Design and Evaluation of Novel Antimicrobial and Anticancer Agents Among Tetrazolo[1,5-c]quinazoline-5-thione S-Derivatives

The novel heterocyclization of 5-(2-aminophenyl)-1H-tetrazole with potassium ethylxanthogenate or carbon disulfide was proposed. The potassium salt of the tetrazolo[1,5-c]quinazoline-5-thione was subsequently modified by alkylation with proper halogen derivatives to (tetrazolo[1,5-c]quinazolin-5-ylthio)alkyls, N,N-dialkylethylamines, 1-aryl-2-ethanones, 1-(alkyl)aryl-2-ethanols, carboxylic acids, and esters. The structures of all newly synthesized compounds were confirmed by FT-IR, UV-vis, LC-MS, ¹H, ¹³C NMR, and elemental analysis data. The substances were screened for antibacterial and antifungal activities (100 μg) against Escherichia coli, Staphylococcus aureus, Enterobacter aerogenes, Entrococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans. Preliminary bioluminescence inhibition tests against Photobacterium leiognathi Sh1 showed that substances 5.2–5.4, 6.1, 7.1 with ethanone or carboxylic acid substituents showed toxicity against bacteria cells. The substances chosen by the US National Cancer Institute (NCI) were screened for their ability to inhibit 60 different human tumor cell lines, where 2-(tetrazolo[1,5-c]quinazolin-5-ylthio)-1-(4-tolyl)ethanone (5.2), 3-(tetrazolo[1,5-c]quinazolin-5-ylthio)propanoic and related 3-metyl-butanoic acids (6.2, 6.3), and ethyl tetrazolo[1,5-c]quinazolin-5-ylthio)acetate (7.2) showed lethal antitumor activity (1.0 μM) against the acute lymphoblastic leukemia cell line (CCRF-CEM), and substances 5.2 and 6.3 exhibited moderate anticancer properties inhibiting growth of the leukemia MOLT-4 and HL06-(TB) cell lines. The moderate antitumor activity was demonstrated in 1-(2,5-dimethoxyphenyl)-2-(tetrazolo[1,5-c]quinazolin-5-ylthio)ethanone (5.4) against the CNS cancer cell line SNB-75. Comparing the docking mode of the Gefitinib and synthesised substances on the ATP binding site of EGFR, it could be assumed that these compounds might act in the same way. The results of the investigation could be considered as a useful base for future development of potent antimicrobials and antitumor agents among tetrazolo[1,5-c]quinazoline-5-thione S-derivatives.     

Synthesis and Antimicrobial Activity of 6-Thioxo-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]-quinazolin-2-one Derivatives

Potassium 8-R¹-9-R²-10-R³-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-thiolates 2.1–2.26 were synthesized via cyclocondensation of 6-R-3-(3-R¹-4-R²-5-R³-aminophenyl)-1,2,4-triazin-5-ones 1.1–1.26 with carbon disulfide, potassium hydroxide, and ethanol or with potassium O-ethyl dithiocarbonate in 2-propanol. The corresponding thiones 3.1–3.26 were obtained by treatment of 2.1–2.26 with hydrochloric acid. It was found that the nature of the substituents in positions 3, 4, and 5 of the corresponding 6-R-3-(3-R¹-4-R²-5-R³-aminophenyl)-1,2,4-triazin-5-ones were affected on the terms of the reaction. The structures of compounds were proven by a complex of physicochemical methods (¹H, ¹³C NMR, LC–MS, and EI-MS). The results of the antibacterial and antifungal activity assay allowed the determination of the high sensitivity of Staphylococcus aureus ATCC 25923 (MIC 6.25–100 μg/mL, MBC 12.5–200 μg/mL) to the synthesized compounds.     

Synthesis and Anticancer Activity of 2-(Alkyl-, Alkaryl-, Aryl-, Hetaryl-)-[1,2,4]triazolo[1,5-c]quinazolines

The combinatorial library of novel potential anticancer agents, namely, 2-(alkyl-, alkaryl-, aryl-, hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines, was synthesized by the heterocyclization of the alkyl-, alkaryl-, aryl-, hetarylcarboxylic acid (3H-quinazoline-4-ylidene)hydrazides by oxidative heterocyclization of the 4-(arylidenehydrazino)quinazolines using bromine, and by the heterocyclization of N-(2-cyanophenyl)formimidic acid ethyl ester. The optimal method for synthesis of the s-triazolo[1,5-c]quinazolines appeared to be cyclocondensation of the corresponding carboxylic acid (3H-quinazoline-4-ylidene)hydrazides. The compounds’ structures were established by ¹H, ¹³C NMR, LC- and EI-MS analysis. The in vitro screening of anticancer activity determined the most active compound to be 3,4,5-trimethoxy-N′-[quinazolin-4(3H)-ylidene]benzohydrazide (3.20) in micromolar concentrations with the GI₅₀ level (MG_MID, GI₅₀ is 2.29). Thus, the cancer cell lines whose growth is greatly inhibited by compound 3.20 are: non-small cell lung cancer (NCI-H522, GI₅₀=0.34), CNS (SF-295, GI₅₀=0.95), ovarian (OVCAR-3, GI₅₀=0.33), prostate (PC-3, GI₅₀=0.56), and breast cancer (MCF7, GI₅₀=0.52), leukemia (K-562, GI₅₀=0.41; SR, GI₅₀=0.29), and melanoma (MDA-MB-435, GI₅₀=0.31; SK-MEL-5, GI₅₀=0.74; UACC-62, GI₅₀=0.32). SAR-analysis is also discussed.     

Substituted 2-[(2-Oxo-2H-[1,2,4]triazino [2,3-c]quinazolin-6-yl)thio]acetamides with Thiazole and Thiadiazole Fragments: Synthesis,Physicochemical Properties,Cytotoxicity, and Anticancer Activity

The series of novel N-R-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]acetamides with thiazole and thiadiazole fragments in a molecule were obtained by alkylation of potassium salts 1.1–1.4 by N-hetaryl-2-chloroacetamides and by aminolysis of activated acids 2.1–2.4 with N,N’-carbonyldiimidazole (CDI). The structures of compounds were determined by IR, ¹H NMR, MS, and EI-MS analysis. The results of cytotoxicity evaluated by the bioluminescence inhibition of bacterium Photobacterium leiognathi, Sh1 showed that the compounds have considerable cytotoxicity. The synthesized compounds were tested for anticancer activity in NCI against 60 cell lines. Among the highly active compounds 3.1, 3.2, and 6.5, 2-[(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]-N-(1,3-thiazol-2-yl)acetamide (3.1) was found to be the most active anticancer agent against the cell lines of colon cancer (GI₅₀ at 0.41–0.69 μM), melanoma (GI₅₀ 0.48–13.50 μM), and ovarian cancer (GI₅₀ 0.25–5.01 μM). The structure-activity relationship (SAR-analysis) was discussed.     

Synthesis and Biological Activity of New [1,3]Thiazolo[4,5-d]pyridazin-4(5H)-ones

A series of novel 2-(N-pyrrolidino, N-piperidino or N-morpholino)-7-phenyl(α-furoyl or α-thienyl)-[1,3]thiazolo[4,5-d]pyridazinones 10a–c, 14–16a,b was synthesized in 78–87% yields via the reaction of methyl 5-benzoyl(α-furoyl or α-thienyl)-2-aminosubstituted-thiazol-4-carboxylates 9a–c, 13a–e with hydrazine. These new compounds have been tested for their in vivo analgesic and anti-inflammatory activities. All compounds have been characterized by ¹H-NMR, ¹³C-NMR spectroscopy, and liquid chromatography–mass spectrometry.     

Synthesis and Antioxidant Activity of 7-Thio Derivatives of 6,7-Dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

New 7-thio derivatives of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione have been synthesized by the reaction of 3-cyclohexyl-7-thio-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione with alkylhalogenides. The synthesized compounds were tested for antioxidant activity on the model of Fe²⁺-dependent oxidation of adrenaline in vitro. It was found that the antiradical activity of 7-thio derivatives of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione significantly depends on the structure of the substituent which is part of the thioether fragment of the base molecule.     

Synthesis,Characterization, and Cytotoxicity of Some New 5-Aminopyrazole and Pyrazolo[1,5-a]pyrimidine Derivatives

5-Amino-N-aryl-3-[(4-methoxyphenyl)amino]-1H-pyrazole-4-carboxamides 4a–c were synthesized by the reaction of N-(aryl)-2-cyano-3-[(4-methoxyphenyl)amino]-3-(methylthio)acrylamides 3a–c with hydrazine hydrate in ethanol. The reaction of 5-amino-N-aryl-1H-pyrazoles 4a–c with acetylacetone 5 or 2-(4-methoxybenzylidene)malononitrile 8 yielded the pyrazolo[1,5-a]pyrimidine derivatives 7a–c and 10a–c, respectively. The structures of the synthesized compounds were established based on elemental analysis and spectral data (IR, MS, ¹H-NMR, and ¹³C-NMR). Representative examples of the new synthesized products were screened for their in vitro cytotoxic activity against Ehrlich Ascites Carcinoma (EAC) cells.     

Antiherpes activity of [E]-5-(1-propenyl)-2′-deoxyuridine and 5-(1-propenyl)-1-β-d-arabinofuranosyluracil

5-(1-Propenyl)-1-β-d-arabinofuranosyluracil has been synthesized, and this compound and [E]-5-(1-propenyl)-2′-deoxyuridine have been tested for inhibition of herpes virus multiplication. Only [E]-5-(1-propenyl)-2′-deoxyuridine was found to be an active inhibitor reducing by 50% the plaque formation of herpes simplex virus type 1 (HSV-1) at about 1 μM. A comparison to the bromovinyl derivatives showed the following order of decreasing activity; $\text{[}\text{E}\text{]-5-(2-}\text{bromovinyl}\text{)-2′-}\text{deoxyuridine}\text{> 5-(2-}\text{bromovinyl}\text{)-1-β-}\text{d}\text{-}\text{arabinofuranosyluracil}\text{≥ [}\text{E}\text{]-5-(1-}\text{propenyl}\text{)-2′-}\text{deoxyuridine}\text{> 5-(1-}\text{propenyl}\text{)-1-β-}\text{arabinofuranosyluracil}$. HSV-1 mutants lacking thymidine kinase or resistant against acycloguanosine were resistant against [E]-5-(1-propenyl)-2′-deoxyuridine. All compounds seemed to be phosphorylated by HSV-1 thymidine kinase in a cell-free assay. The compounds were phosphorylated to a lower extent by cellular or HSV-2 thymidine kinase, and the HSV-2 strains tested were inhibited by less than 50% at 100 μM in plaque assays. A selective inhibition of HSV-1 DNA synthesis by [E]-5-(1-propenyl)-2′-deoxyuridine was observed in infected cells indicating an effect on viral DNA polymerase. [E]-5-(1-Propenyl)-2′-deoxyuridine had a low cellular toxicity and a therapeutic effect when applied topically to HSV-1-infected guinea pig skin.     

Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4

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Synthesis of novel 2-phenyl-3-[2-(substituted amino) ethylamino] quinazolin-4(3H)-ones as a new class of H1-antihistaminic agents

A series of novel 2-phenyl-3-[2-(substituted amino) ethylamino] quinazolin-4(3H)-ones was synthesized by the nucleophilic substitution of 3-(2-bromo ethylamino)-2-phenyl quinazolin-4(3H)-one with various amines. The starting material, 3-(2-bromo ethylamino)-2-phenyl quinazolin-4(3H)-one, was synthesized from anthranilic acid by a multistep synthesis. All the title compounds were tested for their in vivo H₁-antihistaminic activity on conscious guinea pigs at the dose level of 10 mg/kg using chlorpheniramine as the standard drug. The results of the biologic activity revealed that all the test compounds protected the animals from histamine-induced bronchospasm significantly. Compound 2-phenyl-3-[2-(piperazinyl) ethylamino] quinazolin-4(3H)-one (S3) emerged as the most active compound of the series (73.67 % protection) when compared to the standard chlorpheniramine (70.09 % protection). Interestingly, compound S3 shows negligible sedation (8.21 %) compared to chlorpheniramine maleate (29.58 %). Therefore, compound S3 can serve as the lead molecule for further development into a new class of H₁-antihistaminic agents.     

Synthesis,Anti-Inflammatory,and Ulcerogenicity Studies of Novel Substituted and Fused Pyrazolo[3,4-d]pyrimidin-4-ones

In the present investigation, some new pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives (7–12) as well as fused pyrazolo[3′,4′:4,5]pyrimido[1,2-b]pyridazin-4(1H)-one (14–16) and 7,8,9,10-tetrahydropyrazolo[3′,4′:4,5]pyrimido[1,2-b]-cinnolin-4(1H)-one (17) ring systems were synthesized using the starting compound 5-amino-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5). The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. The theoretical calculation of their lipophilicity as C log P was performed. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw edema test in rats using indomethacin as the reference drug. Ulcer indices for the most active compounds were calculated. Seven compounds (10b, 11a–f) showed consistently good anti-inflammatory activity. In particular, 5-{[4-(4-bromophenyl)-3-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]amino}-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (11e) and its 3,4-bis(4-chlorophenyl) analog (11f) were found to be the most effective among the other derivatives, showing activity comparable to that of indomethacin with minimal ulcerogenic effects. Correlation of the biological data of the active compounds with their theoretically calculated C log P values revealed that lipophilicity influences the biological response.     

QSAR modeling of synthesized 3-(1,3-benzothiazol-2-yl) 2-phenyl quinazolin-4(3H)-ones as potent antibacterial agents

Present communication elicits the designing and synthesis of 3-(1,3-benzothiazol-2-yl) 2-phenyl quinazolin-4(3H)-ones as potential antibacterial agents. A number of substituted 2-amino benzothiazoles, 2-amino-5-[(E)-phenyl diazenyl] benzoic acid, and 2-phenyl-4H benzo[d] [1,3] oxazin-4-one were synthesized as the precursor substrates. The compounds were synthesized in excellent yields and the structures were corroborated on the basis of IR, ¹H NMR, Mass, and elemental analysis data. These compounds were screened in vitro for their antibacterial activity against a representative panel of Gram positive and Gram negative bacteria and models were generated through quantitative structure–activity relationship (QSAR).The activity contributions due to structural and substituent effects were determined using sequential regression procedure. The antimicrobial assay data show that the synthesized compounds are found to manifest profound antimicrobial activity.     

Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

Synthese von 5H-Pyrido[2,3-c]-2-benzazepinen

Synthesis of 5H-Pyrido[2,3-c]-2-benzazepines The title compounds can be obtained by two differend ways: Ring closure of 2-benzazepine enaminonitrile 1 and the C₂-building blocks 2, 7 and 8 gives rise to the title compounds 6, 9 and 10 . - The second way starts with Wolff-Kishner-reduction of the 2-amino-3-benzoylpyridines 16a,b to the 2-amino-3-benzylpyridines 18a,b . Benzoylation of 18a,b leads to the dibenzoylated compounds 20 and 21 , respectively, which can be transformed to the monobenzoylated pyridines 22 resp. 23 . Applying the Bischler-Napieralski-reaction on 22a,b and 23a,b leads to the 5H-pyrido[2,3-c]-2-benzazepines 24a,b and 25a,b . By means of ¹H-, ¹³C- and ¹⁵N-NMR-data it is demonstrated that ethyl benzoylcyanacetimidate ( 12a ) exists as benzoylketene-O,N-acetal 12a AE .     

The plasma–occupancy relationship of the novel GABAA receptor benzodiazepine site ligand, α5IA,is similar in rats and primates

Background and purpose:

α5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine) is a triazolophthalazine with subnanomolar affinity for α1-, α2-, α3- and α5-containing GABA_A receptors. Here we have evaluated the relationship between plasma α5IA concentrations and benzodiazepine binding site occupancy in rodents and primates (rhesus monkey).

Experimental approach:

In awake rats, occupancy was measured at various times after oral dosing with α5IA (0.03–30 mg·kg⁻¹) using an in vivo {[³H]flumazenil (8-fluoro 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester)} binding assay. In anaesthetized rhesus monkeys, occupancy was measured using {[¹²³I]iomazenil (ethyl 5,6-dihydro-7-iodo-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester)} γ-scintigraphy and a bolus/infusion paradigm. In both rat and rhesus monkey, the plasma drug concentration corresponding to 50% occupancy (EC₅₀) was calculated.

Key results:

In rats, α5IA occupancy was dose- and time-dependent with maximum occupancy occurring within the first 2 h. However, rat plasma EC₅₀ was time-independent, ranging from 42 to 67 ng·mL⁻¹ over a 24 h time course with the average being 52 ng·mL⁻¹ (i.e. occupancy decreased as plasma drug concentrations fell). In rhesus monkeys, the EC₅₀ for α5IA displacing steady-state [¹²³I]iomazenil binding was 57 ng·mL⁻¹.

Conclusions and implications:

Rat plasma EC₅₀ values did not vary as a function of time indicating that α5IA dissociates readily for the GABA_A receptor in vivo. These data also suggest that despite the different assays used (terminal assays of [³H]flumazenil in vivo binding in rats and [¹²³I]iomazenil γ-scintigraphy in anaesthetized rhesus monkeys), these techniques produced similar plasma α5IA EC₅₀ values (52 and 57 ng·mL⁻¹ respectively) and that the plasma–occupancy relationship for α5IA translates across these two species.     

Synthesis and Evaluation on Anticonvulsant and Antidepressant Activities of 5-Alkoxy-tetrazolo[1,5-a]quinazolines

Several 5-alkoxy-tetrazolo[1,5-a]quinazoline derivatives have been synthesized by reacting 2,4-dichloroquinazoline with various phenols or aliphatic alcohol and then with sodium azide. The structures of these compounds have been confirmed by IR, MS, ¹H-NMR, and elementary analysis. Anticonvulsant activities were evaluated using the maximal electroshock (MES) test. Most of the synthesized compounds displayed weak anticonvulsant activity at a dose of 300 mg/kg. Antidepressant activities were investigated by forced swimming test. Two compounds, namely 5-(hexyloxy)tetrazolo[1,5-a]quinazoline and 5-(4-methoxyphenoxy)tetrazolo[1,5-a]quinazoline, showed significant antidepressant activity, which decreased the immobility time by 62.2 and 51.7% at 100 mg/kg dose level.     

A novel kainate receptor ligand [H]-(2S,4R)-4-methylglutamate: Pharmacological characterization in rabbit brain membranes

Since kainate evokes large non-desensitizing currents at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, kainate is of limited use in discriminating between AMPA and kainate receptors. Following recent reports that (2S,4R)-4-methylglutamate is a kainate receptor-selective agonist, we have radiolabelled and subsequently characterized the binding of [³H]-(2S,4R)-4-methylglutamate to rabbit whole-brain membranes. [³H]-(2S,4R)-4-methylglutamate binding was rapid, reversible and labelled two sites (KD1 = 3.67 ± 0.50 nM/B_max1 = 0.54 ± 0.03 pmol/mg protein and K_D2 = 281.66 ± 12.33 nM/ B_max2 = 1.77 ± 0.09 pmol/mg protein). [³H]-(2S,4R)-4-methylglutamate binding was displaced by several non-NMDA receptor ligands: domoate > kainate -quisqualate -glutamate > 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) (S)-AMPA = (S)-5-fluorowillardiine > NMDA. Neither the metabotropic glutamate receptor agonists (1S,3R)-ACPD or -AP4, together with the -glutamate uptake inhibitor -trans-2,4-PDC, influenced binding when tested at 100 μM. We conclude that [³H]-(2S,4R)-4-methylglutamate is a useful radioligand for labelling kainate receptors. It possesses high selectivity, and possesses a pharmacology similar to that for rat cloned low-affinity (Glu5 and 6) kainate receptor subunits.     

Synthesis and cytotoxic evaluation of some new[1,3]dioxolo[4,5-g]chromen-8-one derivatives

Background

Homoisoflavonoids are naturally occurring compounds belong to flavonoid classes possessing various biological properties such as cytotoxicity. In this work, an efficient strategy for the synthesis of novel homoisoflavonoids, [1,3]dioxolo[4,5-g]chromen-8-ones, was developed and all compounds were evaluated for their cytotoxic activities on three breast cancer cell lines.

Methods

Our synthetic route started from benzo[d][1,3]dioxol-5-ol which was reacted with 3-bromopropanoic acid followed by the reaction of oxalyl chloride to afford 6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one. The aldol condensation of the later compound with aromatic aldehydes led to the formation of the title compounds. Five novel derivatives 4a-e were tested for their cytotoxic activity against three human breast cancer cell lines including MCF-7, T47D, and MDA-MB-231 using the MTT assay.

Results

Among the synthesized compounds, 7-benzylidene-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4a) exhibited the highest activity against three cell lines. Also the analysis of acridine orange/ethidium bromide staining results revealed that 7-benzylidene-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4a) and 7-(2-methoxybenzylidene)-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4b) induced apoptosis in T47D cell line.

Conclusion

Finally, the effect of methoxy group on the cytotoxicity of compounds 4b-4d was investigated in and it was revealed that it did not improve the activity of [1,3]dioxolo[4,5-g]chromen-8-ones against MCF-7, T47D, and MDA-MB-231.     

Bifunktionelle Elektrophile zur Darstellung [c]-heteroanellierter Chinazolinon-Derivate: 2-Isocyanatocyclohex-1-encarbonsäurenitril,ergänzend zu 2-Isocyanatobenzonitril

2-Isocyanatocyclohex-1-ene-carbonitrile and 2-Isocyanatobenzonitrile as Bifunctional Electrophiles in the Synthesis of [c]-Heteroanellated Quinazoline Derivatives. N′-substituted N-(2-cyanophenyl)ureas afford [1,2,4]triazolo[1,5-c]- and imidazo[1,2-c]-quinazolin-5(6H)-ones. 2-Isocyanatocyclohex-1-ene-carbonitrile as starting compound leads to the 7,8,9,10-saturated structural analogues.     

Studies of the antagonist actions of (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) on non-NMDA receptors in cultured rat neurones

1. Whole-cell patch-clamp recordings from single cultured cortical neurones have been used to study the action of (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO), which has previously been proposed to be a potent selective antagonist of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors.
2. ATPO competitively reduced peak responses evoked by semi-rapid applications of AMPA (K_i=16 μM) but had variable effects on plateau responses, which were on average unchanged. Following blockade of AMPA receptor desensitization by cyclothiazide (CTZ, 100 μM), the plateau responses were reduced by ATPO to a similar extent as the peak responses, indicating that ATPO reduces desensitization of AMPA receptors.
3. Semi-rapid application of kainic acid (KA) and the KA receptor-selective agonist, (2S,4R)-4-methylglutamic acid (MeGlu) evoked non-desensitizing responses which were competitively antagonized by ATPO (K_i values: 27 and 23 μM, respectively).
4. Responses to MeGlu were unaffected by CTZ (100 μM), but potentiated 3 fold following blockade of KA receptor desensitization by concanavalin A (Con A, 300 μg ml⁻¹). Responses of spinal cord neurones to MeGlu were blocked by ATPO to a similar extent before and after blockade of KA receptor desensitization by Con A.
5. Although selectively potentiated by Con A, plateau responses to MeGlu were reduced by 69.6% by the AMPA selective antagonist, GYKI 53655 (10 μM). The remaining component was further reduced by ATPO with a K_i of 36 μM, which was not significantly different from that in the absence of GYKI 53655, but was greater than that on responses to AMPA.
6. It is concluded that ATPO is a moderate-potency competitive inhibitor of naturally expressed non-NMDA receptors.