A series of 4-thiazolidinone derivatives were synthesized and evaluated as novel human dihydroorotate dehydrogenase (hDHODH) inhibitors. Compounds 26 and 31 displayed IC50 values of 1.75 and 1.12 μM, respectively. The structure–activity relationship was summarized. Further binding mode analysis revealed that compound 31 could form a hydrogen bond with Tyr38 and a water-mediated hydrogen bond with Ala55, which may be necessary for maintaining the bioactivities of the compounds in this series. Further structural optimization of the para- or meta-position of the phenyl group at R will lead to the identification of more potent hDHODH inhibitors.

A series of novel 1,2,3-benzotriazin-4-one derivatives were designed, synthesized and their inhibitory activities against leukotriene A4 hydrolase aminopeptidase in vitro were evaluated. Many compounds showed moderate to good activities at the concentration of 10 μmol/L. Among them, compound IV-16 exhibited the highest inhibitory activity up to 80.6% with an IC50 of 1.30 ± 0.20 μmol/L. The compound IV-16 was also tested the proliferation inhibitory activities in THP1 human AML cell line and its binding model with LTA4H enzyme by molecular docking was studied. It indicated that 1,2,3-benzotriazin-4-one was a promising scaffold for further study. The relationship between structure and inhibitory activity was also preliminarily discussed.Download high-res image (92KB)Download full-size imageNovel 1,2,3-triazin-4-one derivatives incorporating 4-thiazolidinone moieties were designed and synthesized. Many of them exhibited moderate to good inhibitory activity against LTA4H aminopeptidase at 10 μmol/L, the compound IV-16 with best bioactivity was also tested the proliferation inhibitory activities in THP1 human AML cell line and its binding model with LTA4H enzyme by molecular docking was studied. It indicated that 1,2,3-triazin-4-one was a very promising scaffold to study further.

Two series of novel 1,2,3-benzotriazin-4-one derivatives containing thiourea and acylthiourea were designed and synthesized. The bioassay results showed that most of the test compounds showed good nematicidal activity against M. incognita at the concentration of 10.0 mg L−1 in vivo. The compounds A13, A17 and B3 showed excellent nematicidal activity on the second stage juveniles of the root-knot nematode with the inhibition rate of 51.3%, 58.3% and 51.3% at the concentration of 1.0 mg L−1 respectively. It suggested that the structure of 1,2,3-benzotriazin-4-one derivatives containing thiourea and acylthiourea could be optimized further.Download high-res image (148KB)Download full-size image

A series of fused bicyclic 2-aminothiazolyl compounds were synthesized and evaluated for their synergistic effects with polymyxin B (PB) against Klebsiella pneumoniae (SIPI-KPN-1712). Some of the synthesized compounds exhibited synergistic activity. When 4 μg ml−1 compound B1 was combined with PB, it showed potent antibacterial activity, achieving 64-fold reduction of the MIC of PB. Furthermore, compound B1 showed prominent synergistic efficacy in both concentration gradient and time-kill curves in vitro. In addition, B1 combined with PB also exhibited synergistic and partial synergistic effect against E. coli (ATCC25922 and its clinical isolates), Acinetobacter baumannii (ATCC19606 and its clinical isolates), and Pseudomonas aeruginosa (Pae-1399).

A series of novel 1,2,3-benzotriazin-4-one derivatives were synthesized by the reaction of 3-bromoalkyl-1,2,3-benzotriazin-4-ones with potassium salt of 2-cyanoimino-4-oxothiazolidine in the presence of potassium iodide. Nematicidal assays in vivo showed that some of them exhibited good control efficacy against the cucumber root-knot nematode disease caused by Meloidogyne incognita, up to 100% at the concentration of 10.0 mg L–1, which indicated that 1,2,3-benzotriazin-4-one derivatives might be potential for novel promising nematicides. The nematicidal activity was influenced by the combination of substituent type, substituted position, and linker length in the molecule. The inhibition rate data at the concentrations of 5.0 and 1.0 mg L–1 for the compounds with high inhibitory activities were also provided. When tested in vitro, none of them showed direct inhibition against M. incognita. The investigation of a significant difference between in vivo and in vitro data is in progress.

Chlorothiazole ring, as a substituted heterocycle, frequently occurred in structures of various insecticides, and brought positive effect on bioactivity. In purpose to find novel neonicotinoids, a series of pyrrole- and dihydropyrrole-fused neonicotinoid analogs containing chlorothiazole ring were synthesized for the first time. Results of the following biological assays showed that compounds 5a–c achieved good insecticidal activity against Aphis craccivora, and compound 5h exhibited good activity against Nilaparvata lugens.A series of pyrrole- and dihydropyrrole-fused neonicotinoid analogs containing chlorothiazole ring were synthesized for the first time. The bioassays showed that some of the compounds achieved good insecticidal activity against Aphis craccivora and Nilaparvata lugens.

To discover new chemotypes of nematicides with proper toxicological profiles, a series of novel 1,2,3-benzotriazin-4-one derivatives were synthesized and further bioevaluated. The bioassay results showed that most of the synthesized compounds were endowed with moderate to good control efficacy against Meloidogyne incognita at 10.0 mg/L in vivo. Among them, compounds 6k and 6p displayed 100% inhibitory activities at this concentration, which implied that they could be used as lead compounds for promising nematicides.1,2,3-Benzotriazin-4-one derivatives containing spirocyclic indoline-2-one moieties were designed, synthesized and bioevaluated against Meloidogyne incognita. Some of them exhibited good nematicidal activities, up to 100% at 10.0 mg/L.

A facile access to pyrazolo[1,5-a]pyridopyrazin-one is presented via Smiles rearrangement or direct cyclization. The method allows the convenient construction of a novel biaryl lactam in moderate to excellent yields starting from easily available precursors (18 examples, 75–97% yield). When R is an aryl group, two regioisomeric products were obtained, Smiles rearrangement product and direct cyclization product, but when R is alkyl or benzyl, Smiles rearrangement product was afforded selectively. In order to prove the proposed mechanism, intermediate 6k was trapped.

To study the influence of the ring sizes, 37 novel seven-membered azabridged neonicotinoid analogues were synthesized by reactions of nitromethylene analogues, succinaldehyde, and aniline hydrochlorides. Most of the title compounds presented higher insecticidal activities than that of imidacloprid (IMI), cycloxaprid (CYC), and eight-membered compounds against cowpea aphid (Aphis craccivora), armyworm (Pseudaletia separata Walker), and brown planthopper (Nilaparvata lugens), which indicated that introducing the structure of a seven-membered azabridge could significantly improve the insecticidal activities of neonicotinoid analogues. Docking study and binding mode analysis also revealed that introducing methyl group into position 2 of phenyl ring could increase the hydrophobic interactions with receptor, which implied that position 2 might be the key site to get high insecticidal compounds.

Three series of novel azabridge neonicotinoid analogues were designed and synthesized, which were constructed by starting material A, glutaraldehyde, and primary amine hydrochlorides (aliphatic amines, phenylhydrazines, and anilines). Most of the eight-membered azabridge compounds presented higher insecticidal activities than oxabridged compound B against cowpea aphid (Aphis craccivora) and brown planthopper (Nilaparvata lugens). Compared with imidacloprid, some azabridged compounds exhibited excellent insecticidal activity against brown planthopper. The crystal structures and bioassay indicated that changing bridge atoms from O to N could lead to entirely different conformations, which might be the important influential factor of the bioactivities.

The neonicotinoids with a nitroconjugated system had excellent bioactivity, which could rival imidacloprid, and has been previously reported. However, the photodegradation and hydrolysis of this series of neonicotinoids was very quick according to our further investigation, which cannot be developed as a pesticide further. The approach to further enhance the conjugation was tried not only to increase the bioactivities but also to improve the stability in water and in the sun. A substituted phenyl group was introduced into the furan ring of compound 3. A total of 13 novel neonicotinoid analogues with a higher conjugation system were designed and synthesized. The target molecular structures have been confirmed on the basis of satisfactory analytical and spectral data. All compounds presented significant insecticidal activities on cowpea aphid (Aphis craccivora), cotton aphid (Aphis gossypii), and brown planthopper (Nilaparvata lugens). The stability test exhibited that the stability of novel analogues in water and under the mercury lamp has been improved significantly in comparison to compound 3.

On the basis of the structure of heterocyclic-fused cis configuration derivatives and chain-opening neonicotinoids, two series of novel chain-opening tetrahydropyridine analogues were designed and synthesized. The preliminary bioassay tests were determined on cowpea aphid (Aphis craccivora) and armyworm (Pseudaletia separata Walker). The results showed that some of the target compounds exhibited repellent effects, whereas others showed good insecticidal activities.

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.

Photodegradation of 1-((6-chloropyridin-3-yl)methyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-ol (IPPA152001) and 1-((6-chloropyridin-3-yl)methyl)-7-methyl-8-nitro-5-propoxy-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine (IPPA152004) was studied in distilled water; high-pressure mercury lamp and xenon lamp were used as light sources. The photolytic rate constants of the two compounds and their half-lives were calculated. Compared with imidacloprid, the order of photodegradation rate of three compounds was as follows: imidacloprid > IPPA152001 ≥ IPPA152004. Mercury lamp light intensity was measured with chemical actinometers. The quantum yields for photodegradation of IPPA152001 and IPPA152004 in distilled water were also calculated. Photodegradation products of IPPA152004 were preliminarily identified on the basis of the spectral data of GC-MS, LC-TOF-ESI, and LC-MS-MS in positive mode. The photodegradation pathways of IPPA152004 were proposed according to the structures of photoproducts.

A series of divalent and oxabridged neonicotinoids were synthesized by reactions of nitromethylene analogues of imidacloprid and dialdehydes, and their structures were confirmed by 1H NMR, 13C 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.