This work provides a comprehensive overview of agrochemical properties in terms of the way they change during progression from screen hit to product and in terms of their limits as expressed in modern commercial products. Most herbicides and fungicides readily meet the Lipinski 'rule of five' criteria for drug-like compounds with many meeting the more constrained limits reported for pharmaceutical leads.
The safener-induced maize (Zea mays L.) glutathione S-transferase, GST II (EC 2.5.1.18) and another predominant isoform, GST I, were purified from extracts of maize roots treated with the safeners R-25788 (N,N-diallyl-2-dichloroacetamide) or R-29148 (3-dichloroacetyl-2,2,5-trimethyl-1,3-oxazolidone). The isoforms GST I and GST II are respectively a homodimer of 29-kDa (GST-29) subunits and a heterodimer of 29- and 27-kDa (GST-27) subunits, while GST I is twice as active with 1-chloro-2,4-dinitrobenzene as GST II, GST II is about seven times more active against the herbicide, alachlor. Western blotting using antisera raised against GST-29 and GST-27 showed that GST-29 is present throughout the maize plant prior to safener treatment. In contrast, GST-27 is only present in roots of untreated plants but is induced in all the major aerial organs of maize after root-drenching with safener. The amino-acid sequences of proteolytic fragments of GST-27 show that it is related to GST-29 and identical to the 27-kDa subunit of GST IV.
A series of 1,3,4(2H)-isoquinolinetriones have been found to be fastacting post-emergence herbicides, producing symptoms of desiccation. These redox-active compounds are very potent stimulators of the light-dependent consumption of oxygen at photosystem I in isolated chloroplasts. Pulse radiolysis studies on 2-ethyl-l,3,4(2H)-isoquinolinetrione have shown it to have free-radical properties which could enhance the generation of superoxide radicals in plants.Electrochemical studies further support a redox mediator mode of action for the series. The compounds were found to be unstable towards hydrolysis, and this was considered to be a major factor limiting the overall herbicidal effects. Other parameters, related to uptake and/or translocation, which may limit the full expression of the herbicidal activity of certain compounds, are discussed.which gives rise to the herbicidal activity of the isoquinolinetriones, and describe the results of a preliminary study designed to probe the structureactivity-property relationships within a series of compounds. EXPERIMENTAL METHODS Chemical synthesisThe three general methods used for the preparation of 1,3,4(2H)-isoquinolinetriones are outlined in Fig. 1.Method A involves the oxidation of a homophthalimide derivative to the corresponding isoquinolinetrione. This transformation has been conveniently carried out using a two-step one-pot procedure, in which the homophthalimide is first condensed with N,N-dimethyl-p-nitrosoaniline to give an intermediate imine which is then hydrolysed in situ by the addition of aqueous acid." Method B requires the 49 Pestic. Sci. 0031-613X/95/$09.00 0 1995 SCI. Printed in Great Britain 1,3,4(2H)-isoquinolinetrione herbicides~~~~~~ ~ ~ Average score across weed species, on a scale of 0-9 where 0 indicates no damage five days after treatment and 9 signifies Estimated from a half life of 3.8 min at 40°C. Estimated. Estimated from a measurement made at pH 6. Estimated from a measurement made at pH 5. complete kill (see Section 2.2).' Not measured; this compound could not be obtained >90% pure.
The differences between the one-electron reduction potentials at pH 7 (E:) of a quinone couple (Q/Q-), and seventeen nitroimidazole couples ( S / S -) were estimated for S = substituted 2-, 4-, and 5-nitroimidazoles, by measuring the equilibrium constant Kc of the reaction S-+ Q + S + Q-. The radical-ions Sand Qwere generated by pulse radiolysis, and their concentrations measured spectrophotometrically after the equilibrium was attained (typically 1-50 ps after the pulse). Estimated values of E:(S/S-) range from -243 mV for S = 5-formyl-1-methyl-2-nitroimidazole ; -398 mV for 1 -(2-hydroxyethyl)-2-nitroimidazole ; -486 mV for l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole to < -527 mV for 4-nitroimidazole (all F 10 mV). In the absence of other factors, 2-nitroimidazoles have more positive E$ values than the 5-nitro-analogues, and 4-nitroimidazoles are still weaker oxidants. Substitution with electron-withdrawing groups in the side chain can increase E+ by amounts greater than the difference between 2-and 5-nitroimidazoles. These values are based on E+(Q/Q-) = -244 k 7 mV for duroquinone, and -375 k 8 mV for 9,10-anthraquinone-2-sulphonate.These reference potentials were determined by measuring K, for one-electron transfer equilibria between the quinones and 1,1'-dibenzyl-4,4'-bipyridylium ion (BV2+), assuming E+(BVZ+/BV+) = -354k 6 mV. The usefulness of viologens as redox indicators in this type of study is discussed, There is evidence that modification of the redox properties of nitro-aromatic compounds (by substitution of electron-withdrawing groups in the ring) can have a considerable effect on the potential usefulness of these compounds as hypoxic cell radiosensitizers in radiotherapy. Electron spin resonance (e.s.r.) studies have provided much information concerning the effects of substitution upon nitro-aromatic radical-anionsy2# and Meisel and Neta have shown that these e.s.r. parameters can be related to the one-electron reduction potentials of the parent compounds. Much less is known about the effects of substitution upon the free-radical chemistry of nitro-heterocyclic compounds. Nitroimidazoles are also being investigated as potential radio sensitizer^,^ and we report here measurements of the one-electron reduction potentials of several of these compounds.The position of the one-electron transfer equilibrium : 4* 6-9 S-+Q + S + Q -(1) is a measure of the difference in reduction potential between the reference Q (e.g. duroquinone 4* ' 9 or 9,1O-anthraquinone-2-sulphonate) and the nitro-compound S.If in water at pH 7 the radical-ions S-or Q-are stable only for milliseconds, then production, and measurement of the concentrations of these species are conveniently achieved by pulse radiolysis and fast, kinetic spectrophotometry ; the potentials of the reference compounds have been previously e~timated.~. ** l o g l 1 EXPERIMENTAL Duroquinone (Sigma) was recrystallized from ethanol+ water, and 9, lo-anthraquinone-2-sulphonate (B.D.H., purified) was recrystallized 3 times from water (as the monohydrate). 1 ,l'-...
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