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Synthesis and evaluation of hydroxyazolopyrimidines as herbicides; the generation of amitrole in planta.
Pest Manag Sci. 2016 Dec; 72(12):2254-2272.PM

Abstract

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 β-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 β-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 β-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 β-cyclase also showed tolerance towards two triazolopyrimidines from this study. © 2016 Society of Chemical Industry.

Authors+Show Affiliations

Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK. tim.o_riordan@syngenta.com.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.Syngenta, Jealott's Hill International Research Centre, Bracknell, Berks, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26918632

Citation

Clough, John M., et al. "Synthesis and Evaluation of Hydroxyazolopyrimidines as Herbicides; the Generation of Amitrole in Planta." Pest Management Science, vol. 72, no. 12, 2016, pp. 2254-2272.
Clough JM, Dale RP, Elsdon B, et al. Synthesis and evaluation of hydroxyazolopyrimidines as herbicides; the generation of amitrole in planta. Pest Manag Sci. 2016;72(12):2254-2272.
Clough, J. M., Dale, R. P., Elsdon, B., Hawkes, T. R., Hogg, B. V., Howell, A., Kloer, D. P., Lecoq, K., McLachlan, M. M., Milnes, P. J., O'Riordan, T. J., Ranasinghe, S., Shanahan, S. E., Sumner, K. D., & Tayab, S. (2016). Synthesis and evaluation of hydroxyazolopyrimidines as herbicides; the generation of amitrole in planta. Pest Management Science, 72(12), 2254-2272. https://doi.org/10.1002/ps.4264
Clough JM, et al. Synthesis and Evaluation of Hydroxyazolopyrimidines as Herbicides; the Generation of Amitrole in Planta. Pest Manag Sci. 2016;72(12):2254-2272. PubMed PMID: 26918632.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and evaluation of hydroxyazolopyrimidines as herbicides; the generation of amitrole in planta. AU - Clough,John M, AU - Dale,Richard P, AU - Elsdon,Barry, AU - Hawkes,Timothy R, AU - Hogg,Bridget V, AU - Howell,Anushka, AU - Kloer,Daniel P, AU - Lecoq,Karine, AU - McLachlan,Matthew Mw, AU - Milnes,Phillip J, AU - O'Riordan,Timothy Jc, AU - Ranasinghe,Saranga, AU - Shanahan,Stephen E, AU - Sumner,Karen D, AU - Tayab,Shanaaz, Y1 - 2016/04/04/ PY - 2016/01/08/received PY - 2016/02/19/revised PY - 2016/02/19/accepted PY - 2016/10/28/pubmed PY - 2017/3/14/medline PY - 2016/2/27/entrez KW - amitrole KW - herbicides KW - metabolism KW - mode of action SP - 2254 EP - 2272 JF - Pest management science JO - Pest Manag. Sci. VL - 72 IS - 12 N2 - 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 β-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 β-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 β-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 β-cyclase also showed tolerance towards two triazolopyrimidines from this study. © 2016 Society of Chemical Industry. SN - 1526-4998 UR - https://www.unboundmedicine.com/medline/citation/26918632/Synthesis_and_evaluation_of_hydroxyazolopyrimidines_as_herbicides L2 - https://doi.org/10.1002/ps.4264 DB - PRIME DP - Unbound Medicine ER -