Trifluoromethylpyridine thiourea derivatives: design, synthesis and inhibition of the self‐assembly of tobacco mosaic virus particles

Abstract

BACKGROUND: Devastating plant virus diseases leading to bad harvests and lower quality of crops have made feeding the beyond seven billion population a huge challenge. Nevertheless, growing resistance and cross resistance of crop protection agents have made this challenge harder. Therefore, an efficient crop protection agent with novel structure and mode of action showing higher efficiency and eco-friendly is urgently needed. RESULTS: The coat protein (CP) of a virus is a potential target for the discovery of new antiviral agents. Antiviral molecules can inhibit infection by obstructing the assembly of virus particles. A series of novel phthalamide-like thiourea derivatives containing trifluoromethylpyridine was designed and synthesized. Most of the compounds exhibited good antiviral activity against tobacco mosaic virus (TMV). Compound 7b showed notable curative, protective and inactivation activities against TMV. Its inactivation half-maximal effective concentration (EC 50 ) value (20.5 ∼g mL −1 ) was better even than commercial ningnanmycin (23.2 ∼g mL −1 ). Compound 7b also had stronger TMV-CP binding ability than ningnanmycin and destroyed the external shape of TMV particles and hindered the self-assembly of TMV-CP and TMV-RNA.CONCLUSION: These phthalamide-like thiourea derivatives especially compound 7b containing trifluoromethylpyridine are potential lead compounds and inhibitors of TMV particle self-assembly.

Novel trifluoromethylpyridine piperazine derivatives as potential plant activators

“…It has become one of the main active structures of many commercial pesticides, such as the herbicide pyroxsulam ( Nugent et al., 2015 ), the insecticide fluazuron ( Cai et al., 2010 ; Chen et al., 2019 ), and the fungicide fluopyram ( Xie et al., 2014 ), etc ( Figure 1C ). Our previous work ( Figure 1D , left), revealed the trifluoromethyl pyridine derivatives showed significant anti-viral activity ( Wang et al, 2019a ;; Guo et al., 2021 ; Xu et al., 2022 ). Herein, in order to discover antiviral molecule with trifluoromethyl pyridine, we sought to make a cyclization for the replacement of the thiourea/urea ( Guo et al., 2021 ; Xu et al., 2022 ) by combining the trifluoromethyl pyridine with piperazine, and installing the substitutions via nucleophilic substitution reaction at opposite end of piperazine, which may result in trifluoromethyl pyridine piperazine derivatives with good antiviral activity ( Figure 1D , right).…”

Trifluoromethylpyridine: An Important Active Fragment for the Discovery of New Pesticides

“…The mechanism investigations indicated that the strong hydrogen-bonding interactions (with amino acid residues of TYR139, ASN73, and ALA74), halogen interactions (with TYR72, ALA74, and PHE12), and π–π T-shaped interaction (with PHE12) between active compounds and TMV coat protein (CP) could be observed (Figure B). These strong interactions could inhibit and impact the self-assembly of TMV particles . Chiral compounds with different configurations also showed obvious distinctions on the antiviral bioactivities.…”

“…Currently, bioisosteric replacement combined with SAR studies is still an important strategy for the optimization of TFMP compounds. Furthermore, it is crucial to understand the role that TFMP played in the activity; some studies have used molecular docking to elucidate the roles of TFMPs in an active compound, which has been validated in vitro as well as in vivo . , These works provide a good basis for a rational design based on TFMP. Therefore, taking TFMP as the growth point of the active fragment and tools of fragment-based drug design (e.g., ACFIS), reasonable designs by the introduction of different groups at different positions of the structure of TFMP could be an efficient strategy for discovery of active compounds.…”

“…These strong interactions could inhibit and impact the selfassembly of TMV particles. 67 Chiral compounds with different configurations also showed obvious distinctions on the antiviral bioactivities. The introduction of acyl urea or acyl thiourea as the connecting bridges (e.g., compounds 46 and 47) was also beneficial to the antiviral activities via strong interactions with the TMV CP (Figure 11C) and effective inhibitions in the self-assembly of the RNA and CP of the TMV particles.…”

Design, synthesis, characterization and insecticidal screening of novel anthranilic diamides comprising acyl thiourea substructure

“…Acyl thioureas are potential pharmacophore moieties, reported to display numerous biological activities such as antibacterial, antimicrobial, insecticidal, antitumor, fungicidal, antiviral and herbicidal properties, and are playing an important role in the development of agrochemicals. [27][28][29][30][31][32][33] Considering this, a series of novel anthranilic amide moieties incorporating acyl thiourea were designed and synthesized.…”