyrachlor; aminopyralid; amiprophos-methyl; amitrole; anilofos; asulam; atrazine; azafenidin; azimsulfuron; beflubutamid; benazolin; benazolin-ethyl; benfluralin; benfuresate; bensulfuron-methyl; bensulide; bentazon; benthiocarb; benzfendizone; benzobicyclon; benzofenap; bicyclopyrone; bifenox; bilanaphos; bispyribac; bromacil; bromobutide; bromofenoxim; bromoxynil; butachlor; butafenacil; butamifos; butenachlor ; butralin; butroxydim; butylate; cafenstrole; carbetamide; carfentrazone-ethyl; chlomethoxyfen; chloramben; chlorbromuron; chlorflurenol; chlorimuron-ethyl; chlorotoluron; chloroxuron; chlorphthalim; chlorpropham; chlorsulfuron; chlorthal-dimethyl; chlorthiamid; cinidon-ethyl; cinmethylin; cinosulfuron; clethodim; clodinafop; clodinafop-propargyl; clomazone; clomeprop; clopyralid; cloransulam-methyl; cumyluron; cyanazine; cycloate; cyclosulfamuron; cycloxydim; cyhalofop-butyl; dalapon; dazomet; desmedipham; desmetryne; diallate; dicamba; dichlobenil; dichlorprop; diclofop-methyl; diclosulam; diethatyl-ethyl; difenzoquat; diflufenican; diflufenzopyr; dimefuron; dimepiperate; dimethachlor; dimethametryn; dimethenamid; dimethylarsinic acid; dinitramine; dinoseb; dinoterb; diphenamid; diquat; dithiopyr; diuron; DNOC; DSMA; dymron; endothall; EPTC; esprocarb; ethalfluralin; ethametsulfuron-methyl; ethidimuron; ethiolate; ethofumesate; ethoxyfen-ethyl; ethoxysulfuron; etobenzanid; fenoxaprop; fenoxaprop P-ethyl; fenoxasulfone; fentrazamide; fenuron; flamprop M-isopropyl; flamprop-methyl; flazasulfuron; florasulam; fluazifop; fluazifop-butyl; fluazolate; flucarbazone-sodium; flucetosulfuron; fluchloralin ; flufenacet; flufenpyr-ethyl; flumetsulam; flumiclorac-pentyl; flumioxazin; fluometuron; fluoroglycofen-ethyl; flupoxam; flupropacil; flupropanate; flupyrsulfuron-methyl; fluridone; flurochloridone; fluroxypyr; flurtamone; fluthiacet-methyl; fomesafen; foramsulfuron; fosamine; glufosinate; glyphosate; halosafen; halosulfuron-methyl; haloxyfop-methyl; hexazinone; imazamethabenz-methyl; imazamox; imazapic; imazapyr; imazaquin; imazethapyr; imazosulfuron; indanofan; indaziflam; iodosulfuron; iofensulfuron; ioxynil; ipfencarbazone; isopropalin; isoproturon; isouron; isoxaben; isoxachlortole; isoxaflutole; isoxapyrifop; karbutilate; lactofen; lenacil; linuron; MCPA; MCPA-thioethyl; MCPB; mecoprop; mefenacet; mefluidide; mesosulfuron; mesotrione; metam; metamitron; metazachlor; metazosulfuron; methabenzthiazuron; methazole; methiozolin; methoprotryne; methoxyphenone; methyldymron; metobenzuron; metobromuron; metolachlor; metosulam; metoxuron; metribuzin; metsulfuron-methyl; molinate; monalide; monolinuron; monuron; MSMA; naproanilide; napropamide; naptalam; NC-330; neburon; nicosulfuron; nitrofen; norflurazon; OK-8910; oleic acid; orbencarb; orthosulfamuron; oryzalin; oxadiargyl; oxadiazon; oxasulfuron; oxaziclomefone; oxyfluorfen; paraquat; pebulate; pelargonic acid; pendimethalin; penoxsulam; pentachlorophenol; pentanochlor; pentoxazone; pethoxamid; phenmedipham; picloram; picolinafen; pinoxaden; piperophos; pretilachlor; primisulfuron-methyl; prodiamine; profluazol; profluralin; profoxydim; prometon; prometryne; propachlor; propanil; propaquizafop; propazine; propham; propisochlor; propoxycarbazone-sodium; propyrisulfuron; propyzamide; prosulfocarb; prosulfuron; pyraclonil; pyraflufen-ethyl; pyrasulfotole; pyrazolynate; pyrazon; pyrazosulfuron-ethyl; pyrazoxyfen; pyribenzoxim; pyributicarb; pyridafol; pyridate; pyriftalid; pyriminobac-methyl; pyrimisulfan; pyrithiobac; pyroxasulfone; pyroxsulam; quinclorac; quinmerac; quinoclamine; quizalofop; quizalofop-P-ethyl; quizalofop-P-tefuryl; rimsulfuron; saflufenacil; sethoxydim; siduron; simazine; simetryne; S-metolachlor; sulcotrione; sulfentrazone; sulfometuron-methyl; sulfosate; sulfosulfuron; TCA; TCBA; tebutam; tebuthiuron; tembotrione; tepraloxydim; terbacil; terbucarb; terbumeton; terbuthylazine; terbutryne; thenylchlor; thiazafluron; thiazopyr; thidiazimin; thiencarbazone; thifensulfuron-methyl; tiocarbazil; topramezone; tralkoxydim; triafamone; triallate; triasulfuron; triaziflam; triazofenamide; tribenuron-methyl; triclopyr; trietazine; trifloxysulfuron; trifluralin; triflusulfuron-methyl; tritosulfuron; vernolate.