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 hydrazide hydrazone scaffold as a promising hepatitis C virus (HCV) and hepatocelluler inhibitor. Herein we describe the design a number of 2',4'-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 2',4'-difluoro-4-hydroxy-N'-(2-pyridyl methylidene)biphenyl-3-carbohydrazide 3b and diflunisal (2.5-40 mu M) 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, 1034 16.21 4.74, 9.29 and 8.33 mu M 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. (C) 2015 Elsevier Masson SAS. All rights reserved

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

A series of novel N-alkyl/aryl-N'-[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'-[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 H37Rv 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 6841 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 microg/mL and selectivity index of 1.6

Synthesis of some 3-(Arylalkylthio)-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2, 4-triazole derivatives and their anticonvulsant activity

A series of novel 3-{[(substituted phenyl)methyl]thio}-4-alkyl/aryl-5-(4- aminophenyl)-4H-1,2,4-triazoles 11-20 and several related Schiff's bases, 3-{[(substituted phenyl)-methyl]thio}-4-alkyl/aryl-5-{[[(substituted phenyl/5-nitro-2-furyl)methylene]amino]-phenyl}-4H-1,2,4-triazoles 21-31 were synthesized for evaluation of their biological properties. Structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. All compounds were evaluated for their anticonvulsant activity by maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and neurotoxicity (NT) screens. A number of triazole derivatives, exhibited protection after intraperitoneal administration at the dose of 100 and 300 mg/kg in one or both models employed. Compounds 12, 13 and 14 were subjected to oral MES screening in rats at 30 mg/kg and were observed to protect 50% of the animals employed in the experiment. Antimicrobial and antituberculosis activity of these compounds 11-31 were also screened. Some of the tested compounds showed marginal activity against M. tuberculosis H37 Rv. © 2004 Published by Elsevier SAS

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

A 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

Anticancer and Antimicrobial Activities of Naproxen and Naproxen Derivatives

This review explains the effects of naproxen and the naproxen moiety in important biological activities. Naproxen, 2-(6-methoxynaphthalen-2-yl)propionic acid, is one of the most utilized propionic acid derivatives to the cure of many injuries or pains. Naproxen is a non-steroidal anti-inflammatory drug (NSAID), which is generally used among the NSAIDs. Even though it has gastrointestinal side effects, naproxen has been safely used for many years because of the good cardiovascular sight. In the past years, except for anti-inflammatory effects, other pharmacological activities of naproxen, especially anticancer and antimicrobial activities, gain the attention of researchers. Naproxen shows its activity by inhibiting the COX-2 enzyme. There is significant interest in the possibility that COX-2 inhibitors might retard or prevent the development of various cancer types, which is often characterized by COX-2 expression. The activities of both naproxen and new molecules derived from naproxen were frequently investigated

Synthesis, characterization and anticancer activity of novel hydrazide-hydrazones derived from ethyl paraben

Parabens, which are hydroxybenzoic acid esters, are particularly used as protective against mold and fungus. Ethyl paraben is a compound open to modification for the synthesis of new molecules due to the ester group in its structure. In this study, ethyl paraben was used as a starting material. A new series of novel hydrazide-hydrazones from derived ethyl paraben were synthesized and characterized by spectroscopic techniques such as NMR, FT-IR besides elemental analysis. In order to determine the anticancer activity of the aimed ethyl paraben hydrazidehydrazones we evaluated their cytotoxic activity on liver cancer cell line liver hepatocellular carcinoma (HepG2). Herein we described several 4-hydroxy-N'-[substituted methylidene] benzohydrazides (3a-j) as anticancer agents. We designed, synthesized and characterized the series of novel hydrazide-hydrazones from ethyl paraben. All of the compounds evaluated for anticancer activity by using MTT assay for 24 and 48 h. mRNA transcription levels of Bax, Bcl-2 and caspase-3 genes were determined by realtime polymerase chain reaction (qRT-PCR) analysis. Compounds 3i and 3j showed anticancer activity with 42.4 and 37.4 mu M IC50 values, respectively. Doxorubicin was used as a positive sensitivity reference standard. qRTPCR analysis approved that there was a timedependent rise in the expression levels of Bax, Bcl-2 and Caspase 3 on apoptosis. The activities of the synthesized compounds changed depending on the dose and time of treatment and some of the molecules started to show activity within 48 hours

Synthesis, characterisation and biological activity of novel 4-thiazolidinones, 1,3,4-oxadiazoles and some related compounds

Two novel series of 4-thiazolidinone derivatives, namely 2-substituted-3-([4-(4-methoxybenzoylamino)benzoyl]amino)-4-thiazolidinones (7a-e) and 2-[4-(4-methoxybenzoylamino)benzoylhydrazono]-3-alkyl-4-thiazolidinones (5a-c) together with 2-[4-(4-methoxybenzoylamino)phenyl]-5-(substituted phenyl)amino-1,3,4-oxadiazoles (6a-c) have been synthesised as title compounds. N(1)-[4-(4-methoxybenzoylamino)benzoyl]-N(2)-substituted methylene hydrazines (3a-e) and 1-[4-(4-methoxybenzoylamino)benzoyl]-4-substituted phenyl thiosemicarbazides (4a-f) were also prepared and used as intermediate to give the title compounds. All synthesised compounds were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv and antimicrobial activities against various bacteria and fungi. Compounds 7a and 7b were found as the most active derivatives demonstrating 90 and 98% inhibition of mycobacterial growth of M. tuberculosis H37Rv in the primary screen at 6.25 microg mL(-1), respectively. However, level II assay revealed that the MIC values were not less than 6.25 microg mL(-1). None of the compounds showed significant antimicrobial activity against the microorganisms used whereas 3a and 7a inhibited the growth of several bacteria and fungi

Synthesis, Anticancer Activity on Prostate Cancer Cell Lines and Molecular Modeling Studies of Flurbiprofen-Thioether Derivatives as Potential Target of MetAP (Type II)

Background: Prostate cancer is still one of the serious causes of mortality and morbidity in men. Despite recent advances in anticancer therapy, there is a still need of novel agents with more efficacy and specificity in the treatment of prostate cancer. Because of its function on angiogenesis and overexpression in the prostate cancer, methionine aminopeptidase-2 (MetAP-2) has been a potential target for novel drug design recently. Objective: A novel series of Flurbiprofen derivatives N-(substituted)-2-(2-(2-fluoro-[1,1'-biphenyl]-4-il)propanoyl)hydrazinocarbothioamide (3a-c), 4-substituted-3 -(1 -(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (4a-d), 3-(substitutedthio)-4-(substituted-pheny1)5-(1-(2-fluoro-[1,1'-biphenyt]-4-yl)ethyl)-411-1,2,4-triazole (5a-y) were synthesized. The purpose of the research was to evaluate these derivatives against MetAP-2 in vitro and in silico to obtain novel specific and effective anticancer agents against prostate cancer. Methods: The chemical structures and purities of the compounds were defined by spectral methods (H-1-NMR, C-13-NMR, HR-MS and FT-IR) and elemental analysis. Anticancer activities of the compounds were evaluated in vitro by using MTS method against PC-3 and DU-143 (androgenindependent human prostate cancer cell lines) and LNCaP (androgen-sensitive human prostate adenocarcinoma) prostate cancer cell lines. Cisplatin was used as a positive sensitivity reference standard. Results: Compounds 5b and 5u; 3c, 5b and 5y; 4d and 5o showed the most potent biological activity against PC3 cancer cell line (IC50 = 27.1 mu M, and 5.12 mu M, respectively), DU-145 cancer cell line (IC50 - 11.55 mu M, 6.9 mu M and 9.54 mu M, respectively) and LNCaP cancer cell line (IC50 - 11.45 mu M and 26.91 mu M, respectively). Some compounds were evaluated for their apoptotic caspases protein expression (EGFR/PI31C/AKT pathway) by Western blot analysis in androgen independent-PC3 cells. BAX, caspase 9, caspsase 3 and anti-apoptotic BcL-2 mRNA levels of some compounds were also investigated. In addition, molecular modeling studies of the compounds on MetAP-2 enzyme active site were evaluated in order to get insight into binding mode and energy. Conclusion: A series of Flurbiprofen-thioether derivatives were synthesized. This study presented that some of the synthesized compounds have remarkable anticancer and apoptotic activities against prostate cancer cells. Also, molecular modeling studies exhibited that there is a correlation between molecular modeling and anticancer activity results

Synthesis, Molecular Modelling and Antibacterial Activity Against Helicobacter pylori of Novel Diflunisal Derivatives as Urease Enzyme Inhibitors

Background: The main factor for the prolongation of the ulcer treatment in the gastrointestinal system would be Helicobacter pylori infection, which can possibly lead to gastrointestinal cancer. Triple therapy is the treatment of choice by today's standards. However, observed resistance among the bacterial strains can make the situation even worse. Therefore, there is a need to discover new targeted antibacterial therapy in order to make success in the eradication of H. pylori infections. Methods: The targeted therapy rule is to identify the related macromolecules that are responsible for the survival of the bacteria. Thus, 2-[(2',4'-difluoro-4-hydroxybiphenyl-3-yl)carbonyl]-N-( substituted)hydrazinocarbothioamide (3-13) and 5-(2',4'-difluoro-4-hydroxybiphenyl-3-yl)-4-( substituted)-2,4-dihydro-3H-1,2,4-triazole-3-thiones (14-17) were synthesized and evaluated for antibacterial activity in vitro against H. pylori. Results: All of the tested compounds showed remarkable antibacterial activity compared to the standard drugs (Ornidazole, Metronidazole, Nitrimidazin and Clarithromycin). Compounds 4 and 13 showed activity as 2 mu g/ml MIC value. Conclusion: In addition, we have investigated binding modes and energy of the compounds 4 and 13 on urease enzyme active by using the molecular docking tools