New Lead Discovery of Herbicide Safener for Metolachlor Based on a Scaffold-Hopping Strategy

Abstract

The use of herbicide safeners can significantly alleviate herbicide injury to protect crop plants and expand the application scope of the existing herbicides in the field. Sanshools, which are well known as spices, are N-alkyl substituted compounds extracted from the Zanthoxylum species and have several essential physiological and pharmacological functions. Sanshools display excellent safener activity for the herbicide metolachlor in rice seedlings. However, the high cost of sanshools extraction and difficulties in the synthesis of their complicated chemical structures limit their utilization in agricultural fields. Thus, the present study designed and synthesized various N-alkyl amide derivatives via the scaffold-hopping strategy to solve the challenge of complicated structures and find novel potential safeners for the herbicide metolachlor. In total, 33 N-alkyl amide derivatives (2a–k, 3a–k, and 4a–k) were synthesized using amines and saturated and unsaturated fatty acids as starting materials through acylation and condensation. The identity of all the target compounds was well confirmed by 1H-NMR, 13C-NMR, and high-resolution mass spectrometry (HRMS). The primary evaluation of safener activities for the compounds by the agar method indicated that most of the target compounds could protect rice seedlings from injury caused by metolachlor. Notably, compounds 2k and 4k displayed excellent herbicide safener activities on plant height and demonstrated relatively similar activities to the commercialized compound dichlormid. Moreover, we showed that compounds 2k and 4k had higher glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and polyphenol oxidase (PPO) activities in rice seedlings, compared to the metolachlor treatment. In particular, 2k and 4k are safer for aquatic organisms than dichlormid. Results from the current work exhibit that compounds 2k and 4k have excellent crop safener activities toward rice and can, thus, be promising candidates for further structural optimization in rice protection.

Design, Synthesis, and Bioactivity of Novel Ester-Substituted Cyclohexenone Derivatives as Safeners

“…As of now, various natural products can be used as safeners. Jablonkai noted the relevance of a secondary plant metabolite, cyclic hydroxamic acids with a 1,4-benzoxazin-3-one skeleton, found in cereals such as wheat, maize, and rye, for the catalytic effect of non-enzymatic hydrolysis of 2-chloro-triazine herbicides such as atrazine and simazine to generate non-phytotoxic 2-hydroxy derivatives. , Deng noted that N -alkyl-substituted compounds are obtained from Zanthoxylum species and possess some important physiological and pharmacological functions . Abscisic acid (ABA), as a natural product, is an important phytohormone that participates in many aspects of plant growth and development .…”

Research Progress on the Action Mechanism of Herbicide Safeners: A Review

“…The antioxidant enzyme activity (e.g., SOD, CAT, and POD) of rice seedlings can be better improved by them compared with metolachlor treatment. 93 Hu et al showed that pretreatment caused an increase in malondialdehyde (MDA) content as well as SOD, CAT, and POD activity in rice seedlings. The combined application of Fen could reverse the MDA accumulation caused by Pre.…”

“…Furthermore, N -alkyl amide derivatives (compound 5 : CH 3 (CH 2 ) 5 CONHCH 2 CH­(CH 3 ) 2 ; and compound 6 : CH 3 (CH 2 ) 5 CONHCH 2 C­(CH 2 )­CH 3 ) were potential safeners for s-metolachlor, which had excellent crop safener activities. The antioxidant enzyme activity (e.g., SOD, CAT, and POD) of rice seedlings can be better improved by them compared with metolachlor treatment . Hu et al showed that pretreatment caused an increase in malondialdehyde (MDA) content as well as SOD, CAT, and POD activity in rice seedlings.…”

Research Progress in the Design and Synthesis of Herbicide Safeners: A Review

“…Active substructure splicing, intermediate derivatization methods (IDMs), scaffold hopping, natural product structure optimization, etc. have become the core technologies for finding candidate herbicide safeners. − …”

“…Amide Herbicide Safeners. The chain-shortening method was used by Deng et al 61 The unsaturated long alkyl carbon chains were replaced by saturated and unsaturated alkyl carbon chains of 1−6 carbon atoms, and the structure of sanshools was simplified (Scheme 13). Notably, N-alkyl amide derivatives were synthesized from amines and saturated and unsaturated fatty acids through acylation and condensation via scaffold hopping.…”