Potency and Target Surface Interaction of Diazinoyl Nicotinic Insecticides.

Structure-activity relationships of diazinoyl nicotinic insecticides (diazinoyl isomers and 5- or 6-substituted pyrazin-2-oyl analogues) are considered in terms of affinity to the insect nicotinic acetylcholine receptor (nAChR) and insecticidal activity against the imidacloprid-resistant brown planthopper. Among the test compounds, 3-(6-chloropyridin-3-ylmethyl)-2-(pyrazinoyl)iminothiazoline shows the highest potency in nAChR affinity and insecticidal activity. Aplysia californica acetylcholine binding protein (AChBP) mutants (Y55W + Q57R and Y55W + Q57T) are utilized to compare molecular recognition of nicotinic insecticides with diverse pharmacophores. N-nitro- or N-cyanoimine imidacloprid or acetamiprid, respectively, exhibits a high affinity to these AChBP mutants at a similar potency level. Intriguingly, the pyrazin-2-oyl analogue has a higher affinity to AChBP Y55W + Q57R than that to Y55W + Q57T, thereby indicating that pyrazine nitrogen atoms contact Arg57 guanidinium and Trp55 indole NH. Furthermore, nicotine prefers AChBP Y55W + Q57T over Y55W + Q57R, conceivably suggesting that the protonated nicotine is repulsed by Arg57 guanidinium, consistent with its inferior potency to insect nAChR.

Discovery of flometoquin, a novel quinoline insecticide.

Flometoquin, 2-ethyl-3,7-dimethyl-6-[4-(trifluoromethoxy)phenoxy]quinolin-4-yl methyl carbonate, is a novel insecticide with a structurally unique phenoxy-quinoline. It was discovered in 2004 by the collaborative research of Nippon Kayaku and Meiji Seika Kaisha, Ltd. (currently, Mitsui Chemicals Crop & Life Solutions, Inc.). The compound demonstrates strong and quick insecticidal action against a variety of thrips species at the nymphal and adult stages through contact and feeding activity, which could minimize crop damage and economic loss by insect pest species. In addition, flometoquin is safe for tested non-target arthropods, which makes it suitable for controlling the insect pests mentioned above under Integrated Pest Management (IPM) programs. Here, we describe a structure-activity relationship study from lead generation to the discovery of flometoquin and its insecticidal properties, including knockdown activity and effects against non-targeted arthropods.

Afidopyropen, a novel insecticide originating from microbial secondary extracts.

Afidopyropen, a novel insecticide, is a derivative of pyripyropene A, which is produced by the filamentous fungus Penicillium coprobium. Afidopyropen has strong insecticidal activity against aphids and is currently used as a control agent of sucking pests worldwide. In this study, we summarized the biological properties and field efficacies of its derivatives against agricultural pests using official field trials conducted in Japan. Afidopyropen showed good residual efficacies against a variety of aphids, whiteflies and other sucking pests under field conditions. Furthermore, toxicological studies revealed its safety profiles against nontarget organisms, such as the honeybee, natural enemies and other beneficial insects, as well as mammals. Thus, afidopyropen is a next-generation agrochemical for crop protection that has a low environmental impact.

Deciphering the Flupyrimin Binding Surface on the Insect Nicotinic Acetylcholine Receptor.

A novel insecticide flupyrimin (FLP) with a trifluoroacetyl pharmacophore acts as an antagonist at the insect nicotinic acetylcholine receptor (nAChR). This investigation examines a hypothesis that the FLP C(O)CF3 moiety is primarily recognized by the ß subunit-face in the ligand-binding pocket (interface between α and ß subunits) of the insect nAChR. Accordingly, we evaluate the atomic interaction between a fluorine atom of FLP and the partnering amino acid side chain on the ß subunit employing a recombinant hybrid nAChR consisting of aphid Mpα2 and rat Rß2 subunits (with a mutation at T77 on the Rß2). The H-donating T77R, T77K, T77N, or T77Q nAChR enhances the FLP binding potency relative to that of the wild-type receptor, whereas the affinity of neonicotinoid imidaclprid (IMI) with a nitroguanidine pharmacophore remains unchanged. These results facilitate the establishment of the unique FLP molecular recognition at the Mpα2/Mpß1 interface structural model, thereby underscoring a distinction in its binding mechanism from IMI.

Synthesis of pyripyropene derivatives and their pest-control efficacy.

Pyripyropene A (PP-A), a secondary metabolite produced by filamentous fungi, shows insecticidal activity against agricultural insect pests. Synthesized PP derivatives also show a narrow insecticidal spectrum but high insecticidal activities against such sucking pests. PP-A has a low eco-toxicological impact and satisfies a prerequisite for next-generation insecticides. We investigated the effects of conversion of the 3-pyridyl and α-pyrone rings to other rings, as well as the effects of esterification, dehydration, and oxidization at the C-13 position in natural PP analogues, on the insecticidal activity and spectrum. The conversions of the 3-pyridyl and α-pyrone rings markedly reduced the insecticidal activity with a minimal impact on the spectrum, indicative of an important role for these rings in insecticidal activity. Some derivatives with modified structures at the C-13 position showed a higher inhibitory effect on the motility of canine heartworms and mosquito vectors than did PP-A, suggesting their utility as filaria control drugs.

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II-Invention of afidopyropen.

The synthesis and insecticidal activity of a series of pyripyropene derivatives with cyclopropanecarbonyloxy group(s) at the C-1, C-7 and/or C-11 position(s) were investigated to find novel insecticides. Insecticidal screening of the synthesized PP derivatives revealed that derivative 13, which had cyclopropanecarbonyloxy groups at the C-1 and C-11 positions and a hydroxyl group at the C-7 position, showed the highest insecticidal activity against aphids in laboratory tests. Finally, we selected 13 as a new insecticide candidate for agricultural sucking pests, which is now commercialized under the common name afidopyropen.

Insecticidal properties of pyripyropene A, a microbial secondary metabolite, against agricultural pests.

We previously reported the strong insecticidal activity of a microbial secondary metabolite, pyripyropene A (PP-A), against aphids. Pyripyropenes (PPs) have been known to show weak feeding inhibition against lepidopteran pests, but their strong aphicidal activities were first reported in our former study. Here we investigated the details of the insecticidal property of PP-A. Our biological evaluation of PP-A found that it shows high insecticidal activities against some sucking pests, such as whiteflies, as well as aphids, and preferable biological profiles as agricultural insecticides. Furthermore, PP-A controlled aphids well under field conditions.

Synthesis and insecticidal efficacy of pyripyropene derivatives focusing on the C-1, C-7, and C-11 positions' substituent groups.

The C-1, C-7, and C-11 positions of pyripyropene A were chemically modified to improve the insecticidal activity. Some derivatives showed higher insecticidal activities against aphids than pyripyropene A. In particular, the derivative 5c, which possesses three cyclopropyl carbonyl groups at the C-1, C-7, and C-11 positions, had excellent insecticidal activity levels in field and laboratory trials.

Flupyrimin: A Novel Insecticide Acting at the Nicotinic Acetylcholine Receptors.

A novel chemotype insecticide flupyrimin (FLP) [N-[(E)-1-(6-chloro-3-pyridinylmethyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide], discovered by Meiji Seika Pharma, has unique biological properties, including outstanding potency to imidacloprid (IMI)-resistant rice pests together with superior safety toward pollinators. Intriguingly, FLP acts as a nicotinic antagonist in American cockroach neurons, and [3H]FLP binds to the multiple high-affinity binding components in house fly nicotinic acetylcholine (ACh) receptor (nAChR) preparation. One of the [3H]FLP receptors is identical to the IMI receptor, and the alternative is IMI-insensitive subtype. Furthermore, FLP is favorably safe to rats as predicted by the very low affinity to the rat α4ß2 nAChR. Structure-activity relationships of FLP analogues in terms of receptor potency, featuring the pyridinylidene and trifluoroacetyl pharmacophores, were examined, thereby establishing the FLP molecular recognition at the Aplysia californica ACh-binding protein, a suitable structural surrogate of the insect nAChR. These FLP pharmacophores account for the excellent receptor affinity, accordingly revealing differences in its binding mechanism from IMI.

Identification of pyripyropene A as a promising insecticidal compound in a microbial metabolite screening.

Approximately 300 microbial natural products in our library were screened for insecticidal activities against three species of agricultural pests, including aphids. Among the several compounds that showed insecticidal activities, pyripyropene A had high aphicidal activity in vivo. Furthermore, in advanced tests, pyripyropene A applications with foliar sprays and soil drenching controlled aphids on cabbage. On the basis of its unique and promising activities, we selected pyripyropene A as the active component of potential insecticides.

Metal complexes from 1,1'-di(pyrazinyl)ferrocene: coordination polymers and bridged diferrocenes.

Ferrocene-based ligands 1,1'-di(pyrazinyl)ferrocene (L1) and 1,1'-di(2-pyrimidinyl)ferrocene (L2) were synthesized and copper and silver complexes were obtained from L1. Coordination polymers [{Cu(2)(PhCOO)(4)}(L1)](n) (1), [{Cu(2)(C(5)H(11)COO)(4)}(L1)](n) (2), and [{Cu(2)(OAc)(4)}(L1)](n).0.5n[Cu(2)(OAc)(4)(H(2)O)(2)].1.5nCH(3)CN (3) resulted from the reaction with the corresponding copper carboxylates. In all three complexes, L1 links the dinuclear copper carboxylate units to form one-dimensional step-like chains. In 2, these chains are further linked by [Cu(2)(OAc)(4)(H(2)O)(2)] dinuclear units via hydrogen bonding to form sheet structures. The reaction of L1 with copper(I) iodide resulted in a multinuclear complex [(CuI)(4)(L1)(2)].(L1) (4), which contains a [(CuI)(4)(L1)(2)] diferrocene unit with a step-like (CuI)(4) core. Reactions of L1 with silver(I) salts resulted in silver-bridged diferrocenes [Ag(2)(L1)(2)]X(2) (X = ClO(4) (5a, b), NO(3) (6a-c) and PF(6) (7)), some of which incorporate aromatic solvents into their crystal lattices. The intramolecular Ag...Ag separations in these metallamacrocycles (3.211-3.430 A) depended upon the counter-anions and on the coordination mode of the silver ions. In all of these coordination complexes, L1adopts a synperiplanar eclipsed conformation and acts as a bidentate ligand, with only the 5-nitrogen of each pyrazine ring involved in coordination.

Metal-centered ferrocene clusters from 5-ferrocenylpyrimidine and ferrocenylpyrazine.

A series of metal-centered ferrocene compounds has been designed by using 5-ferrocenylpyrimidine (L1) and ferrocenylpyrazine (L2). These ligands, when combined with transition metal salts, produce mixed-metal polynuclear complexes with structural diversity. Reaction of L1 with M(SCN)(2) (M = Ni, Co) produces the pinwheel-like 4:1 complexes (L1)(4).M(SCN)(2), while reactions of L1 and L2 with Cu(NO(3))(2) give the 3:1 complex (L1)(3).Cu(NO(3))(2) and the 2:1 complex (L2)(2).Cu(NO(3))(2), respectively. Reactions of L1 and L2 with M(hfac)(2) (hfac = 1,1,1,5,5,5-hexafluoroacetylacetonate, M = Mn, Ni, Cu, Zn) produce 2:1 complexes (L)(2).M(hfac)(2) with cis and trans configurations, respectively. Crystal structures as well as solid-state electrochemical properties of these redox active complexes were investigated.

Synthesis and characterization of redox-active coordination polymers generated from ferrocene-containing bridging ligands.

Coordination polymers showing redox activity have been constructed by using ferrocene-based bidentate ligands, 1,1'-(4-dipyridinethio)ferrocene (1) and 1,1'-(2-dipyridinethio)ferrocene (2). The ligand of 1 formed an Ag(I) coordination polymer, 1 x AgPF(6) x (CH(3)CN)(2) (3). This complex showed a 1-D double-chain structure, with a weak interchain Ag...Ag interaction. Combination of 1 with M(hfac)(2) (M = Mn, Cu, Zn) afforded 1-D chain complexes, 1 x M(hfac)(2) (M = Mn (5), Cu (6), Zn (7)). The complex 2 x CuPF(6) (8) showed a 1-D twisted helix-like chain structure.