Search

In this research study, the authors successfully synthesized potent new anticancer agents derived from indazol-pyrimidine. All the prepared compounds were tested for in vitro cell line inhibitory activity against three different cancerous cell lines. Results demonstrated that five of the novel compounds- 4f , 4i , 4a , 4g , and 4d -possessed significant cytotoxic inhibitory activity against the MCF-7 cell line, with IC 50 values of 1.629, 1.841, 2.958, 4.680, and 4.798 μM, respectively, compared to the reference drug with an IC 50 value of 8.029 μM, thus demonstrating promising suppression power. Compounds 4i , 4g , 4e , 4d , and 4a showed effective cytotoxic activity stronger than the standard against Caco2 cells. Moreover, compounds 4a and 4i exhibited potent antiproliferative activity against the A549 cell line that was stronger than the reference drug. The most active products, 4f and 4i , werr e further examined for their mechanism of action. It turns out that they were capable of activating caspase-3/7 and, therefore, inducing apoptosis. However, produced a higher safety profile than the reference drug, towards the normal cells (MCF10a). Furthermore, the dynamic nature, binding interaction, and protein-ligand stability were explored through a Molecular Dynamics (MD) simulation study. Various analysis parameters (RMSD, RMSF, RoG, and SASA) from the MD simulation trajectory have suggested the stability of the compounds during the 20 ns MD simulation study. In silico ADMET results revealed that the synthesized compounds had low toxicity, good solubility, and an absorption profile since they met Lipinski's rule of five and Veber's rule. The present research highlights the potential of derivatives with indazole scaffolds bearing pyrimidine as a lead compound for designing anticancer agents.

In the present work, a new series of dihydronaphthalene derivatives were synthesized starting with 6-methoxy-1-tetralone 1 , and the corresponding hydrazine derivative 2 . Reaction of compound 2 with aryl isothiocyanates produced thiosemicarbazides 3a-d , which were reacted with ethyl chloroacetate to give thiazolidinone derivatives 4a-d . Pyrano thiazolecarbonitrile derivatives 5a - f were prepared by heating a mixture of compounds 4a or 4c , aryl aldehydes, and malononitrile utilizing distilled water in the presence of catalytic amount of potassium hydrogen phthalate. Also, treatment of 4a with DMF-DMA under solvent-free conditions gave enaminone derivative 6 , which condensed with ethyl acetoacetate or acetylacetone or malononitrile or cyanothioacetamide to give compounds 7 - 10 , respectively. Finally, reaction of the enaminone 6 with 2-aminoimidazol or 2-aminothiazol in the presence of glacial acetic acid produced derivatives 11 and 12 , respectively. Cytotoxic evaluation of eleven compounds, against MCF-7 (human breast adenocarcinoma) cell lines, was estimated. Results revealed that five of the examined compounds 5a , 5d , 5e , 10 , and 3d showed potent cytotoxic activities recording, IC 50 values; 0.93 ± 0.02, 1.76 ± 0.04, 2.36 ± 0.06, 2.83 ± 0.07, and 3.73 ± 0.09  μ M, respectively, which were more potent than the reference used (Saturosporin, IC 50 6.08 ± 0.15  μ M). The new products were also examined towards normal epithelial breast cells (MCF10A). All of them showed very good safety profile with different degrees and were safer than the reference drug used. Compound 5a was the most effective against MCF-7 cells and was less toxic than Saturosporin by about 18.45-folds towards MCF01A normal cells. All the new compounds were fully characterized by the different spectral and analytical tools. Herein, detailed syntheses, spectroscopic, and biological data are reported., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Nesreen S. Ahmed et al.)

New pyranocoumarin and coumarin-sulfonamide derivatives were prepared and evaluated for their antioxidant, antimicrobial, and/or anti-inflammatory activities. Coumarin-sulfonamide compounds 8a-d demonstrated significant antioxidant activity, while 7c , d , 8c , d , and 9c , d exhibited antimicrobial activity equal to or higher than the standard antimicrobials against at least one tested microorganism. Regarding the anti-inflammatory testing, pyranocoumarins 2b , 3a , b and 5c and coumarin-sulfonamide compound 9a showed more potent antiproteinase activity than aspirin in vitro; however, five compounds were as potent as aspirin. The anti-inflammatory activity of the promising compounds was further assessed pharmacologically on formaldehyde-induced rat paw oedema and showed significant inhibition of oedema. For in vitro COX-inhibitory activity of coumarin derivatives, pyranocoumarin derivative 5a was the most selective (SI = 152) and coumarin-sulfonamide derivative 8d was most active toward COX-2 isozyme. The most active derivatives met the in silico criteria for orally active drugs; thus, they may serve as promising candidates to develop more potent and highly efficient antioxidant, antimicrobial, and/or anti-inflammatory agents.

A novel series of cyanopyridinyl tetrahydronaphthalene incorporated with different heterocycles were synthesized. The key compounds 2a,b were condensed with chloroacetone and ethyl chloroacetate to give 3a,b and 4a,b, respectively. Also condensation of 4a,b with hydrazine hydrate gave the corresponding hydrazide 5a,b. Reaction of 5b with different isothiocyanates gave the corresponding thiosemicarbazide derivatives 6a-c. Also, condensation of 5a with chloroacetic acid, methyl iodide and/or acetic anhydride yielded 7- 9, respectively. Moreover, reaction of 5a with acetylacetone, ethyl acetoacetate, diethylmalonate, ethyl cyanoacetate, chloroacetone, ethyl chloroacetate, urea, phthalic anhydride, malic anhydride and/ or different aldehydes yielded the corresponding derivatives 10-18, respectively. Newly synthesized compounds were screened for their antibacterial (Staphylococcus aureus, Bacillus subtilis, Bacillus megaterium, Sarcina lutea, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli) and antifungal (Saccharomyces cerevisiae and Candida albicans) activity. The results revealed that some of novel compounds have exhibited significant biological activity against the tested microorganisms.

A new series of novel substituted 3,4-dihydronaphthalene incorporated to benzo[h]quinoline, benzo[g]indazole, thiazolidin-4-one, pyrazolo[3,4-d]thiazol and thiazolo[4,5-b]pyridine ring systems were synthesized and evaluated for their cytotoxicity against selected human cancer cell lines. Some of the tested compounds exhibited promising carcinoma growth inhibition. The detailed synthesis, spectroscopic data and biological activities of the tested compounds were reported., (© Georg Thieme Verlag KG Stuttgart · New York.)

The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio > 75%).

Herein, novel hybrid compounds of celecoxib and 2-aminoanthraquinone derivatives have been synthesized using condensation reactions of celecoxib with 2-aminoanthraquinone derivatives or 2-aminoanthraquinon with celecoxib derivatives. Celecoxib was reacted with different acid chlorides, 2-chloroethylisocyanate and bis (2-chloroethyl) amine hydrochloride. These intermediates were then reacted with 2-aminoanthraquinone. Also the same different acid chlorides and 2-chloroethylisocyanate were reacted with 2-aminoanthraquinone and the resulting intermediates were reacted with celecoxib to give isomers for the previous compounds. The antitumor activities against hepatic carcinoma tumor cell line (HEPG2) have been investigated in vitro, and all these compounds showed promising activities, especially compound 3c, 7, and 12. Flexible docking studies involving AutoDock 4.2 was investigated to identify the potential binding affinities and the mode of interaction of the hybrid compounds into two protein tyrosine kinases namely, SRC (Pp60v-src) and platelet-derived growth factor receptor, PDGFR (c-Kit). The compounds in this study have a preferential affinity for the c-Kit PDGFR PTK over the non-receptor tyrosine kinase SRC (Pp60v-src).

In continuation of our previous work, a novel series of polycyclic derivatives 2-8 incorporated heterocyclic and sugar moieties were synthesized by using pyren-1-aldehyde (1) as starting material and their tested as antiviral activities. Initially, the toxicity of the compounds was assayed via the determination of their EC(50). Some of the synthesized compounds were tested as antiviral activity against HIV-1 and HSV-1. The structure of the new compounds was confirmed by using chemical and spectroscopic evidences. The detailed of synthesis, spectroscopic data, antiviral activities of the synthesized compounds were reported., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A facile, convenient and high yielding synthesis of novel S-glycosides and N-glycosides incorporating 1,2,3,4-tetrahydronaphthalene and or 1,2-dihydropyridines moieties has been described. The aglycons 2, 4, and 7 were coupled with different activated halosugars in the presence of basic and acidic medium. The preliminary in-vitro cytotoxic evaluation revealed that compounds 3c, 3f, 5c and 7b show promising activity. A molecular docking study was performed against tyrosine kinase (TK) (PDB code: 1t46) by Autodock Vina. The docking output was analyzed and some compounds have shown hydrogen bond (H-B) formation with reasonable distances ranged from 2.06 A° to 3.06 A° with Thr 670 and Cys 673 residues found in the specified pocket. No hydrogen bond was observed with either Glu 640 nor Asp 810 residues, as was expected from pdbsum.

A new series of (benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl) pyrimidine derivatives were synthesized from 3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-carbaldehyde (1) through different routes of cyclocondensation reactions. Condensation of 1 with active methylene compounds afforded compounds 2-8. The cyclization of 2 with chloroacetic acid, ortho substituted benzoic acid and/or ethanolamine gave compounds 9-12. Also condensation of 2 with hydrazine hydrate followed by cyclocondensation afforded corresponding triazines and pyrazole derivatives 18-27. Some docking studies of the newly prepared compounds as thymidylate synthase inhibitors have been done. Also the cytotoxic activity of some of the prepared compounds as a representative examples was evaluated against HEPG2 (human liver carcinoma cell line) in comparison with 5-fluorouracil (5-Fu).

Condensation of 2-acetyltetralin with ethylcyanoacetate and/or malononitrile and some aldehydes in the presence of excess of ammonium acetate afforded the respective hydroxycyanopyridines or aminocyanopyridines 1a-f and 2a-f. Treatment of 2-acetyltetralin with some sulfonylhydrazides yielded the hydrazone derivatives 3a-d, respectively, which upon treatment with thioglycolic acid gave the corresponding thiazole derivatives 4a-d, respectively. Compounds 4a-d underwent cyclocondensation with different arylidene derivatives to give the corresponding pyrane derivatives 5a-d. Upon the reaction of compounds 4a-d with some secondary amines and paraformaldehyde the corresponding Mannich bases 6a,c, 7b,d and 8a,d were obtained. Compounds 1c, 1d, 1e, 2e, 3a and 3d were evaluated as analgesic, anti-iflammatory and antipyretic agents.

Some N-p-substituted phenyl uracil-5-sulphonamide derivatives have been synthesized to be evaluated as molluscicides against Biomphalanaria alexandrina snails, the intermediate host of Schistosoma mansoni. Schistosoma mansoni infected mice were treated with hemolymph obtained from pre-treated Biomphalana alexandrina snails with the products 4a, 10a, 10b and 4b or obtained from non-treated snails. The selection of the concentration based on the predetermined dose which caused mortality of less than 50% of snails/24 h. LC50 of compounds 4a, 10a, 10b and 4b was 50, 100, 200 and 50 ppm respectively. The result showed that immunostimulatory effect of treated hemolymph with compounds 4a, 10a and 4b was related to significant protective effects (44.4, 34.6 and 50.4% reduction in worm burden respectively). In addition, mean total worm burdens were significantly reduced in non treated hemolymph by 33.8%. The effect of hemolymph obtained from treated or non treated snails on S. mansoni adult worms antigens was studied by indirect immunofluorescence technique using chronic mouse sera (CMS). The results indicated that there was a strong reaction with epitopes in gut epithelium, tubercles, teigument and subtegumental musculature of untreated and treated S. mansoni adult worms antigens. Therefore, treatment of hemolymph obtained from pre-treated snails with compounds 4a, 10a, and 4b can stimulate specific immune response and induce protective effects against S. mansoni infection.