Photochemical transformation of a cellulose biosynthesis inhibitor into phytoene desaturase inhibitors.

Mode of action studies showed that 5-methyl-N,N-bis[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-amine (4), a representative from a new class of herbicidal tris-pyridyl amines, is an inhibitor of cellulose biosynthesis (CB). The compound undergoes an oxidative photocyclization, when exposed to UV-B light (300-340 nm) in the presence of oxygen, to give a new class of herbicidal pyrrolodipyridines. These compounds are potent inhibitors of the herbicide target enzyme phytoene desaturase and no longer inhibit CB.

Mechanism and structure based design of inhibitors of AMP and adenosine deaminase.

Inhibitors of the enzyme adenosine monophosphate deaminase (AMPD) show interesting levels of herbicidal activity. An enzyme mechanism-based approach has been used to design new inhibitors of AMPD starting from nebularine (6) and resulting in the synthesis of 2-deoxy isonebularine (16). This compound is a potent inhibitor of the related enzyme adenosine deaminase (ADA; IC50 16 nM), binding over 5000 times more strongly than nebularine. It is proposed that the herbicidal activity of compound 16 is due to 5́-phosphorylation in planta to give an inhibitor of AMPD. Subsequently, an enzyme structure-based approach was used to design new non-ribosyl AMPD inhibitors. The initial lead structure was discovered by in silico screening of a virtual library against plant AMPD. In a second step, binding to AMPD was further optimised via more detailed molecular modeling leading to 2-(benzyloxy)-5-(imidazo[2,1-f][1,2,4]triazin-7-yl)benzoic acid (36) (IC50 300 nM). This compound does not inhibit ADA and shows excellent selectivity for plant over human AMPD.

Trifluoromethyl Vinyl Sulfide: A Building Block for the Synthesis of CF3S-Containing Isoxazolidines.

Trifluoromethyl vinyl sulfide, a potential building block for pharmaceutically and agrochemically relevant products, is prepared and used for the first time in high-pressure-mediated 1,3-dipolar cycloaddition reactions with nitrones to synthesize (trifluoromethyl)sulfanyl isoxazolidines.

Synthesis of the C19 methyl ether of aspercyclide A via germyl-Stille macrocyclisation and ELISA evaluation of both enantiomers following optical resolution.

Aspercyclide A (1) is a biaryl ether containing 11-membered macrocyclic natural product antagonist of the human IgE-FcεRI protein-protein interaction (PPI); a key interaction in the signal transduction pathway for allergic disorders such as asthma. Herein we report a novel approach to the synthesis of the C19 methyl ether of aspercyclide A, employing a Pd(0)-catalysed, fluorous-tagged alkenylgermane/arylbromide macrocyclisation (germyl-Stille reaction) as the key step, and evaluation of both enantiomers of this compound via ELISA following optical resolution by CSP-HPLC. A crystal structure for germyl hydride 27 is also reported.

Combinatorial chemistry in the agrosciences.

Combinatorial chemistry and high throughput screening have had a profound effect upon the way in which agrochemical companies conduct their lead discovery research. The article reviews recent applications of combinatorial synthesis in the lead discovery process for new fungicides, herbicides and insecticides. The role and importance of bioavailability guidelines, natural products, privileged structures, virtual screening and X-ray crystallographic protein structures on the design of solid- and solution-phase compound libraries is discussed and illustrated.

Solid-phase organic synthesis of difluoroalkyl entities using a novel fluorinating cleavage strategy: part 1. Linker development: scope and limitations.

An efficient method to synthesize gem-difluorinated compounds on solid supports is described. The strategy is based on the design of a novel sulfur linker system that enables, to the best of our knowledge for the first time, the release of target structures from the resin under simultaneous fluorination. Starting from an immobilized dithiol, coupling with an excess of aldehyde or ketone furnished dithianes. These can be further functionalized prior to release from the resin using our newly developed fluorinating cleavage conditions. Amide forming reactions, palladium-catalyzed reactions (Heck, Suzuki, and Sonogashira couplings), reductions, alkylations, and olefinations were successfully explored on the linker. The difluorinated target substances were obtained in modest to excellent yields and in high purities.

The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity.

Resistance to 157 different herbicides and 88% of known sites of action has been observed, with many weeds resistant to two or more modes. Coupled with tighter environmental regulation, this demonstrates the need to identify new modes of action and novel herbicides. The plant sphingolipid biosynthetic enzyme, inositol phosphorylceramide synthase (IPCS), has been identified as a novel, putative herbicide target. The non-mammalian nature of this enzyme offers the potential of discovering plant specific inhibitory compounds with minimal impact on animals and humans, perhaps leading to the development of new non-toxic herbicides. The best characterised and most highly expressed isoform of the enzyme in the model-dicot Arabidopsis, AtIPCS2, was formatted into a yeast-based assay which was then utilized to screen a proprietary library of over 11,000 compounds provided by Bayer AG. Hits from this screen were validated in a secondary in vitro enzyme assay. These studies led to the identification of a potent inhibitor that showed selectivity for AtIPCS2 over the yeast orthologue, and activity against Arabidopsis seedlings. This work highlighted the use of a yeast-based screening assay to discover herbicidal compounds and the status of the plant IPCS as a novel herbicidal target.

The combinatorial synthesis of organophosphorus compounds.

The primary literature concerning the combinatorial synthesis of organophosphorus compounds is reviewed and discussed. The subject matter is divided into three main sections describing the solid phase, solution phase and solvent-free synthesis of phosphorus containing organic molecules. The review covers the synthesis of compounds in which the final products contain phosphorus-carbon bonds, primarily phosphonates, phosphinates, phosphine oxides and phosphines.

Synthesis of 3-(carboxyarylalkyl)imidazo[2,1-f][1,2,4]triazines as potential inhibitors of AMP deaminase.

C-Ribosyl 1,2,4-triazolo[1,2,4]triazines which are able to undergo covalent hydration are of interest as potential inhibitors of AMP deaminase. In a search for compounds with improved bioavailability we have synthesized compounds in which the sugar has been replaced by carboxyarylalkyl based ribose phosphate mimics. The target carboxyarylalkyl imidazotriazines 11 and 12 were synthesized using a linear seven step sequence starting from simple benzoate derivatives. Alternatively, the hydroxyethyl imidazotriazine 39 is available in five steps and this synthon was used to prepare the imidazotriazines 34 and 48 in a short convergent manner.

Prospects for combinatorial chemistry in the agrosciences.

The recent progress and future prospects for the successful application of combinatorial chemistry and high throughput screening within the agrochemical lead discovery process are outlined and discussed. Solid and solution phase library synthesis technologies are reviewed and compared, and the role and importance of bioavailability, diversity and virtual screening in rational library design are detailed.

The design, synthesis and screening of a muscarinic acetylcholine receptor targeted compound library.

Potent new agonists of the insect muscarinic acetylcholine receptor (mAChR) have been discovered by synthesizing and screening a library of 225 oxime ether amines. Library evaluation was facilitated by the development of a high throughput test enabling the rapid determination of muscarinic agonist activity. The most interesting compounds were the thiadiazole 17 and the isoxazole 24 which were potent muscarinic agonists (EC50 13 and 21 nM, respectively) and showed lead levels of insecticidal activity.

Synthesis and Biochemical Testing of 3-(Carboxyphenylethyl)imidazo[2,1-f][1,2,4]triazines as Inhibitors of AMP Deaminase.

C-Ribosyl imidazo[2,1-f][1,2,4]triazines and 3-[2-(3-carboxyphenyl)ethyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ols represent two classes of known AMP deaminase inhibitors. A combination of the aglycone from the former class with the ribose phosphate mimic from the latter led to the 3-[2-(3-carboxyphenyl)ethyl]imidazo[2,1-f][1,2,4]triazines, which represent a new class of AMP deaminase inhibitors. The best compound, 3-[2-(3-carboxy-5,6,7,8-tetrahydronaphthyl)ethyl]imidazo[2,1-f][1,2,4]triazine (8), was a good inhibitor of all three human AMPD recombinant isozymes (AMPD1, AMPD2, and AMPD3; IC50 = 0.9-5.7 µM) but a poor inhibitor of the plant recombinant enzyme (Arabidopsis FAC1; IC50 = 200 µM).

Total synthesis of (+/-)-aspercyclide A and its C19 methyl ether.

The total syntheses of (+/-)-aspercyclide A (1) and its C19 methyl ether (15a) featuring Heck-Mizoroki macrocyclisation to form the 11-membered (E)-styrenyl biaryl ether lactone core are described.

Adenine nucleotide pool perturbation is a metabolic trigger for AMP deaminase inhibitor-based herbicide toxicity.

AMP deaminase (AMPD) is essential for plant life, but the underlying mechanisms responsible for lethality caused by genetic and herbicide-based limitations in catalytic activity are unknown. Deaminoformycin (DF) is a synthetic modified nucleoside that is taken up by plant cells and 5'-phosphorylated into a potent transition state-type inhibitor of AMPD. Systemic exposure of Arabidopsis (Arabidopsis thaliana) seedlings to DF results in dose-dependent (150-450 nm) and time-dependent decreases in plant growth that are accompanied by 2- to 5-fold increases in the intracellular concentrations of all adenine ribonucleotides. No measurable rescue is observed with either hypoxanthine or xanthine (250 microm), indicating that downstream effects of AMPD inhibition, such as limitations in adenine-to-guanine nucleotide conversion or ureide synthesis, do not play important roles in DF toxicity. However, adenine (250 microm) acts synergistically with a nontoxic dose of DF (150 nm) to produce growth inhibition and adenine nucleotide pool expansion comparable to that observed with a toxic concentration of the herbicide alone (300 nm). Conversely, adenine alone (60-250 microm) has no measurable effects on these parameters. These combined results support the hypothesis that AMPD is the primary intracellular target for this class of herbicides and strongly suggest that adenine nucleotide accumulation is a metabolic trigger for DF toxicity. AMP binds to 14-3-3 proteins and can interrupt client interactions that appear to drive their distributions. Trichome subcellular localization of the phi isoform is disrupted within 8 to 24 h after seedlings are semisubmersed in a solution of DF (100 nm), further suggesting that disrupted 14-3-3 protein function plays a role in the associated herbicidal activity.

The design and synthesis of novel inhibitors of NADH:ubiquinone oxidoreductase.

Potent new inhibitors of NADH:ubiquinone oxidoreductase (complex I) have been designed, with the help of molecular modelling, by hybridisation of known complex I inhibitors with inhibitors of cytochrome c oxidoreductase. The most interesting compound was the chromone 7 which was a selective inhibitor of complex I (IC(50) 15 nM) and showed acaricidal activity against spider mites.

Synthesis and chemistry of 4,5-dimagnesioimidazole dianions.

An experimentally convenient procedure for the generation of 4,5-dimagnesioimidazoles is described. N-Protected 2-substituted 4,5-diiodoimidazoles were treated with i-PrMgCl (2.4 equiv) in THF at 0-5 degrees C. The resulting vicinal dianions reacted with electrophiles to give 4,5-disubstituted imidazoles in 27-71% yields.