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.

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.

The Synthesis of Certain Phomentrioloxin A Analogues and Their Evaluation as Herbicidal Agents.

A series of 28 analogues of the phytotoxic geranylcyclohexentriol (-)-phomentrioloxin A (1) has been synthesized through cross-couplings of various enantiomerically pure haloconduritols or certain deoxygenated derivatives with either terminal alkynes or borylated alkenes. Some of these analogues display modest herbicidal activities, and physiological profiling studies suggest that analogue 4 inhibits photosystem II in isolated thylakoids in vitro.

In search of new herbicidal inhibitors of the non-mevalonate pathway.

The first five steps of the non-mevalonate pathway have been tested in high-throughput screening (HTS) campaigns, using enzymes of plant origin. Hit rates were in general relatively low, which could be attributed to the high polarity and charged nature of substrates and active sites of these enzymes. Still, for all the enzymes, apart from IspF (2-methylerythritol 2,4-cyclodiphosphate synthase), inhibitors could be identified with activities below 100 μM, and these were followed up to identify structure-activity relationships (SARs).

Activation of C-Cl by ground-state aluminum atoms: an EPR and DFT investigation.

The reaction of ground-state Al atoms with dichloromethane (CH(2)Cl(2)) in an adamantane matrix at 77 K yielded two mononuclear Al species. The magnetic parameters, extracted from the axial EPR spectrum of Species A/A' (g(1) = 2.0037, g(2) = g(3) = 2.

The characterization of Lucilia cuprina acetylcholinesterase as a drug target, and the identification of novel inhibitors by high throughput screening.

Acetylcholinesterase (AChE, EC3.1.1.

Exploitation of structural and regulatory diversity in glutamate racemases.

Glutamate racemase is an enzyme essential to the bacterial cell wall biosynthesis pathway, and has therefore been considered as a target for antibacterial drug discovery. We characterized the glutamate racemases of several pathogenic bacteria using structural and biochemical approaches. Here we describe three distinct mechanisms of regulation for the family of glutamate racemases: allosteric activation by metabolic precursors, kinetic regulation through substrate inhibition, and D-glutamate recycling using a d-amino acid transaminase.