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Matei L.,Stefan S Nicolau Institute Of Virology | Matei L.,University of Bucharest | Bleotu C.,Stefan S Nicolau Institute Of Virology | Baciu I.,University of Bucharest | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2013

The aim of the study was to synthesize some new compounds with potential anti-tuberculosis activity, containing isoniazid and α,β-unsaturated thiocinnamamide-like thioamides as precursors. The obtained derivatives were evaluated regarding their biological activity (antioxidant and antibacterial), as well as their influence on the eukaryotic cell cycle. The results suggested that the newly obtained derivatives of isoniazid exhibited different biological activities, depending on their structure; thus, the most active compound in terms of anti-oxidant and anti-Mycobacterium tuberculosis effects proved to be the isonicotinic acid N′-(1-amino-1-mercapto-3-phenyl-propen-1-yl)- hydrazide. This compound also increased the expression of NAT1 and NAT2 genes, which are implicated in the metabolism of the isoniazid, demonstrating that it could be rapidly metabolized, and thus well tolerated. The largest spectrum of antibacterial activity (excluding M. tuberculosis) was noticed for the isonicotinic acid N′-[1-amino-1-mercapto-3-(p-chloro-phenyl)-propen-1-yl]- hydrazide, which was also the most cytotoxic, especially at high concentrations, although not significantly affecting the cellular cycle phases. The obtained results showed that the new derivatives could represent potential candidates for the treatment of M. tuberculosis infections, but further research is needed in order to improve their pharmacological properties, by increasing their antimicrobial activity and reducing the risk of side-effects. © 2013 Elsevier Ltd. All rights reserved. Source


Nitulescu G.M.,Carol Davila University of Medicine and Pharmacy | Matei L.,Stefan S Nicolau Institute Of Virology | Aldea I.M.,Stefan S Nicolau Institute Of Virology | Draghici C.,Cd Nenitzescu Institute Of Organic Chemistry | And 2 more authors.
Arabian Journal of Chemistry | Year: 2015

We designed new pyrazole derivatives as inhibitors of the cell cycle kinases and developed a simple environmentally sustainable synthesis process. We synthesized the pyrazolyl thiourea derivatives using rapid ultrasound mediated methods and confirmed their structures by NMR and IR spectra. The apoptosis and necrosis inducing effects of the new compounds were investigated. Cell cycle analysis and expression of genes involved in apoptosis, cell cycle and xenobiotic metabolism were studied. The compounds presented modest apoptotic effects in human cancer cells. The N-[[3-(4-bromophenyl)-1H-pyrazol-5-yl]carbamothioyl]-4-chloro-benzamide compound (4e) induced a significant increase of cells in G2/M phases in conjunction with an increased expression of cyclin A and cyclin B, emerging as a promising anticancer drug, to be further developed in animal models of cancer. © 2015 The Authors. Source


Nitulescu G.M.,Carol Davila University of Medicine and Pharmacy | Draghici C.,Cd Nenitzescu Institute Of Organic Chemistry | Olaru O.T.,Carol Davila University of Medicine and Pharmacy | Matei L.,Stefan S Nicolau Institute Of Virology | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

We designed and synthesized new pyrazole thiourea chimeric derivatives and confirmed their structures by NMR and IR spectra. Apoptotic effects were studied in human cancer cells. The N-[(1-methyl-1. H-pyrazol-4-yl)carbonyl]-N'-(3-bromophenyl)-thiourea compound (4b) exhibited the highest apoptosis-inducing effect. Compound 4b and the thiazole derivatives, 5b and 6b, increased the expression of tumor necrosis factor receptors TRAIL-R2 and TRAIL-R1, accompanied by down-modulation of pro-caspase 3 levels, and the augmentation of cleaved caspase 3. They also reduced the levels of apoptosis inhibitory proteins and the expression of the heat-shock proteins Hsp27 and Hsp70. All the tested pyrazole derivatives induced a concentration-dependent increase of cells in G2/M phases. The analysis of the experimental data indicates the reduction of Akt phosphorylation as the most probable cellular mechanism of action for the tested compounds. The in vitro study indicated that compound 4b could be a promising anti-cancer drug, to be further developed in animal models of cancer. © 2015 Elsevier Ltd. Source

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