Synthesis, Physicochemical Properties, and Biological Activities of 4-(S-Methyl-N-(2,2,2-Trifluoroacetyl)Sulfilimidoyl) Anthranilic Diamide

Novel anthranilic diamides with sulfilimidoyl and sulfoximidoyl functionalities were successfully prepared. Among newly-prepared organosulfur compounds, 3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylthio)phenyl)-1H-pyrazole-5-carboxamide and (S,E)-3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfinimidoyl)-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide showed good levels of efficacy and a strong correlation between insecticidal activities and physical properties, respectively. In particular, available data indicated that the N-trifluoroacetyl sulfilimine moiety could be an appealing structural scaffold for the discovery of a new crop-protecting agent.


Introduction
After the discovery of sulfoxaflor by Dow AgroScience [1][2][3], compounds with sulfoximine moiety have received remarkable attention in crop protection. Consequently, a large number of studies have examined the chemistry and mode of action of sulfoxaflor and sulfoximine insecticides [4][5][6][7][8]. As shown in Figure 1, the interest in the sulfoximine moiety has led to the discovery of highly-active sulfilimine-containing insecticides 1-4 [9][10][11][12][13]. For patent applications, researchers at BASF prepared sulfilimine-based anthranilic diamides 4 and reported that it is highly active in insects which are resistant to ryanodine modulator insecticide [13]. Furthermore, various sulfoximine-containing anthranilamides 6 have been reported by researchers at Syngenta (Figure 1) [14,15]. In addition to crop-protection applications, many research groups reported that sulfoximine could be a bioisostere of sulfones and sulfonamides with enhanced absorption, distribution, metabolism, and excretion (ADME) properties. These suggests that introducing a sulfur-nitrogen bond could be a promising approach for the discovery of new biologically-active molecules [16][17][18][19][20][21][22]. For the preparation of sulfilimineand sulfoximine-based compounds, synthetic methods and strategies have been widely investigated by many research groups [23][24][25][26][27]. In particular, Bolm et al. reported facile and practical synthetic approaches [28], which are applied in this study. the 4-position on the anthranilamide ring ( Figure 2). We hypothesized that better insecticidal activity could be obtained by these small, lipophilic, electron-withdrawing substituents [1, 29,30].

Results
In our previous study on a novel anthranilic diamide insecticide 7, we showed that the replacement of N-methylcarbamoyl with O-methyl carbamate had a beneficial effect, resulting in high insecticidal activity and low toxicity ( Figure 2) [31]. Encouraged by these results, we have initially investigated the synthesis of the sulfilimine-and sulfoximine-based diamide 15, 16 derivatives ( Figure 2).

Results
In our previous study on a novel anthranilic diamide insecticide 7, we showed that the replacement of N-methylcarbamoyl with O-methyl carbamate had a beneficial effect, resulting in high insecticidal activity and low toxicity ( Figure 2) [31]. Encouraged by these results, we have initially investigated the synthesis of the sulfilimine-and sulfoximine-based diamide 15, 16 derivatives ( Figure 2).
In addition to sulfilimine 15a and sulfoximine 16a, all other synthetic compounds, that is, sulfide 14, sulfoxide 15b, and sulfone 16b, were also tested for their larvicidal activities (Table 2). Among them, sulfide 14 and N-trifluoroacetyl sulfilimine 15a showed good activities with high inhibition of feeding behaviors (eating area-14 and 15a: 5-10%, ref.: 0-5%, For the practical test, newly-prepared compounds 14-16 were evaluated for their insecticidal activities against the third instar larvae of Spodoptera litura according to the reported leaf-dip method [35]. In addition to sulfilimine 15a and sulfoximine 16a, all other synthetic compounds, that is, sulfide 14, sulfoxide 15b, and sulfone 16b, were also tested for their larvicidal activities (Table 2). Among them, sulfide 14 and N-trifluoroacetyl sulfilimine 15a showed good activities with high inhibition of feeding behaviors (eating area-14 and 15a: 5-10%, ref.: 0-5%, Table 2) (for images, please see the Supplementary Materials). Highly sensitive and functional group specific insecticidal activities were observed. 15b a Concentration of 14 and 15a was 50 ppm.
Because we believed that the physicochemical properties of newly-prepared diamides play important roles in their insecticidal activities [14,36], the studies were extended to investigate the bioavailability of organosulfur-based crop-protecting agents 14, 15a, 15b, 16a, and 16b in terms of plant systemic properties [14] and membrane permeability [36]. As references, their properties of chlorantraniliprole and cyantraniliprole were also measured. Equilibrium solubility, log P, and parallel artificial membrane permeability assay (PAMPA) values are reported in Figure 3 [37]. Because we believed that the physicochemical properties of newly-prepared diamides play important roles in their insecticidal activities [14,36], the studies were extended to investigate the bioavailability of organosulfur-based crop-protecting agents 14, 15a, 15b, 16a, and 16b in terms of plant systemic properties [14] and membrane permeability [36]. As references, their properties of chlorantraniliprole and cyantraniliprole were also measured. Equilibrium solubility, log P, and parallel artificial membrane permeability assay (PAMPA) values are reported in Figure 3 [37].  [38][39][40]: Open and solid circles represent permeability (parallel artificial permeability assay, PAMPA) and solubility (equilibrium), respectively; horizontal dash box describes similar permeability (PAMPA) with chlorantraniliprole (dark yellow) and cyantraniliprole (violet); vertical dash box represents similar log P with cyantraniliprole (violet).
Although poor water solubility was observed, sulfide 14 displayed relatively low log P and high permeability value (black circle, Figure 3). According to the solubility and log P data, sulfoxide 15b is believed to have hydrophilic properties (red circle, Figure 3) [41]. In the case of N-trifluoroacetyl sulfilimine 15a and sulfoximine 16a, it seems that sulfilimine 15a is more bioavailable than sulfoximine 16a, especially considering its log P value (blue circle vs pink circle, Figure 3). In Figure 3. Physical properties of organosulfur-substituted anthranilic diamides 14-16 [38][39][40]: Open and solid circles represent permeability (parallel artificial permeability assay, PAMPA) and solubility (equilibrium), respectively; horizontal dash box describes similar permeability (PAMPA) with chlorantraniliprole (dark yellow) and cyantraniliprole (violet); vertical dash box represents similar log P with cyantraniliprole (violet).
Although poor water solubility was observed, sulfide 14 displayed relatively low log P and high permeability value (black circle, Figure 3). According to the solubility and log P data, sulfoxide 15b is believed to have hydrophilic properties (red circle, Figure 3) [41]. In the case of N-trifluoroacetyl sulfilimine 15a and sulfoximine 16a, it seems that sulfilimine 15a is more bioavailable than sulfoximine 16a, especially considering its log P value (blue circle vs pink circle, Figure 3). In physicochemical property tests on organosulfur-based anthranilic diamides, it has been proven that similar values (log P and permeability) of sulfide 14 and N-trifluoroacetyl sulfilimine 15a to cyantraniliprole have resulted in promising insecticidal activities. It is worth noting that sulfilimine 15a has highly competitive water solubility and permeability to cyantraniliprole, which should aid in plant uptake and translocation [29].

Conclusions
In summary, novel anthranilic diamides, in which organosulfur groups were substituted at the 4-position on the phenyl ring, were prepared and tested for their insecticidal activities and physical properties. For preparation of the target molecules, we expanded reported sulfur imination procedures [28] to amide groups containing sulfide 14. Our results concerning the relationship between insecticidal activities and physical properties showed that a better bioavailability profile (relatively low log P and high permeability) results in efficacy of sulfide 14 and sulfilimine 15a (Table 2 and Figure 3). Due to its higher water solubility, N-trifluoroacetyl sulfilimine 15a could be considered the most promising candidate for discovery of a new diamide insecticide. Notably, these studies have demonstrated that changing the substituents on sulfur atoms could lead to compounds with the desired physicochemical property profiles. Among organosulfur groups, N-trifluoroacetyl sulfilimine motif brings about desired properties such as solubility, lipophilicity, and permeability.