Synthesis and evaluation of hydroxyazolopyrimidines as herbicides; the generation of amitrole in planta.

BACKGROUND: Exploiting novel herbicidal modes of action is an important method to overcome the challenges faced by increasing resistance and regulatory pressure on existing commercial herbicides. Recent reports of inhibitors of enzymes in the non-mevalonate pathway of isoprenoid biosynthesis led to the design of a novel class of azolopyrimidines which were assessed for their herbicidal activity. Studies were also undertaken to determine the mode of action responsible for the observed herbicidal activity. RESULTS: In total, 30 novel azolopyrimidines were synthesised and their structures were unambiguously determined by 1 H NMR, mass spectroscopy and X-ray crystallographic analysis. The herbicidal activity of this new chemical class was assessed against six common weed species, with compounds from this series displaying bleaching symptomology in post-emergence tests. A structure-activity relationship for the novel compounds was determined, which showed that only those belonging to the hydroxytriazolopyrimidine subclass displayed significant herbicidal activity. Observed similarities between the bleaching symptomology displayed by these herbicides and amitrole suggested that hydroxytriazolopyrimidines could be acting as elaborate propesticides of amitrole, and this was subsequently demonstrated in plant metabolism studies using Amaranthus retroflexus. It was shown that selected hydroxytriazolopyrimidines that displayed promising herbicidal activity generated amitrole, with peak concentrations of amitrole generally being observed 1 day after application. Additionally, the herbicidal activity of selected compounds was profiled against tobacco plants engineered to overexpress 4-diphosphocytidyl-2C-methyl-d-erythritol synthase (IspD) or lycopene ß-cyclase, and the results suggested that, where significant herbicidal activity was observed, inhibition of IspD was not responsible for the activity. Tobacco plants overexpressing lycopene ß-cyclase showed tolerance to amitrole and the two most herbicidally active triazolopyrimidines. CONCLUSIONS: Inhibition of IspD leading to herbicidal activity has been ruled out as the mode of action for the hydroxytriazolopyrimidine class of herbicides. Additionally, tobacco plants overexpressing lycopene ß-cyclase showed tolerance to amitrole, which indicates that this is the main herbicidal mode of action for amitrole. Results from the metabolic fate study of selected hydroxytriazolopyrimidines suggested that the herbicidal activity displayed by these compounds is due to amitrole production, which was confirmed when tobacco plants overexpressing lycopene ß-cyclase also showed tolerance towards two triazolopyrimidines from this study. © 2016 Society of Chemical Industry.

(99m)Tc-amitrole as a novel selective imaging probe for solid tumor: In silico and preclinical pharmacological study.

Lactoperoxidase (LPO) inhibitors are very selective for solid tumor due to their high binding affinity to the LPO enzyme. A computational study was used to select top-ranked LPO inhibitor (alone and in complex with (99m)Tc) with high in silico affinity. The novel prepared (99m)Tc-amitrole complex demonstrated both in silico and in vivo high affinity toward solid tumors.(99m)Tc-amitrole was radio-synthesized with a high radiochemical yield (89.7±3.25). It showed in vitro stability for up to 6h. Its preclinical evaluation in solid tumor-bearing mice showed high retention and biological accumulation in solid tumor cells with a high Target/Non-Target (T/NT) ratio equal to 4.9 at 60min post-injection. The data described previously could recommend (99m)Tc-amitrole as potential targeting scintigraphic probe for solid tumor imaging.

The pattern of systemic acquired resistance induction within the Arabidopsis rosette in relation to the pattern of translocation.

Local leaf infections by a necrogenic pathogen can lead to systemic acquired resistance (SAR) in untreated leaves. We reasoned that, whatever the nature of the long-distance signal, if it is transported in the phloem, the pattern of SAR induced within the plant by treatment of a single leaf should match the pattern of translocation out of that leaf. The source-sink relationships (orthostichies) in the Arabidopsis rosette were established with [14C]Suc or phloem-mobile 3-aminotriazole at herbicidal concentrations. SAR was activated by infiltrating a single Columbia leaf with Pseudomonas syringae pv maculicola DC3000/avrRPM1, which causes a hypersensitive response. The pattern of SAR in the rosette was monitored by assessing the growth of wild-type DC3000 and by measuring the SAR markers salicylic acid and PR1 transcripts. Although the orthostichy of a single leaf was clearly limited to a row of vertically aligned leaves, SAR and SAR markers were also found outside the orthostichy. This indicates that, whatever the nature of the long-distance signal from the treated leaf to the upper responding leaves, its transport is either not limited exclusively to the phloem or the minor proportion of translocate that is not confined to the orthostichy contains enough of the SAR systemic signal to set in motion events leading to the establishment of the SAR state in the upper leaves.

Dose- and time-dependent effect of an acute 3-amino-1,2,4-triazole injection on rat brain catalase activity.

The results presented in this study demonstrate a progressive inhibition of rat brain catalase activity by AT in vivo. Furthermore, the inhibition of brain catalase by AT demonstrates the presence of hydrogen peroxide in brain, since AT inhibits catalase in the presence of this compound. The rate of inhibition of catalase seems to be dependent upon the rate by which H2O2 is generated. A time course study showed slower onset of the inhibition of brain as compared to liver catalase, possibly reflecting tissue hydrogen peroxide levels or, alternatively, a rate-limiting penetration of AT into brain and into the catalase compartment. The presence of AT in brain was confirmed over the time period of the observed inhibition of brain catalase. Catalase inhibitors are of particular interest in the study of the physiological role of catalase. This study further supports the use of AT in investigations designed to further understand the role of brain catalase.