The structure-based design and synthesis of a series of novel neonicotinoid analogues are described. The novel neonicotinoid analogues were designed based upon the reaction of enamine derivatives with electron-withdrawing <em>β</em>-substituents with electrophilic thiocyanogen reagents. These compounds were characterized by spectroscopic methods. Bioassays indicated that some of the synthesized compounds exhibited excellent bioactivity against cowpea aphids (<em>Aphis craccivora</em>). The LC₅₀ values of compounds <strong>7</strong>,<strong>9</strong>,<strong>12</strong>,<strong>13</strong>,<strong>15</strong>,<strong>17</strong>,<strong>19</strong>,<strong>20</strong> and commercial imidacloprid were 0.01567, 0.00974, 0.02494, 0.01893, 0.02677, 0.01778, 0.0220, 0.02447 and 0.03502 mmol L^-1, respectively, which suggested that they could be used as leads for future development of new insecticides.

cis-Neonicotinoids are a type of neonicotinoid, in which the nitro or the cyano group are in cis-configuration relative to heteroaromatic moiety, which show excellent activities against a range of insect species. This review covers cis-neonicotinoids with commercialization perspectives, structural optimization (phenylazoneonicotinoids and chlorothiazolyl analogues of Paichongding), modes of action studies, radiao-synthesis of Paichongding and Cycloxaprid, and photostability of neonicotinoids.

To keep the nitro group in the cis position, a series of nitromethylene neonicotinoids containing a tetrahydropyridine ring with exo-ring ether modifications were designed and synthesized. All of the compounds were characterized and confirmed by 1H NMR, high-resolution mass spectroscopy, elemental analysis, and IR. The bioassay tests showed that some of them exhibited good insecticidal activities against pea aphids. On the basis of 10 nitromethylene derivatives, the quantitative structure-bioactivity relationship (QSAR) was analyzed and established. The results suggested that AlogP98 and Dipole_Mopac might be the important parameters related with biological activities.

A series of neonicotinoids analogues of hexahydroimidazo[1,2-alpha]pyridine were modified at 5-, 6-, and 7-positions, and their insecticidal activities were evaluated. Introducing a methyl or ethyl at 7-position increased the insecticidal activities, while other substituents decreased activities. When alkyl substituents were introduced to 7-position, the insecticidal activities against Pea aphids decreased in the order methyl (7a)>ethyl (7b)>n-butyl (7e)>phenyl (7f)>n-propyl (7c)>iso-propyl (7d), p-NO(2)-phenyl (7g). Modifications at 5-, 6- or both at 6- and 7-positions with methyl or ethyl were unfavorable to activities. Interestingly, introducing methyl to 7-position not only increased insecticidal activities against pea aphids, but also show higher insecticidal activities than imidacloprid against imidacloprid-resistant brown planthopper.

To replace nitromethylene pharmacophore with a nitroconjugated system, a series of novel neonicotinoid analogues bearing five-membered aromatic heterocycles were designed and synthesized. Bioassays indicated that some of the synthesized compounds exhibited higher insecticidal activities than imidacloprid against cowpea aphids ( Aphis craccivora ), armyworm ( Pseudaletia separate Walker), Nephotettix bipunctatus (Fabricius), and small brown rice planthopper ( Laodelphasx striatellus ). Exhilaratingly, the activity levels of derivatives 13a and 13j rivaled that of imidacloprid.

A series of hexahydroimidazo[1,2-a]pyridine derivatives were designed and synthesized through aza-Diels-Alder reactions and evaluated for insecticidal activities. Compounds 6a-d with endo-conformation were endowed with excellent insecticidal activities against cowpea aphid ( Aphis craccivora ) and armyworm ( Pseudaletia separata Walker), whereas exo-compounds 7a-d showed only low activities against cowpea aphid. The difference in activities between the endo- and exo-conformations indicated that conformation was the determinant of life or death of the insects for these compounds.

A series of divalent and oxabridged neonicotinoids were synthesized by reactions of nitromethylene analogues of imidacloprid and dialdehydes, and their structures were confirmed by (1)H NMR,(13)C NMR, high-resolution mass spectroscopy, and X-ray diffraction analysis. The bioassays indicated that some of them were endowed with excellent insecticidal activities against cowpea aphid ( Aphis craccivora ), armyworm ( Pseudaletia separata Walker), and brown planthopper ( Nilaparvata lugens ). Divalent neonicotinoid 6 and oxabridged 8a had higher activities than imidacloprid against cowpea aphids and armyworm; furthermore, the activity of 8a was 40.4-fold higher than that of imidacloprid against imidacloprid-resistant brown planthopper.

1-[(4-Aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine (PAPP) is a 5-HT(1A) agonist and was reported to display high affinity for serotonin (5-HT) receptor from the parasitic nematode Haemonchus contortus . The present investigation explored the possibility of using PAPP as a lead compound of new insecticides with novel mode of action. On the basis of the PAPP scaffold, a series of 1-arylmethyl-4-[(trifluoromethyl)pyridin-2-yl]piperazine derivatives were designed, synthesized, and evaluated for biological activities against the armyworm Pseudaletia separata (Walker). Bioassays showed that most of the target compounds displayed certain growth-inhibiting activities or larvicidal activities against armyworm. The quantitative structure-activity relationship (QSAR) for growth-inhibiting activities was also analyzed and established.