Design,synthesis and anti-acetylcholinesterase evaluation of some new pyrazolo[4,3-<Emphasis Type="Italic">e</Emphasis>]-1,2,4-triazolo[1,5-<Emphasis Type="Italic">c</Emphasis>]pyrimidine derivatives

The target new hybrid molecule types pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines phosphonates 4 and 2-(coumarin-3’’-yl)-7-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines 5 were prepared via Michaelis–Arbuzov rearrangement (Arbuzov reaction) of pyrazolotriazolopyrimidines chloride 3a–c, with trialkyl phosphate and Knoevenagel reaction of 2-cyanomethyl derivatives 3d–f with salicylic aldehyde, respectively. The precursors 3 were obtained in two steps starting from aminopyrazole 1. Target compounds 4 and 5 were completely characterized by ¹H NMR, ¹³C NMR, ³¹P NMR, IR and HRMS. The anti-acetylcholinesterase activity of compounds 4 and 5 was evaluated, and results found indicated that they have possessed significant activities (IC₅₀ = 1.73–39.86 µM), and the preliminary SAR of these compounds was investigated.     

Synthesis and anticonvulsant activity of 1-formamide-triazolo[4,3-<Emphasis Type="Italic">a</Emphasis>]quinoline derivatives

Using 6-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material, a series of 1-formamide-triazolo[4, 3-a]quinoline derivatives (6a-6n) was synthesized, the anticonvulsant effect and neurotoxicity of the compounds was calculated with maximal electroshock test and rotarod tests with intraperitoneally injected in KunMing mice. The results demonstrated that compound 7-(hexyloxy)-4,5-dihydro-[1,2,4] triazolo[4,3-a]quinoline-1-carboxamide (6d) was the most active one and also had the lowest toxicity. In the anti-maximal electroshock potency test, it showed median effective dose (ED₅₀) of 30.1 mg/kg, median toxicity dose (TD₅₀) of 286 mg/kg, and the protective index of 9.5 which is greater than the reference drug carbamazepine with the protective index value of 6.0.     

Synthesis and biological evaluation of quinolines,thiazolo[3,2-<Emphasis Type="Italic">a</Emphasis>]pyrimidines,thiadiazolo[3,2-<Emphasis Type="Italic">a</Emphasis>]pyrimidines and triazolo[3,4-<Emphasis Type="Italic">b</Emphasis>][1,3,4]thiadiazepines as antimicrobial agents

Series of quinolines, thiazolo[3,2-a]pyrimidines, thiadiazolo[3,2-a]pyrimidines and triazolo[3,4-b][1,3,4]thiadiazepines were synthesized by the reaction of amino compound, aromatic aldehyde and malononitrile/ethyl cyanoacetate, using 2-[5-(4-methoxyphenyl)-4H-1,2,4-triazol-3-ylthio]acetic acid as an organocatalyst in water–ethanol mixture. Synthesized compounds were evaluated for in vitro antibacterial and antifungal activities against three fungal and five bacterial strains. Some of them exhibited good activity in comparison with the standard fluconazole and streptomycin such as compound 16h has shown best antifungal activity with MIC value of 60 µg/mL against A. niger and 12g exhibited best antibacterial activity with MIC value of 50 µg/mL against E. coli.     

Synthesis and anticonvulsant evaluation of<Emphasis Type="Italic">N</Emphasis>-substituted-isoindolinedione derivatives

A series of N-substituted-1,3-isoindolinedione derivatives (2-16) were synthesized for the purpose of defining the effect of N-substitution on the anticonvulsant activity of these derivatives. The target compounds (2-16) were obtained by condensation of phthalic anhydride with the corresponding amine derivative. The structures of the synthesized derivatives (2-16) were confirmed by means of IR, 1H-NMR, 13C-NMR, MS and elemental analyses. The anticonvulsant activity of all compounds (2-16) were evaluated by subcutaneous pentylenetetrazole seizure threshold test at doses of 0.2, 0.4 and 0.8 mmol/kg compared with sodium valproate as a positive control. Their neurotoxicity were determined by the rotorod test. Many of the present series of compounds showed good anticonvulsant activity at the tested doses, as compared to sodium valproate. Three of them (4, 6 and 11) exhibited 100% protection against convulsions, neurotoxicity and death at all tested doses. Out of the series, two compounds (12 and 13) were completely inactive with 100% mortality. 3-(p-chlorophenyl)-4-(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)butanoic acid derivative (11) has emerged as the most active compound which is 20 times more active than valproate with ED50 8.7, 169 mg/kg; TD50 413, 406 mg/kg and PI 47.5, 2.4. The results revealed the importance of the combination of baclofenic and phthalimide moieties (compound 11) as a promising anticonvulsant candidate.     

Synthesis and biological evaluation of 3,6-diaryl-7<Emphasis Type="Italic">H</Emphasis>-thiazolo[3,2-<Emphasis Type="Italic">b</Emphasis>] [1,2,4]triazin-7-one derivatives as acetylcholinesterase inhibitors

Acetylcholinesterase (AChE) inhibitors played an important role in developing a cure for Alzheimer’ s disease. In order to study on the influence of modifications at different groups and side chains on the AChE inhibitory ability and the active sites of 7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives, fourteen 3,6-diaryl-7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives were designed and synthesized. The study of AChE inhibitory activity was carried out using the Ellman colorimetric assay with huperzine-A as the positive control drug. Most of the target compounds exhibited more than 50% inhibition at 10 μM. Some target compounds showed strong inhibition against AChE. The molecular fields analysis and preliminary structureactivity relationships are discussed.     

Bioactive enmein-type 6,7-<Emphasis Type="Italic">seco</Emphasis>-<Emphasis Type="Italic">ent</Emphasis>-kaurane diterpenoids: natural products,synthetic derivatives and apoptosis related mechanism

Diterpenoids are important and widely distributed natural compounds with various biological effects, including antitumor, anti-inflammatory and so on. Great efforts have been put in phytochemistry research on diterpenoids. A number of structural modified derivatives and pharmacophore incorporated hybrids were also designed and synthesized with promising therapeutic effects. Among the hopefuls, enmein-type 6,7-seco-ent-kaurane diterpenoids with unique ring system and stereogenic centers exhibit attractive activities. Based on their lead-like properties, enmein-type diterpenoids are suitable for further medicinal study. The derivatives were biologically evaluated and showed promising activities, which warranted in-depth research for further understanding. In this review, the natural bioactive enmein-type diterpenoids and the synthetic derivatives were comprehensively summarized.     

Synthesis and evaluation of <Emphasis Type="Italic">p</Emphasis>-<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-dialkyl substituted chalcones as anti-cancer agents

Several new N,N-dialkyl substituted chalcones (chalconoids or benzylideneacetophenones) have been synthesized via the condensation of corresponding N,N-dialkylbenzaldehyde with various aryl methyl ketones. All the chalcones have been synthesized from readily available and cheap starting materials under environmentally benign conditions in very high yields without work up and column chromatographic purification. Synthesized compounds have been tested for their biological activity against pathogenic microorganisms such as Escherichia coli, Bacillus subtilis, and Mycobacterium smegmatis. Anti-cancer activity of these compounds has also been tested against multiple myeloma (RPMI-8226) and human mammary adenocarcinoma (MCF-7) cell lines. The most hydrophilic molecules 23 and 24 showed very good anti-cancer activity against MCF-7 cell lines at low micro-molar concentrations. All the compounds have also been evaluated for their activity against Beta-secretase 1 enzyme. One of the synthesized compounds showed Beta-secretase 1 enzyme inhibition activity at micro-molar concentration.     

Synthesis and <Emphasis Type="Italic">in Vitro</Emphasis> cytotoxic activities of 2-alkyl-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-2,6-diazacyclopenta[<Emphasis Type="Italic">b</Emphasis>]anthracene-5,10-diones

A series of 2-alkyl-2,3-dihydro-1H-2,6-diazacyclopenta[b]anthracene-5,10-diones (4a–f) was synthesized and their in vitro cytotoxic activities were evaluated against six human cancer cell lines (HCT15, SK-OV-3, SNB19, A549, MCF7 and MCF7/ADR). They all appeared to be less potent than doxorubicin against all doxorubicin sensitive human cancer cell lines tested. However, these compounds retained considerable cytotoxic activity against the doxorubicin-resistant cell line MCF7/ADR, implying their therapeutic potential to treat doxorubicin-resistant tumors. The most active compound 4c was equipotent with doxorubicin against HCT15 cell line.     

Synthesis and biological evaluation of new imidazo[2,1-<Emphasis Type="Italic">b</Emphasis>]thiazole derivatives as anticancer agents

A series of arylidenehydrazide compounds (3a–3j) were synthesized from [6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]acetic acid hydrazide. The newly synthesized compounds 3b and 3h were subjected to the National Cancer Institute’s in vitro disease-oriented antitumor screening to be evaluated for antitumor activity. Compound 3b, the most potent compound examined, displayed broad spectrum antiproliferative activity against all of the tested cell lines with log₁₀GI₅₀ values between ?4.41 and ?6.44. The greatest growth inhibitions were observed against an ovarian cancer cell line(OVCAR-3), a colon cancer cell line (HCT-15), two renal cancer cell lines (CAKI-1 and UO-31) and two leukemia cell lines (CCRF-CEM and SR) with log₁₀GI₁₀ values ?6.44, ?6.33, ?6.11, ?6.30, ?6.13 and ?6.22, respectively. Open image in new window     

Differences between<Emphasis Type="Italic"> d</Emphasis>-methamphetamine and<Emphasis Type="Italic"> d</Emphasis>-amphetamine in rats: working memory,tolerance, and extinction

Rationale Previously, we have shown that d-amphetamine (AMPH) was more potent than d-methamphetamine (METH) at increasing extracellular levels of dopamine (DA) in the prefrontal cortex (PFC) at doses that had similar effects in the nucleus accumbens. Since working memory depends on PFC DA, it was postulated that AMPH would also be more potent than METH at affecting working memory. Objective To determine if AMPH is more potent than METH at affecting working memory. Methods Working memory was measured in adult female Sprague-Dawley rats using a delayed-alternation T-maze task with multiple delays (1, 10, 60 s) and food rewards. The percentage of food rewards consumed was also recorded. Animals were tested with METH and AMPH before and after a chronic protocol, with measurements of locomotor activity used to test for pharmacological tolerance or sensitization. The effects of METH and AMPH on extinction were also examined by omitting the food rewards from the T-maze. Results Both METH and AMPH produced dose-related bimodal effects on working memory at the intermediate delay (10 s); however, AMPH was more potent than METH. Both METH and AMPH initially also decreased the percentage of food rewards consumed in the T-maze. After chronic testing, animals displayed tolerance to both the working memory impairments and the reduction in food reward intake produced by AMPH. Animals did not display significant tolerance to the effects of METH on food reward consumption and performed worse in the T-maze after chronic testing. METH, but not AMPH, interfered with extinction. Conclusions These results indicate that METH and AMPH differ in altering working memory and the expression of tolerance, perhaps due to differences in behavioral inhibition.     

Anticancer activity of some [1,2,4]triazepino[2,3-<Emphasis Type="Italic">a</Emphasis>] quinazoline derivatives: monolayer and multicellular spheroids in vitro models

In this study, five derivatives of triazepino[2,3-a] quinazoline-2,7(1H)-dione were synthesized and their anticancer activities were investigated both in two-dimensional-monolayer and three-dimensional-multicellular spheroids cancer models. All the five compounds showed very high anticancer activities against the 11 cancer cell types that have been investigated in the monolayer model. Comparing the results of both monolayer and multicellular spheroids models of the anticancer activity of these five compounds, we can conclude that the meta-methyl derivative induced its anticancer activity through apoptosis to give the best results in the monolayer model. However, in the multicellular spheroids model its apoptotic activity induced moderate anticancer activity (64?% cytotoxicity). On the other hand, both two nitro-derivatives either in meta-position or para-position, did not show potent pro-apoptotic activities toward the monolayer model but showed very high cytotoxic activity toward the multicellular spheroids model (100?%). These results reveal that the cell death mechanism induced by both nitro-compounds is exerted via other path than the apoptosis. Interestingly, all the tested compounds were generally safe to normal cells spheroids when tested at the same concentration.     

Design,docking studies and molecular iodine catalyzed synthesis of benzo[<Emphasis Type="Italic">a</Emphasis>]xanthen-one derivatives as <Emphasis Type="Italic">hyaluronidase</Emphasis> inhibitors

A series of novel benzo[a]xanthen-11(12H)-one derivatives 4a–m were designed and subjected to docking studies. The title compounds were synthesized from 3-aryl-4-formylsydnones 1a–m, β-naphthol and dimedone in presence of molecular iodine as a catalyst and evaluated for their in vitro inhibitory effects on the hyaluronidase.