Synthesis, Herbicidal Activity, Mode of Action, and In Silico Analysis of Novel Pyrido[2,3-d]pyrimidine Compounds

Author:

Min Lijing1,Liang Wei2,Bajsa-Hirschel Joanna3,Ye Peng4,Wang Qiao2,Sun Xinpeng25,Cantrell Charles L.3ORCID,Han Liang2,Sun Nabo5,Duke Stephen O.6,Liu Xinghai2ORCID

Affiliation:

1. Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, College of Life Science, Huzhou University, Huzhou 313000, China

2. College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China

3. Natural Products Utilization Research Unit, Agricultural Research Service, U.S. Department of Agriculture, University, MS 38677, USA

4. Shanghai Souguo Science & Technology Co. Ltd., Shanghai 201708, China

5. College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, China

6. National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA

Abstract

Natural products are a main source of new chemical entities for use in drug and pesticide discovery. In order to discover lead compounds with high herbicidal activity, a series of new pyrido[2,3-d] pyrimidine derivatives were designed and synthesized using 2-chloronicotinic acid as the starting material. Their structures were characterized with 1H NMR, 13C NMR and HRMS, and the herbicidal activities against dicotyledonous lettuce (Lactuca sativa), field mustard (Brassica campestris), monocotyledonous bentgrass (Agrostis stolonifera) and wheat (Triticum aestivum) were determined. The results indicated that most of the pyrido[2,3-d] pyrimidine derivatives had no marked inhibitory effect on lettuce at 1 mM. However, most of the pyrido[2,3-d] pyrimidine derivatives possessed good activity against bentgrass at 1 mM. Among them, the most active compound, 3-methyl-1-(2,3,4-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2o), was as active as the positive controls, the commercial herbicides clomazone and flumioxazin. Molecular simulation was performed with molecular docking and DFT calculations. The docking studies provided strong evidence that 2o acts as an herbicide by inhibition of protoporphyrinogen oxidase. However, the physiological results indicate that it does not act on this target in vivo, implying that it could be metabolically converted to a compound with a different molecular target.

Funder

National Key Research and Development Program of China

Zhejiang Provincial Natural Science Foundation of China

USDA

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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