124845-05-2

Upstream product

• 32249-35-7 methyl 3-cyclopropyl-3-oxopropanoate 
• 124845-04-1 5-cyclopropylisoxazole-4-carboxylic acid 

Relevant academic research and scientific papers

Design, synthesis and herbicidal activity of 5-cyclopropyl-N-phenylisoxazole-4-carboxamides

4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are a type of important herbicides, and they cause bleaching symptoms by indirectly inhibiting the biosynthesis of carotenoids. In this study, thirty isoxazolamide compounds were designed based on the structure of Isoxaflutole, a commercial HPPD herbicide. Starting from 1,1-dimethoxy-N,N-dimethyl-methanamine and methyl 3-cyclopropyl-3-oxo-propanoate, the title compounds were readily prepared and their structures were determined by MS and NMR analysis. In Petri dish tests, most of the title compounds showed strong inhibitory effect on the root and stem growth of both monocotyledon and dicotyledon weeds, and it was clearly different from the symptoms caused by HPPD inhibitors. However, several of them, especially I-17, showed characteristic bleaching symptoms of HPPD herbicides and good post-emergence herbicidal activity on tested weeds in glasshouse assay. These compounds are prodrugs, and compounds undergo conversion to the active entity diketonitrile (DKN) in plant and soil. The result of molecular docking analysis revealed that the DKN moiety of I-17 excellently binds to the active sites of HPPD. The 1,3-diketone can form bidentate interaction with FeII, and the benzene ring can form π-π interaction with Phe 360 and Phe 403. These results indicated that the title compounds bears other herbicidal mechanism except for HPPD inhibitor. Therefore, a lead compound for the discovery of novel multi-target herbicides is provided.

Design, Synthesis, and Herbicidal Activity of N-Benzyl-5-cyclopropyl-isoxazole-4-carboxamides

Based on the structures of isoxaflutole (IFT) and N-isobutyl-N-(4-chloro-benzyl)-4-chloro-2-pentenamide, a series of N-benzyl-5-cyclopropyl-isoxazole-4-carboxamides was designed by connecting their pharmacophores (i.e., a multitarget drug design strategy). A total of 27 N-benzyl-5-cyclopropyl-isoxazole-4-carboxamides were prepared from 5-cyclopropylisoxazole-4-carboxylic acid and substituted benzylamines, and their structures were confirmed by NMR and MS. Laboratory bioassays indicated that I-26 showed 100% inhibition against Portulaca oleracea and Abutilon theophrasti at a concentration of 10 mg/L, better than the positive control butachlor (50% inhibition for both weeds). A strong growth inhibition was observed, but a typical bleaching phenomenon of IFT could not be observed in the Petri dish assay. I-05 displayed excellent postemergence herbicidal activity against Echinochloa crusgalli and A. theophrasti at a rate of 150 g/ha, and bleaching symptoms were observed in the leaves of treated weeds. The bleaching effect of Chlamydomonas reinhardtii treated by I-05 could be reversed by adding homogentisate. Enzymatic bioassays indicated that I-05 could not inhibit 4-hydroxyphenylpyruvate dioxygenase (HPPD) activity, but II-05, an isoxazole ring-opening product of I-05, could inhibit HPPD activity with an EC50 value of 1.05 μM, similar to that of mesotrione (with an EC50 value of 1.35 μM). Detailed discussion about observed herbicidal symptoms is provided in the Results and Discussion section. This investigation provided a proof-of-concept foundation that a multitarget drug design strategy could be applied in agrochemical research.

Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl- 3-hydroxy. N-[3'-methyl-4'-(trifluoromethyl)phenyl]propenamide and related compounds

The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.

Antiarthritic β-cycloalkyl-β-oxopropionitriles

Disclosed herein are novel β-cycloalkyl-β-oxopropionitriles which exhibit anti-inflammatory/antiarthritic activities.