Design, synthesis and antitumor evaluation of novel pyrazolopyrimidines and pyrazoloquinazolines

A series of N-aryl-7-aryl-pyrazolo[1,5-a]pyrimidines 18a–u and N-aryl-pyrazolo[1,5-a] quinazolines 25a–c were designed and synthesized via the reaction of 5-aminopyrazoles 11a–c with enaminones 12a–g or 19, respectively. The new compounds were screened for their in vitro antitumor activity toward liver (HepG-2) and breast (MCF-7) human cancer cells using 3-[4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide MTT assay. From the results, it was found that all compounds showed dose-dependent cytotoxic activities against both HepG-2 and MCF-7 cells. Two compounds 18o and 18a were selected for further investigations. Cell cycle analysis of liver (HepG-2) cells treated with 18o and breast (MCF-7) cells treated with 18a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.publishedVersio

Biological and spectroscopic investigations of new tenoxicam and 1.10-phenthroline metal complexes

In the present work, tenoxicam (H2Ten) reacted with Mn(II), Co(II), Ni(II), Cu(II) and Zn (II) ions in the presence of 1.10-phenthroline (Phen), forming new mixed ligand metal complexes. The properties of the formed complexes were depicted by elemental analyses, infrared, electronic spectra, proton nuclear magnetic resonance (1H NMR), mass spectrometry, thermogravimetric (TGA) and differential thermogravimetric (DTG) analysis, molar conductance and magnetic moment. IR spectra demonstrated that H2Ten acted as a neutral bidentate ligand, coordinated to the metal ions via the pyridine-N and carbonyl group of the amide moiety, and Phen through the nitrogen atoms. Kinetic thermodynamics parameters activation energy (E*), enthalpy of activation (ΔH*), entropy of activation (ΔS*), Gibbs, free energy (ΔG*) associated to the complexes have been evaluated. Antibacterial screening of the compounds was carried out in vitro against Clavibacter michiganensis, Xanthomonas campestris and Bacillus megaterium. Antifungal activity was performed in vitro against Monilinia fructicola, Penicillium digitatum and Colletotrichum acutatum. The possible phytotoxic effect of the studied compounds was also investigated on Solanum lycopersicum (tomatoes) and Lepidium sativum (garden cress) seeds. The anticancer activity was screened against cell cultures of HCT-116 (human colorectal carcinoma), HepG2 (human hepatocellular carcinoma) and MCF-7 (human breast adenocarcinoma)

Extraction and partial purification of Aspergillus flavus cell wall associated saponin hydrolase

In spite of the importance of saponin hydrolase (SH) enzyme, in the production of biologically active compounds from natural saponins, it is surprising that many aspects of its nature are unknown. The results of the present work revealed that Aspergillus flavus was capable of expressing three SH forms; extracellular, intracellular and cell wall-bound forms. SH cell bound enzyme constituted to more than 75% of the total enzymatic activity in the production medium. The sequential extraction process of SH cell bound enzyme revealed that 47.5% of SH was cytosolic and the rest (52.5%) was associated with the cell wall. The highest SH extraction yield was achieved when 0.25 M Tris-HCl lysis buffer supplemented with 1% Triton X-100 for 24 h at 4-25 °C and pH 8 were applied. Under these optimized conditions, A. flavus SH yield increased from 23.6 to 85.83%. The partial purification was achieved by applying successively acetone precipitation, lyophilization, dialysis, and anion exchange chromatography on Fractogel EMD DEAE-650S to the extract. The specific activity of the enzyme extract was 0.27 U/mg after 75% acetone fractionation, while that after anion exchange chromatography was 0.65 U/mg protein. The final enzyme preparation was 7.3-fold purer than the crude extract

One-Pot Multicomponent Synthesis and Cytotoxic Evaluation of Novel 7-Substituted-5-(1H-Indol-3-yl)Tetrazolo[1,5-a] Pyrimidine-6-Carbonitrile

A series of novel 7-substituted-5-(1H-indol-3-yl)tetrazolo[1,5-a]pyrimidine-6-carbonitrile was synthesized via a one-pot, three-multicomponent reaction of appropriate aldehydes, 1H-tetrazole-5-amine and 3-cyanoacetyl indole in catalytic triethylamine. The cytotoxic activity of the new synthesized tetrazolopyrimidine-6-carbonitrile compounds was investigated against HCT-116, MCF-7, MDA-MB-231, A549 human cancer cell lines and one human healthy normal cell line (RPE-1) using the MTT cytotoxicity assay. Compounds 4h, 4b, 4c, 4i and 4a showed potent anticancer activities against human colon cancer. Additionally, all the compounds showed potent anticancer activities on human lung cancer

Design, Synthesis, Anticancer Evaluation, Enzymatic Assays, and a Molecular Modeling Study of Novel Pyrazole−Indole Hybrids

The molecular hybridization concept has recently emerged as a powerful approach in drug discovery. A series of novel indole derivatives linked to the pyrazole moiety were designed and developed via a molecular hybridization protocol as antitumor agents. The target compounds (5a–j and 7a–e) were prepared by the reaction of 5-aminopyrazoles (1a–e) with N-substituted isatin (4a,b) and 1H-indole-3-carbaldehyde (6), respectively. All products were characterized via several analytical and spectroscopic techniques. Compounds (5a–j and 7a–e) were screened for their cytotoxicity activities in vitro against four human cancer types [human colorectal carcinoma (HCT-116), human breast adenocarcinoma (MCF-7), human liver carcinoma (HepG2), and human lung carcinoma (A549)] using the MTT assay. The obtained results showed that the newly synthesized compounds displayed good-to-excellent antitumor activity. For example, 5-((1H-indol-3-yl)methyleneamino)-N-phenyl-3-(phenylamino)-1H-pyrazole-4-carboxamide (7a) and 5-((1H-indol-3-yl)methyleneamino)-3-(phenylamino)-N-(4-methylphenyl)-1H-pyrazole-4-carboxamide (7b) provided excellent anticancer inhibition performance against the HepG2 cancer cell line with IC50 values of 6.1 ± 1.9 and 7.9 ± 1.9 μM, respectively, compared to the standard reference drug, doxorubicin (IC50 = 24.7 ± 3.2 μM). The two powerful anticancer compounds (7a and 7b) were further subjected to cell cycle analysis and apoptosis investigation in HepG2 using flow cytometry. We have also studied the enzymatic assay of these two compounds against some enzymes, namely, caspase-3, Bcl-2, Bax, and CDK-2. Interestingly, the molecular docking study revealed that compounds 7a and 7b could well embed in the active pocket of the CDK-2 enzyme via different interactions. Overall, the prepared pyrazole–indole hybrids (7a and 7b) can be proposed as strong anticancer candidate drugs against various cancer cell lines.publishedVersio

Design, Synthesis and Antitumor Evaluation of Novel Pyrazolopyrimidines and Pyrazoloquinazolines

A series of N-aryl-7-aryl-pyrazolo[1,5-a]pyrimidines 18a–u and N-aryl-pyrazolo[1,5-a]quinazolines 25a–c were designed and synthesized via the reaction of 5-aminopyrazoles 11a–c with enaminones 12a–g or 19, respectively. The new compounds were screened for their in vitro antitumor activity toward liver (HepG-2) and breast (MCF-7) human cancer cells using 3-[4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide MTT assay. From the results, it was found that all compounds showed dose-dependent cytotoxic activities against both HepG-2 and MCF-7 cells. Two compounds 18o and 18a were selected for further investigations. Cell cycle analysis of liver (HepG-2) cells treated with 18o and breast (MCF-7) cells treated with 18a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining

Synthesis and <i>in vitro</i> anticancer activity of pyrazolo[1,5-<i>a</i>]pyrimidines and pyrazolo[3,4-<i>d</i>][1,2,3]triazines

<p>A novel series of pyrazolo[1,5-<i>a</i>]pyrimidines <b>14a–j</b> and pyrazolo[1,5-<i>a</i>]quinazolines <b>18a, b</b> were synthesized <i>via</i> condensation of 5-amino-1<i>H</i>-pyrazoles <b>10a, b</b> with 3-(dimethylamino)-1-aryl-prop-2-en-1-ones <b>11a–e</b> and 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione (<b>15</b>), respectively, in glacial acetic acid. Finally, treatment of <b>10a, b</b> with sodium nitrite (NaNO₂) afforded pyrazolo[3,4-<i>d</i>]triazines <b>20a, b</b>. Structures of compounds were confirmed by their spectral data. These compounds were screened for their <i>in vitro</i> cytotoxic activities against human cancer cell lines (HepG-2 and MCF-7) using 3-[4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2<i>H</i>-tetrazolium bromide (MTT) assay. The results reveal that, the compounds <b>14b</b> and <b>14h</b> were the most potent in comparison with doxorubicin. The structure–activity relationship was discussed.</p

Synthesis and Anticancer Activity of New 1-Thia-4-azaspiro[4.5]decane, Their Derived Thiazolopyrimidine and 1,3,4-Thiadiazole Thioglycosides

New 1-thia-azaspiro[4.5]decane derivatives, their derived thiazolopyrimidine and 1,3,4-thiadiazole compounds were synthesized. The thioglycoside derivatives of the synthesized (1,3,4-thiadiazolyl)thiaazaspiro[4.5]decane and thiazolopyrimidinethione compounds were synthesized by glycosylation reactions using acetylated glycosyl bromides. The anticancer activity of synthesized compounds was studied against the cell culture of HepG-2 (human liver hepatocellular carcinoma), PC-3 (human prostate adenocarcinoma) and HCT116 (human colorectal carcinoma) cell lines and a number of compounds showed moderate to high inhibition activities

Design, Synthesis, Anticancer Evaluation, Enzymatic Assays, and a Molecular Modeling Study of Novel Pyrazole−Indole Hybrids

The molecular hybridization concept has recently emerged as a powerful approach in drug discovery. A series of novel indole derivatives linked to the pyrazole moiety were designed and developed via a molecular hybridization protocol as antitumor agents. The target compounds (5a–j and 7a–e) were prepared by the reaction of 5-aminopyrazoles (1a–e) with N-substituted isatin (4a,b) and 1H-indole-3-carbaldehyde (6), respectively. All products were characterized via several analytical and spectroscopic techniques. Compounds (5a–j and 7a–e) were screened for their cytotoxicity activities in vitro against four human cancer types [human colorectal carcinoma (HCT-116), human breast adenocarcinoma (MCF-7), human liver carcinoma (HepG2), and human lung carcinoma (A549)] using the MTT assay. The obtained results showed that the newly synthesized compounds displayed good-to-excellent antitumor activity. For example, 5-((1H-indol-3-yl)methyleneamino)-N-phenyl-3-(phenylamino)-1H-pyrazole-4-carboxamide (7a) and 5-((1H-indol-3-yl)methyleneamino)-3-(phenylamino)-N-(4-methylphenyl)-1H-pyrazole-4-carboxamide (7b) provided excellent anticancer inhibition performance against the HepG2 cancer cell line with IC50 values of 6.1 ± 1.9 and 7.9 ± 1.9 μM, respectively, compared to the standard reference drug, doxorubicin (IC50 = 24.7 ± 3.2 μM). The two powerful anticancer compounds (7a and 7b) were further subjected to cell cycle analysis and apoptosis investigation in HepG2 using flow cytometry. We have also studied the enzymatic assay of these two compounds against some enzymes, namely, caspase-3, Bcl-2, Bax, and CDK-2. Interestingly, the molecular docking study revealed that compounds 7a and 7b could well embed in the active pocket of the CDK-2 enzyme via different interactions. Overall, the prepared pyrazole–indole hybrids (7a and 7b) can be proposed as strong anticancer candidate drugs against various cancer cell lines