Predicting pharmacophore signals for post-coital antifertility activity of 1-trifluoromethyl-1,2,2-triphenylethylene derivatives: a statistical approximation using E-state index

Considering the worth of developing non-steroidal estrogen analogues, the present research explores the pharmacophores of 1-trifluoromethyl-1,2,2-triphenylethylenes (Fig. 1) for post-coital antifertility activity using electrotopological state atom (E-state) index. The study shows the efficacy of E-state index in developing statistically acceptable model, which explains the electronic environment and topological states of different atoms in a molecule. The exploration concluded that phenyl ring attached to an ethylenic moiety, para substitution by nucleophilic group on the phenyl ring and presence of strong electronegative group as the 4th substituent on the 1st carbon of the ethylenic moiety might be crucial for activity.     

The neonicotinoid electronegative pharmacophore plays the crucial role in the high affinity and selectivity for the Drosophila nicotinic receptor: an anomaly for the nicotinoid cation--pi interaction model

Cation-pi interaction, a prominent feature in agonist recognition by neurotransmitter-gated ion channels, does not apply to the anomalous action of neonicotinoids at the insect nicotinic acetylcholine receptor (nAChR). Insect-selective neonicotinoids have an electronegative pharmacophore (tip) in place of the ammonium or iminium cation of the vertebrate-selective nicotinoids, suggesting topological divergence of the agonist-binding sites in insect and vertebrate nAChRs. This study defines the molecular and electronic basis for the potent and selective interaction of the neonicotinoid electronegative pharmacophore with a unique subsite of the Drosophila but not of the vertebrate alpha4beta2 nAChR. Target site potency and selectivity are retained when the usual neonicotinoid N-nitroimine (=NNO(2)) electronegative tip is replaced with N-nitrosoimine (=NNO) or N-(trifluoroacetyl)imine (=NCOCF(3)) in combination with an imidazolidine, imidazoline, thiazolidine, or thiazoline heterocycle. X-ray crystallography establishes coplanarity between the heterocyclic and imine planes, including the electronegative substituent in the trans configuration. The functional tip is the coplanar oxygen atom of the N-nitrosoimine or the equivalent oxygen of the N-nitroimine. Quantum mechanics in the gas and aqueous phases fully support the conserved coplanarity and projection of the strongly electronegative tip. Further, a bicyclic analogue with a nitro tip in the cis configuration but retaining coplanarity has a high potency, whereas the N-trifluoromethanesulfonylimine (=NSO(2)CF(3)) moiety lacking coplanarity confers very low activity. The coplanar system between the electronegative tip and guanidine-amidine moiety extends the conjugation and facilitates negative charge (delta(-)) flow toward the tip, thereby enhancing interaction with the proposed cationic subsite such as lysine or arginine in the Drosophila nAChR.     

A novel halogen bond and a better-known hydrogen bond cooperation of neonicotinoid and insect nicotinic acetylcholine receptor recognition

Neonicotinoid insecticides target the insect nicotinic acetylcholine receptor (nAChR) and are highly effective against the piercing-sucking pests. To explore the molecular interaction mechanism between the neonicotinoids and the insect nAChR, some key neonicotinoid compounds were docked into Aplysia californica acetylcholine binding protein (Ac-AChBP), which serves as a suitable structural surrogate of the insect nAChR. The binding mode study showed that the hydrogen bond force between the electronegative pharmacophore of the neonicotinoids and Cys190NH of the target binding pocket is crucial to the high efficiency of the neonicotinoids. Increasing the coplanarity between the guanidine or amidine and the electronegative pharmacophore of the neonicotinoids could increase the Π-Π stacking effect with Tyr188 of the Ac-AChBP and thus enhance the insecticidal potency. The introduction of an azide group to the chloropyridine ring of the neonicotinoids would reduce its binding ability due to the disappearance of a novel halogen bonding interaction. A series of novel neonicotinoid molecules were designed based on the halogen bonding interaction and two compounds with 6-bromopyridine-3-yl and 6-(trifluoromethyl)-3-pyridinyl were found to be with potential insecticidal activities.     

萜类驱避化合物与引诱物三分子缔合的计算研究

【目的】目前驱避剂的作用机理研究还不理想,本研究从单个萜类驱避化合物分子与不同种类引诱气味分子同时相互缔合的角度入手,通过理论计算探究该缔合与蚊虫驱避作用的关系,从而为驱避作用机理研究提供新认识。【方法】利用Gaussian View 4.1和Gaussian 03W软件构建和优化萜类驱避化合物单体、单体与引诱物L-乳酸及氨分子同时缔合后三分子缔合体的结构,获得其最低能量结构和缔合能;通过程序Ampac 8.16将前述结构导入到程序Codessa 2.7.10,计算各类结构描述符;再利用Codessa 2.7.10的启发式方法得到一系列缔合体结构描述符与驱避活性之间的定量关系模型,并通过转折点确定、模型验证后确定最佳定量关系计算模型。【结果】三分子缔合的缔合能基本上在20~50 kJ/mol的范围,所得最佳三参数定量计算模型的R²值为0.9098,包含的3个结构描述符分别是三分子缔合体的maximum nucleophilic reactivity index for a C atom,topographic electronic index (all bonds) ［Zefirov’s PC］和exchange energy + e-e repulsion for a H-O bond。【结论】萜类驱避化合物分子可同时与2个不同种类的引诱物分子发生缔合作用,该缔合作用符合氢键的能量基本特征;缔合体的碳原子最大原子核反应指数、所有键的拓扑电子指数、氢氧键电子间交换互斥能对驱避活性影响显著。这些结果初步说明萜类驱避化合物与引诱物三分子缔合作用确实存在,且该缔合作用对驱避活性具有显著影响,这为驱避机理的研究提供了新的理论依据。     

Novel nicotinic action of the sulfoximine insecticide sulfoxaflor

The novel sulfoximine insecticide sulfoxaflor is as potent or more effective than the neonicotinoids for toxicity to green peach aphids (GPA, Myzus persicae). The action of sulfoxaflor was characterized at insect nicotinic acetylcholine receptors (nAChRs) using electrophysiological and radioligand binding techniques. When tested for agonist properties on Drosophila melanogaster D??2 nAChR subunit co-expressed in Xenopus laevis oocytes with the chicken ??2 subunit, sulfoxaflor elicited very high amplitude (efficacy) currents. Sulfoximine analogs of sulfoxaflor were also agonists on D??2/??2 nAChRs, but none produced maximal currents equivalent to sulfoxaflor nor were any as toxic to GPAs. Additionally, except for clothianidin, none of the neonicotinoids produced maximal currents as large as those produced by sulfoxaflor. These data suggest that the potent insecticidal activity of sulfoxaflor may be due to its very high efficacy at nAChRs. In contrast, sulfoxaflor displaced [³H]imidacloprid (IMI) from GPA nAChR membrane preparations with weak affinity compared to most of the neonicotinoids examined. The nature of the interaction of sulfoxaflor with nAChRs apparently differs from that of IMI and other neonicotinoids, and when coupled with other known characteristics (novel chemical structure, lack of cross-resistance, and metabolic stability), indicate that sulfoxaflor represents a significant new insecticide option for the control of sap-feeding insects.