Synthesis,Characterization,Nematocidal Activity and Docking Study of Novel Pyrazole-4-carboxamide Derivatives

A series of novel 1-methyl-3-（trifluoromethyl）-^1H-pyrazole-4-carboxamide derivatives were designed based on our previous work and synthesized. All these title compounds were confirmed by NMR and MS. The primarily nematocidal activity results indicated that some of them exhibited good control efficacy against the tomato root-knot nematode disease caused by M. incognita. The docking results indicated that compound 6n interacts with amino acid residue Trp 279 of Ach E via hydrogen bond and amino acid residue Trp 84 of Ach E via π-π interaction.

Synthesis,Crystal Structure,Antitumor Activities and Docking Study of 1-(2-(1H-Indol-3-yl)ethyl)-3-(2-methoxyphenyl)urea

The title compound,1-（2-（1 H-indol-3-yl）ethyl）-3-（2-methoxyphenyl）urea（C（18）H（19）N3O2,Mr = 309.36） has been synthesized,and its structure was characterized by ^1H-NMR,^13C-NMR,ESI-MS and single-crystal X-ray diffraction.It crystallizes in the monoclinic space group P21/c with a = 16.2774（15）,b = 11.1082（10）,c = 9.0819（3） A,β = 103.09（9）°,V = 1599.5（3） A^3,Z = 4,T = 293（2） K,μ（MoKα） = 0.086 mm^（-1,Dc = 1.285 g/cm^3,F（000） = 656 and GOOF = 0.981.5973 reflections were measured（7.04≤2θ≤52.04°）,and 3143 were unique（Rint= 0.0393,Rsigma = 0.0546） and used in all calculations.The final R = 0.0756（I 〉 2σ（I）） and w R = 0.1976（all data）.The antitumor activity of the title compound was analyzed by MTT assay.Meanwhile,to rationalize its potencies in the CDK4 target,the title compound was docked into CDK4 protein and the interactions with the active site residues were analyzed.

p-TSA-catalyzed one-pot synthesis and docking studies of some 5H-indeno[ 1,2-b]quinoline-9,11 (6H,10H)-dione derivatives as anticonvulsant agents

The present work describes a facile, one-pot three component environment friendly, green synthesis of a series of 5-（4-methoxyphenyl）-7,7-dimethyl-10-phenyl-7,8-dihydro-SH-indeno[ 1,2-b]quinoline- 9,11 （6H,10H）-dione derivatives 8（a-n）. 1,3-indanedione, awl-aldehyde and enaminone was thoroughly ground in the presence of catalytic amount of p-toluene sulfonic acid （p-TSA） to give the titled compounds in good yields. All the synthesized derivatives were evaluated for their anticonvulsant activity using the maximal electroshock （MES） method with phenytoin as a standard drug along with their neurotoxicity effect. Derivatives 8b, 8e and 8k exhibited significant anticonvulsant activity （P 〈 0.001）. The neurotoxicity study clearly revealed that all the tested compounds are non-toxic at a dose of 40 mg/kg. The molecular modeling studies also predicted good binding interactions of most active molecules with the serotonin 5-HT2A receptor. Therefore, it can be safely concluded that synthesized derivatives 8（a-n） would represent useful leads for further investigation in the development of a new class of anticonvulsant agents.

Conventional and microwave irradiated synthesis,biological activity evaluation and molecular docking studies of highly substituted piperazine-azole hybrids

Azole derivatives（3,6） obtained starting from 1-（2-methoxyphenyl） piperazine were converted to the corresponding Mannich bases containing β-lactame or flouroquinolone core via a one pot three component reaction.The synthesis of conazole analogues was carried out starting from triazoles by three steps.Reactions were carried out under conventional and microwave mediated conditions.All the newly synthesized compounds were screened for their antimicrobial,enzyme inhibition and antioxidant activity,and most of them displayed good-moderate activity.Binding affinities and non-covalent interactions between enzyme-ligand complexes were predicted with molecular docking method at molecular level.Docking results complemented well the experimental results on α-glucosidase and urease inhibitory effects of the compounds.Higher binding affinities and much more interaction networks were observed for active compounds in contrary to inactive ones.It was predicted with the docking studies that triazole and anisole moieties in the structure of the synthesized compounds contributed to the stabilization of corresponding enzymes through noncovalent interactions.

New triazole derivatives containing substituted 1,2,3-triazole side chains:Design,synthesis and antifungal activity

In order to discover new generation of triazole antifungal agents,a series of novel antifungal triazoles were designed and synthesized by structural simplification of our previously identified triazolepiperdine-heterocycle lead compounds.Several target compounds showed good antifungal activity with a broad spectrum.In particular,compound 71 was highly active against Candida albicans and Candida glabrata.Moreover,compound 71 showed potent in vivo antifungal efficacy in the Caenorhabditis elegans-C.albicans infection model.

Inhibition of thrombin by functionalized C_(60)nanoparticles revealed via in vitro assays and in silico studies

The studies on the human toxicity of nanoparticles（NPs） are far behind the rapid development of engineered functionalized NPs. Fullerene has been widely used as drug carrier skeleton due to its reported low risk. However, different from other kinds of NPs, fullerene-based NPs（C_（60） NPs） have been found to have an anticoagulation effect, although the potential target is still unknown. In the study, both experimental and computational methods were adopted to gain mechanistic insight into the modulation of thrombin activity by nine kinds of C_（60） NPs with diverse surface chemistry properties. In vitro enzyme activity assays showed that all tested surface-modified C_（60） NPs exhibited thrombin inhibition ability. Kinetic studies coupled with competitive testing using 3 known inhibitors indicated that six of the C_（60） NPs, of greater hydrophobicity and hydrogen bond（HB） donor acidity or acceptor basicity, acted as competitive inhibitors of thrombin by directly interacting with the active site of thrombin. A simple quantitative nanostructure-activity relationship model relating the surface substituent properties to the inhibition potential was then established for the six competitive inhibitors.Molecular docking analysis revealed that the intermolecular HB interactions were important for the specific binding of C_（60） NPs to the active site canyon, while the additional stability provided by the surface groups through van der Waals interaction also play a key role in the thrombin binding affinity of the NPs. Our results suggest that thrombin is a possible target of the surface-functionalized C_（60） NPs relevant to their anticoagulation effect.

C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance

We formulated and analyzed a novel nanoformulation of the anticancer drug cisplatin （Cis） with C60 fullerene （C60＋Cis complex） and showed its higher toxicity toward tumor cell lines in vitro when compared to Cis alone. The highest toxicity of the complex was observed in HL-60/adr and HL-60/vinc chemotherapy- resistant human leukemia cell sublines （resistant to Adriamycin and Vinculin, respectively）. We discovered that the action of the C60＋Cis complex is associated with overcoming the drug resistance of the tumor cell lines through observing an increased number of apoptotic cells in the Annexin V/PI assay. Moreover, in vivo assays with Lewis lung carcinoma （LLC） C57BL/6J male mice showed that the C60＋Cis complex increases tumor growth inhibition, when compared to Cis or C60 fullerenes alone. Simultaneously, we conducted a molecular docking study and performed an Ames test. Molecular docking specifies the capability of a C60 fullerene to form van der Waals interactions with potential binding sites on P-glycoprotein （P-gp）, multidrug resistance protein 1 （MRP-1）, and multidrug resistance protein 2 （MRP-2） molecules. The observed phenomenon revealed a possible mechanism to bypass tumor cell drug resistance by the C60＋Cis complex. Additionally, the results of the Ames test show that the formation of such a complex diminishes the Cis mutagenic activity and may reduce the probability of secondary neoplasm formation. In conclusion, the C60＋Cis complex effectively induced tumor cell death in vitro and inhibited tumor growth in vivo, overcoming drug resistance likely by the potential of the C60 fullerene to interact with P-gp, MRP-1, and MRP-2 molecules. Thus, the C60＋Cis complex might be a potential novel chemotherapy modification.