Novel trifluoromethylpyridine piperazine derivatives as potential plant activators

Abstract

Plant virus diseases seriously affect crop yield, especially tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). The development of plant immune activators has been an important direction in the innovation of new pesticides. Therefore, we designed and synthesized a series of trifluoromethyl pyridine piperazine derivatives (A1-A27), and explored the action mechanism of active compound. The antiviral activity test showed that compounds A1, A2, A3, A9, A10, A16, A17 and A21 possessed higher activities than commercialized ningnanmycin. Particularly, the in vivo antiviral activity indicated that compound A16 showed the most potent protective activity toward TMV (EC50 = 18.4 μg/mL) and CMV (EC50 = 347.8 μg/mL), compared to ningnanmycin (50.2 μg /mL for TMV, 359.6 μg/mL for CMV). The activities of defense enzyme, label -free proteomic and qRT-PCR analysis showed that compound A16 could enhance the defensive enzyme activities of superoxide dismutase (SOD),polyphenol oxidase (PPO) and phenylalanine ammonialyase (PAL), and activate the phenylpropanoid biosynthesis pathway to strenthen the antiviral activities of tobacco. This study provides reliable support for the development of new antiviral pesticides and potential antiviral mechanism.

Trifluoromethylpyridine piperazine derivatives: synthesis and anti‐plant virus activity

“…As demonstrated in Scheme and in line with our previous work 17 . 3‐Chloro‐5‐(trifluoromethyl)picolinic acid ( A ) was reacted with oxalyl chloride to remove the –OH group to form 3‐chloro‐5‐(trifluoromethyl)picolinoyl chloride ( B ), then piperazine‐BOC was introduced under alkaline conditions to produce compound C .…”

“…However, the protective and inactivation activities were poor. Compared to the previous work, 17 the insertion of the amide group resulted in an enhancement of the anti‐CMV activities (curative, protective, and inactivation activity). Notably, the inactivation activity was notably increased.…”

“…We also found that the anti‐CMV activities were higher when R was benzene ring derivatives. Furthermore, benzene ring derivatives without substituent are not as effective as those containing substituent, particularly those with electron‐absorbing groups, which have been found to have the best anti‐CMV activity 17,18 . However, the position of electron‐absorbing groups also affects their activity.…”

“…As demonstrated in Scheme 1 and in line with our previous work. 17 3-Chloro-5-(trifluoromethyl)picolinic acid (A) was reacted with oxalyl chloride to remove the -OH group to form 3-chloro-5-(trifluoromethyl)picolinoyl chloride (B), then piperazine-BOC was introduced under alkaline conditions to produce compound C. the -BOC group of C was removed from under acidic conditions to produce intermediate D. Finally, under basic conditions, 2-chloro-N-substituted amide (F), which is prepared by the reaction of chloroacetyl chloride with a substituted amine, reacts with D to produce the target compounds (S1-S28).…”

“…In addition, the introduction of piperazine improves the biological activities of compounds, contributing to its high enthalpy of formation, good thermal stability, and better nitrogen balance symmetry for structures 14–16 . Therefore, in the previous work, we combined trifluoromethylpyridine with piperazine and found that most of the compounds had good anti‐plant virus activities 17 . Amide has a broad spectrum of biological activities, and the combination of amide with piperazine often achieves good results 18 .…”