Zi-Ning Cui

Synthesis and bioactivity of pyrazole and triazole derivatives as potential PDE4 inhibitors.

A series of pyrazole and triazole derivatives containing 5-phenyl-2-furan functionality were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Meanwhile, the activity of compounds containing 1,2,4-triazole (series II) was higher than that of pyrazole-attached derivatives (series I). The primary structure-activity relationship study and docking results showed that the 1,2,4-triazole moiety of compound IIk played a key role to form integral hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound IIk would be great promise as a hit compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as potential PDE4 inhibitors.

The design, synthesis, and biological evaluation of new phosphodiesterase type 4 (PDE4) inhibitors, which possessed 7-(cyclopentyloxy)-6-methoxy 1,2,3,4-tetrahydroisoquinoline ring, were described. Compound 8 [(7-cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxy-3-methoxy-phenyl)methanone] showed the best inhibitory activity and good selectivity against PDE4B. The docking results showed that the catechol diether moiety of compound 8 played a key role to form integral hydrogen bonds with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound 8 would be great promise as a hit compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

Design, synthesis and biological evaluation of 2,4-disubstituted oxazole derivatives as potential PDE4 inhibitors

In this study, a series of pyrazole derivatives containing 4-phenyl-2-oxazole moiety were designed and synthesized in a concise way, some of which exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF-α release. Compound 4c displayed the strongest inhibition activity (IC50=1.6±0.4μM) and good selectivity against PDE4B. Meanwhile, compound 4c showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship study showed the 3,5-dimethylpyrazole residue was essential for the bioactivity, and the substituted group R1 at the benzene ring also affected the activity. Docking results showed that compound 4c played a key role to form integral hydrogen bonds and a π-π stacking interaction, using hydrazide scaffold (CONN) and pyrazole ring respectively, with PDE4B protein. While the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Compound 4c would be great promise as a lead compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

Synthesis and Fungicidal Activity of N-(2,4,5-trichlorophenyl)-2-Oxo-and 2-Hydroxycycloalkylsulfonamides

A series of N-(2,4,5-trichlorophenyl)-2-Oxo- and 2-Hydroxycycloalkyl- sulfonamides (series II and III) were designed and synthesized based on the leading compound chesulfamide (code name: CAUWL-2004-L-13). Their struc- tures were confirmed by 1 H NMR, IR and elemental analysis. Compounds II and III showed excellent activities against the Botrytis cinerea both in vitro and in vivo. Mycelia growth and conidial germination assays exhibited that EC50 of compound IId were 0.64 μg mL -1 and 0.34 μg mL -1 respectively. For in vivo control of B. cinerea in cucumber seedlings, compounds IIb and IId showed better control effect than the commercial fungicides procymidone and pyrimethanil. In addition, these new compounds had broader fungicidal spectra than chlorothalonil. The fungicidal activity was affected obviously by the size of cycloalkane. All the compounds with six-, seven-, and eight-membered ring showed high fungi- cidal activities.

Synthesis of 2-Acyloxycyclohexylsulfonamides and Evaluation on Their Fungicidal Activity

Eighteen N-substituted phenyl-2-acyloxycyclohexylsulfonamides (III) were designed and synthesized by the reaction of N-substituted phenyl-2-hydroxyl-cycloalkylsulfonamides (I, R1) with acyl chloride (II, R2) in dichloromethane under the catalysis of TMEDA and molecular sieve. High fungicidal active compound N-(2,4,5-trichlorophenyl)-2-(2-ethoxyacetoxy) cyclohexylsulfonamide (III-18) was screened out. Mycelia growth assay against the Botrytis cinerea exhibited that EC50 and EC80 of compound III-18 were 4.17 and 17.15 μg mL−1 respectively, which was better than the commercial fungicide procymidone (EC50 = 4.46 μg mL−1 and EC80 = 35.02 μg mL−1). For in vivo activity against B. cinerea in living leaf of cucumber, the control effect of compound III-18 was better than the fungicide cyprodinil. In addition, this new compound had broader fungicidal spectra than chlorothalonil.

Synthesis and fungicidal activity of novel 2,5-disubstituted-1,3,4- thiadiazole derivatives containing 5-phenyl-2-furan

A series of 2,5-disubstituted-1,3,4-thiadiazoles were synthesized using Lawesson’s reagent by an efficient approach under microwave irradiation in good yields. Their structures were characterized by MS, IR, 1H NMR, 13C NMR, and elemental analysis. Their in vitro and in vivo fungicidal activities revealed that the title compounds exhibited considerable activity against five selected fungi, especially to Phytophthora infestans. In order to illustrate the mechanism of title compounds against P. infestans, scanning electron micrographs (SEM) and transmission electron micrographs (TEM) were applied. The morphological and ultrastructural studies demonstrated that compound I18 led to swelling of hyphae, thickening and proliferating multilayer cell walls, excessive septation and accumulation of dense bodies. The bioassay results indicated compound I18 might act on cell wall biosynthesis, and blocked the nutrition transportation and led to cells senescence and death. Meanwhile, compound I18 had broad fungicidal activity against other twenty different kinds of fungi. These results suggested that title compounds were eligible to be development candidates and compound I18 as a promising lead compound was worthy to be further discovery, especially against P. infestans.

Synthesis and Bioactivity of 5-Substituted-2-furoyl Diacylhydazide Derivatives with Aliphatic Chain

A series of 5-substituted-2-furoyl diacylhydazide derivatives with aliphatic chain were designed and synthesized. Their structures were characterized by IR, 1H NMR, elemental analysis, and X-ray single crystal diffraction. The anti-tumor bioassay revealed that some title compounds exhibited promising activity against the selected cancer cell lines, especially against the human promyelocytic leukemic cells (HL-60). Their fungicidal tests indicated that most of the title compounds showed significant anti-fungal activity. The preliminary structure-activity relationship showed that the aliphatic chain length and differences in the R2 group had obvious effects on the anti-tumor and anti-fungal activities. The bioassay results demonstrated that the title compounds hold great promise as novel lead compounds for further drug discovery.

Synthesis and bioactivity of novel xanthone and thioxanthone L-rhamnopyranosides

A series of xanthone and thioxanthone rhamnopyranosides were designed and synthesized. Their in vitro cytotoxicity and topoisomerase inhibitory activity were evaluated. The bioassay results indicated that the introduction of the 2,3-di-O-acetyl-α-L-rhamnopyranosyl moiety to anthracene was helpful to improve the cytotoxicity in vitro. The modifications of anthracene had an important effect on the tumor cell growth inhibitory activity. Interestingly, consistency was observed between the cytotoxicity and topo I activity in these anthracene analogs, suggesting that the incorporation of either a polymethyleneamine side chain or a pyrazole ring into the anthraquinone chromophore was able to enhance topo I inhibitory activity as well as cytotoxicity simultaneously. Among them, compound 11 as a new lead compound was discovered, which showed wide in vitro cytotoxicity against 12 tumor cell lines and potential antimultidrug resistance capability. It was proved that compound 11 could induce cell apoptosis in KB cells via both extrinsic and intrinsic pathways. Flow cytometric analysis exhibited that treatment of KB cells with compound 11 led to cell apoptosis accompanied by cell cycle arrest at the G2/M phase. Furthermore, compound 11 caused a significant and dose-dependent inhibition of topoisomerase I catalytic activity.

Synthesis and Larvicidal Activity of Novel Thenoylhydrazide Derivatives

A pair of chemical isomeric structures of novel N-tert-butylphenyl thenoylhydrazide compounds I and II were designed and synthesized. Their structures were characterized by MS, IR, 1H NMR, elemental analysis and X-ray single crystal diffraction. The regioselectivity of the Meerwein arylation reaction and the electrophilic substitution reaction of N-tert-butyl hydrazine were studied by density functional theory (DFT) quantum chemical method. The larvicidal tests revealed that some compounds I had excellent larvicidal activity against Culex pipiens pallens. As the candidates of insect growth regulators (IGRs), the larval growth inhibition and regulation against Culex pipiens pallens were examined for some compounds, especially I1 and I7. Compounds I1 and I7 were further indicated as an ecdysteroid agonist by reporter gene assay on the Spodoptera frugiperda cell line (Sf9 cells). Finally, a molecular docking study of compound I7 was conducted, which was not only beneficial to understand the structure-activity relationship, but also useful for development of new IGRs for the control of mosquitos.

Synthesis, Fungicidal Activity and Mode of Action of 4-Phenyl-6-trifluoromethyl-2-aminopyrimidines against Botrytis cinerea.

Anilinopyrimidines are the main chemical agents for management of Botrytis cinerea. However, the drug resistance in fungi against this kind of compounds is very serious. To explore new potential fungicides against B. cinerea, a series of 4-phenyl-6-trifluoromethyl-2-amino-pyrimidine compounds (compounds III-1 to III-22) were synthesized, and their structures were confirmed by 1H-NMR, IR and MS. Most of these compounds possessed excellent fungicidal activity. The compounds III-3 and III-13 showed higher fungicidal activity than the positive control pyrimethanil on fructose gelatin agar (FGA), and compound III-3 on potato dextrose agar (PDA) indicated high activity compared to the positive control cyprodinil. In vivo greenhouse results indicated that the activity of compounds III-3, III-8, and III-11 was significantly higher than that of the fungicide pyrimethanil. Scanning electron micrography (SEM) and transmission electron micrography (TEM) were applied to illustrate the mechanism of title compounds against B. cinerea. The title compounds, especially those containing a fluorine atom at the ortho-position on the benzene ring, could maintain the antifungal activity against B. cinerea, but their mechanism of action is different from that of cyprodinil. The present study lays a good foundation for us to find more efficient reagents against B. cinerea.