Synthesis of novel diflunisal hydrazide-hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors

Hepatitis C virus (HCV) infection is a main cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma (HCC). The objective of our research was to develop effective agents against viral replication. We have previously identified the hydrazideehydrazone scaffold as a promising hepatitis C virus (HCV) and hepatocelluler inhibitor. Herein we describe the design a number of 20,40-difluoro-4-hydroxy-N'-(arylmethylidene) biphenyl-3-carbohydrazide (3a-t) as anti-HCV and anticancer agents. Results from evaluation of anti-HCV activity indicated that most of the synthesized hydrazone derivatives inhibited viral replication in the Huh7/Rep-Feo1b and Huh 7.5-FGR-JCI-Rluc2A reporter systems. Antiproliferative activities of increasing concentrations of 20,40-difluoro-4-hydroxy-N'-(2-pyridyl methylidene)biphenyl-3-carbohydrazide 3b and diflunisal (2.5e40 μM) were assessed in liver cancer cell lines (Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475) with sulforhodamine B assay for 72 h. Compound 3b with 2-pyridinyl group in the hydrazone part exhibited promising cytotoxic activity against all cell lines with IC50 values of 10, 10.34 16.21 4.74, 9.29 and 8.33 μM for Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475 cells, respectively, and produced dramatic cell cycle arrest at SubG1/G0 phase as an indicator of apoptotic cell death induction. © 2015 Elsevier Masson SAS

Sinteza 2-(1H-indol-3-il)acetil-N-(supstituiranih fenil)hidrazinkarbotioamida i srodnih heterocikličkih spojeva te procjena njihovog antikonvulzivnog djelovanja i toksičnosti

A series of new 5-(1H-indol-3-yl)methyl-4-(substituted aryl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones (4a-g), 5-(1H-indol-3-yl)methyl-N-(substituted aryl)-1,3,4-oxadiazol-2-amines (5a-g) and 5-(1H-indol-3-yl)methyl-N-(substituted aryl)-1,3,4-thiadiazol-2-amines (6a-g) were prepared by treating 2-(1H-indol-3-yl)acetyl-N-(substituted phenyl)hydrazine carbothioamides (3a-g) with suitable reagents. All the newly synthesized compounds were screened for their anticonvulsant activity in the MES model and were compared with the standard drugs phenytoin sodium and carbamazepine. Out of the twenty-one compounds studied, 4b, 4e, 4f, 5b, 5d, 5g, 6b, 6d and 6e showed comparable MES activity to phenytoin and carbamazepine after 0.5 h. Compound 5b showed to be more potent than carbamazepine after 4 h. Compounds 4a, 4c, 4d, 5a, 5c, 5e, 5f, 6f and 6g showed lower neurotoxicity than phenytoin.Reakcijom 2-(1H-indol-3-il)acetil-N-(supstituiranih fenil)hidrazinkarbotioamida (3a-g) s odgovarajućim reaktantom sintetizirana je serija novih 5-(1H-indol-3-il)metil-4-(supstituiranih aril)-2,4-dihidro-3H-1,2,4-triazol-3-tiona (4a-g), 5-(1H-indol-3-yl)metil-N-(supstituiranih aril)-1,3,4-oksadiazol-2-amina (5a-g) i 5-(1H-indol-3-il)metil-N-(supstituiranih aril)-1,3,4-tiadiazol-2-amina (6a-g). Ispitano je antikonvulzivno djelovanje sintetiziranih spojeva na MES modelu i uspoređeno s djelovanjem fenitoin natrija i karbamazepina. Spojevi 4b, 4e, 4f, 5b, 5d, 5g, 6b, 6d i 6e pokazali su MES djelovanje usporedivo s djelovanjem fenitoina i karbamazepina nakon 0,5 h, dok je spoj 5b nakon 4 sata imao snažnije djelovanje od karbamazepina. Osim toga, spojevi 4a, 4c, 4d, 5a, 5c, 5e, 5f, 6f i 6g su manje neurotoksični od fenitoina

Some 3-thioxo/alkylthio-1,2,4-triazoles with a substituted thiourea moiety as possible antimycobacterials

A series of novel N-alkyl/aryl-N-1-[4-(4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione-5-yl)phenyl]thioureas 1-19 and three S-alkylated representatives of the former, N-alkyl/aryl-N-1-[4-(3-aralkylthio-4-alkyl/aryl -4H-1,2,4-triazole-5-yl)phenyl]thioureas 20-22, were synthesized and tested for antimycobacterial activity against Mycobacterium tuberculosis H37 Rv as well as Mycobacterium fortuitum ATCC 6841 which is a rapid growing opportunistic pathogen. Compounds 4 and 9-11 were found to possess the same MIC value with that of Tobramycin against M. fortuitum ATCC 6541 whereas 1-3 and 21 had positive response against;M. tuberculosis H37Rv at varying degrees. Compound 21 was identified as the most potent derivative of the 1-22 series by an MIC value of 6.25 mug/mL and selectivity index of 1.6. (C) 2001 Elsevier Science Ltd. All rights reserved

Column Liquid Chromatography

The objective of the current study was the development and subsequent validation of a simple, sensitive, precise and stability-indicating reversed-phase HPLC method for the determination of ciprofloxacin HCl in pharmaceutical dosage forms in the presence of its potential impurities. The chromatographic separation of ciprofloxacin HCl and its related compounds was achieved on an Inertsil ODS3 column using UV detection. The optimized mobile phase consisted of phosphoric acid solution: acetonitril. The proposed method provided linear responses within the concentration range 250-750 µg mL ˉ¹ for ciprofloxacin HCl and 0.5-1.5 µg mLˉ¹ for its related compounds. LOD and LOQ values for the active substance were 5.159 and 15.632 µg mLˉ¹, respectively. Correlation coefficients (r) of the regression equations for the impurities were greater than 0.99 in all cases. The precision of the method was demonstrated using intra- and inter-day assay RSD% values which were less than 1% in all instances. No interference from any components of pharmaceutical dosage forms or degradation products was observed. 2007 Friedr. Vieweg & Sohn Verlag/GWV Fachverlage GmbH

Synthesis, molecular modeling, in vivo study, and anticancer activity of 1,2,4-triazole containing hydrazide-hydrazones derived from (S)-naproxen

WOS: 000470905700004PubMed ID: 31115928A new series of 1,2,4-triazole containing hydrazide-hydrazones derived from (S)-naproxen (7a-m) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier-transform infrared spectroscopy, H-1-nuclear magnetic resonance (NMR), C-13-NMR, and high-resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase-2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU-145, and LNCaP) using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU-145 and LNCaP cancer cell lines with IC50 values of 26.0, 34.5, and 48.8 mu M, respectively. Compounds 7b, 7k, and 7m showed anticancer activity against cancer cell lines PC3 and DU-145 with IC50 values of 43.0, 36.5, 29.3 mu M and 49.8, 49.1, 31.6 mu M, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC50 values of 43.4 and 34.5 mu M, respectively. To assess the biodistribution in mice of IRDye800, dye-labeled compound 7a or 100 mu M of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.Turkiye Bilimsel ve Teknolojik Arastirma KurumuTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [215S009, 117S435]; Scientific and Technical Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu, Grant/Award Numbers: 215S009, 117S435; The Scientific and Technical Research Council of Turke