Xiangdong Mei

Synthesis and insecticidal activity of novel carbamate derivatives as potential dual-binding site acetylcholinesterase inhibitors.

In biological systems, bivalent ligands often possess increased functional affinity for their receptors compared with monovalent ligands. On the basis of the structure of acetylcholinesterase (AChE), a series of novel carbamate heterodimetic derivatives were designed and synthesized with the aim of increasing the potency toward AChE inhibition. The AChE inhibitory ability of all the novel compounds was tested using AChE obtained from the brain of the housefly. The bioassay results showed that compounds 6j, 6k, 6m, 6n, 6p, and 6q had increased inhibitory activities in comparison with parent phenyl N-methylcarbamate (MH) at the concentration of 100 mg/L. Among them, the most potent AChE inhibitor of these compounds was 6q (IC(50) = 12 μM), which showed 62-fold greater AChE inhibitory activity than that of MH and 12-fold greater activity than metolcarb (MT), which suggested that the 3-nitrophenoxy moiety of compound 6q was able to interact with the aromatic amino acid residues lining the gorge and the phenyl N-methylcarbamate moiety was able to interact with the catalytic sites of AChE, simultaneously. The insecticidal activities of compounds 6j, 6k, 6m, 6n, 6p, and 6q were further evaluated. Consistent with the result in vitro bioassay, those compounds demonstrated better activities against Lipaphis erysimi than parent compound MH at the concentration of 300 mg/L, and compound 6q showed the best insecticidal activity, causing 98% mortality after 24 h of treatment.

Synthesis and herbicidal activity of novel N-(2,2,2)-trifluoroethylpyrazole derivatives.

A series of novel N-(2,2,2)-trifluoroethylpyrazole derivatives were synthesized, and their structures were characterized by IR, mass spectroscopy, (1)H NMR, and elementary analysis. The herbicidal activities of target compounds 10a-c and 11a-c were assessed. The bioassay results showed that these pyrazole derivatives exhibited good herbicidal activity. Compound 11a showed the best pre-emergence herbicidal effects against both dicotyledonous and monocotyledonous weeds with good safety to maize and rape at the dosage of 150 g a.i. ha(-1) in greenhouse. Field trials indicated that compound 11a exhibited better herbicidal activity by soil application than the commercial herbicide, metolachlor. Moreover, compound 11a showed the same level of safety to maize as metolachlor.

4-(4-Chloro-5-methyl-3-trifluoro­meth­yl-1H-pyrazol-1-yl)-6-(prop-2-ynyl­oxy)pyrimidine

The molecule of the title compound, C12H8ClF3N4O, is twisted as indicated by the C—O—C—C torsion angle of 76.9 (3)°. Moreover, the trifluoromethyl group shows rotational disorder of the F atoms, with site-occupancy factors of 0.653 (6) and 0.347 (6). The dihedral angle between the rings is 1.88 (12) Å.

4,6-Bis[5-methyl-3-(trifluoro­meth­yl)pyrazol-1-yl]pyrimidine

The complete mol-ecule of the the title compound, C(14)H(10)F(6)N(6), is generated by crystallographic twofold symmetry, with two C atoms lying on the roatation axis. The dihedral angle between the central and peripheral rings is 25.97 (8)°.

SYNTHESIS OF BIVALENT ORGANOPHOSPHORUS COMPOUNDS AS ACETYLCHOLINESTERASE INHIBITORS

It has been reported that in biological systems, multivalent binding provides a broad range of benefits that are not achievable with the corresponding monovalent interactions.] One of classical examples of multivalent interactions, known as the “cluster effect”, was described by Lee et a1.2 The activity of some multivalent drug molecules were significantly enhanced by their cluster effe~t.3.~ Pang et al. reported highly potent, selective, and low cost bifunctional acetylcholinesterase (AChE) inhibitors: Since the cluster effect has been applied in drug design, we believe that the theoretical hypothesis can serve as reference and guidance for the discovery of new agrochemicals. Organophosphorus compounds act as classical acetylcholinesterase(AChEi) inhibitors.‘ The unique toxicology of insects provides safety mechanisms for the organophosphorus insecticides, the selectivity of insecticidal nerve poisons being attributable to structural differences in binding subsites (acetylcholinesterase)? Based on the geometry of the active-site gorge of A C E , with specific sites at its two extremities, Glu199, Asp-276 and the hydrophobic residues lining the entrance gorge of AChE? through binding to both catalytic and peripheral sites of the enzyme, a new series of dual binding site AChE inhibitors have been designed and synthesized.1° The cluster effect, combined with information about the structure of acetylcholinesterase, led us to design and synthesize some bivalent organphosphorus compounds as potential acetylcholinesterase inhibitors. We anticipated that the target compounds would bind to both catalytic and peripheral sites of the enzyme that lead to more stable AChE-organphosphorus complexes. Compounds 3a-h, consist of two subunits, connected either with a rigid or flexible linker, as shown in Scheme 1. Another series of compounds containing polyethylene glycol linkers were synthesized, as shown in the Scheme 2. The oxygen atoms in the linkers may lead to a change in the physicochemical properties of the compounds such as the logP value and the pKa value. The phthalimide ring can occupy a similar position at the peripheral site of AChE and can remain stacked onto the aromatic ring of Trp279.” Thus we synthesized the third series of

4-Chloro-5-[(5,5-dimethyl-4,5-dihydro­isoxazol-3-yl)sulfonyl­meth­yl]-3-methyl-1-(2,2,2-trifluoro­ethyl)-1H-pyrazole

In the title compound, C12H15BrF3N3O3S, which has potential herbicidal activity, the molecule is twisted, as indicated by the C—S—C—C torsion angle of 67.86 (19)° for the atoms linking the ring systems. An intramolecular C—H⋯F short contact occurs and intermolecular C—H⋯O interactions link the molecules in the crystal.

4-(But-3-yn-yloxy)-6-(4-iodo-1H-pyrazol-1-yl)pyrimidine.

In the title compound, C11H9IN4O, the dihedral angle between the pyrazole and pyrimidine rings is 6.30 (16)°. In the crystal, weak C—H⋯O interactions link the molecules.