Improved herbicide discovery using physico-chemical rules refined by antimalarial library screening.

Herbicides have physico-chemical properties not unlike orally-delivered human drugs, but are known to diverge in their limits for proton donors, partition coefficients and molecular weight. To further refine rules specific for herbicides, we exploited the close evolutionary relationship between and plants by screening the entire Malaria Box, a chemical library of novel chemical scaffolds with activity against the blood stage of . Initial screening against on agar media and subsequently on soil demonstrated the crucial nature of log  and formal charge are to active molecules.

Targeting plant DIHYDROFOLATE REDUCTASE with antifolates and mechanisms for genetic resistance.

The folate biosynthetic pathway and its key enzyme dihydrofolate reductase (DHFR) is a popular target for drug development due to its essential role in the synthesis of DNA precursors and some amino acids. Despite its importance, little is known about plant DHFRs, which, like the enzymes from the malarial parasite Plasmodium, are bifunctional, possessing DHFR and thymidylate synthase (TS) domains. Here using genetic knockout lines we confirmed that either DHFR-TS1 or DHFR-TS2 (but not DHFR-TS3) was essential for seed development.

Developing ciprofloxacin analogues against plant DNA gyrase: a novel herbicide mode of action.

Ciprofloxacin has been shown to exhibit potent herbicidal activity through action against plant DNA gyrase, presenting a novel mode of action. Analogues of ciprofloxacin have been prepared with increased herbicidal activity and diminished antibacterial activity, compared to ciprofloxacin, as demonstrated using model systems.

A herbicide structure-activity analysis of the antimalarial lead compound MMV007978 against Arabidopsis thaliana.

Background: To fight herbicide-resistant weeds, new herbicides are needed; particularly ones with new modes of action. Building on the revelation that many antimalarial drugs are herbicidal, here we focus on the Medicines for Malaria Venture antimalarial lead compound MMV007978 that has herbicidal activity against the model plant Arabidopsis thaliana.

Results: Twenty-two variations of the lead compound thiophenyl motif revealed that change was tolerated provided ring size and charge were retained.

Exploiting the Evolutionary Relationship between Malarial Parasites and Plants To Develop New Herbicides.

Herbicide resistance is driving a need to develop new herbicides. The evolutionary relationship between apicomplexan parasites, such as those causing malaria, and plants is close enough that many antimalarial drugs are herbicidal and so represent novel scaffolds for herbicide development. Using a compound library from the Medicines for Malaria Venture, the model plant Arabidopsis thaliana, and a physicochemical database of known herbicides, a compound was discovered that showed post-emergence herbicidal activity equal to commercial herbicides.

Herbicidal properties of antimalarial drugs.

The evolutionary relationship between plants and the malarial parasite Plasmodium falciparum is well established and underscored by the P. falciparum apicoplast, an essential chloroplast-like organelle. As a result of this relationship, studies have demonstrated that herbicides active against plants are also active against P.

An interactive database to explore herbicide physicochemical properties.

Herbicides are an essential tool not only in weed management, but also in conservation tillage approaches to cropping. The first commercial herbicides were released in the 1940s and hundreds more since then, although genetic resistance to them is an issue. Here, we review the experimental and estimated physicochemical properties of 334 successful herbicidal compounds and make available a dynamic electronic database containing detailed analyses of the main chemical properties for herbicides and which adopts the Simplified Molecular-Input Line-Entry System (SMILES) for describing the structure of chemical molecules.