The most common cancer in women worldwide is still breast cancer. Among its subtypes, luminal A and triple-negative breast cancers present significant therapeutic challenges due to intrinsic drug resistance and absence of effective targeted treatments. The pharmacological potential of heterocyclic compounds has garnered more attention in recent years, and structures like pyrazolines, hydrazones, and triazoles are important in the development of new drugs. Compounds incorporating these scaffolds have been shown in numerous studies to have strong anticancer action. In this regard, pyrazoline derivatives have become a viable field of study for focused treatment approaches. This study focused on evaluating the cytotoxic potential of the 2-pyrazoline-5-one derivative compound against luminal-A (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell lines. The CCK-8 test was used to assess the impact on cell viability. Additionally, Annexin V/PI staining was used to identify the apoptotic effects, and fluorescence microscopy was used for analysis. The wound healing experiment was used to measure the capacity of cells to migrate, and migration process was monitored following scratch formation. The colony formation assay was used to assess the potential for cell proliferation, and clonal growth capacities were compared. Bax protein levels in compound-treated cancer cells were quantified by ELISA to investigate the apoptotic mechanism. IC50 values in MCF-7 and MDA-MB-231 cell lines were used to evaluate the cytotoxic effects of the 2-pyrazoline-5-one derivative. The compound exhibited strong cytotoxic activity and reduced cell viability in both cell lines in a concentration-dependent manner, with IC50 values of 13 µM in MCF-7 cells and 16 µM in MDA-MB-231 cell. Furthermore, the compound effectively induced apoptosis and significantly suppressed colony formation and cell migration in both cell lines. Additionally, it showed a concentration-dependent rise in Bax protein levels, suggesting a pro-apoptotic action. These results confirm that the 2-pyrazoline-5-one derivative has strong antiproliferative and pro-apoptotic activity through Bax activation, providing a possible pathway for the creation of targeted treatments for breast cancer.

There is a growing demand in the printing industry for pigment-based inks with excellent lightfastness and rub resistance qualities. In this work, a novel ink with the formulation ethyl 2-[4-(1,3,4-oxadiazole-2(3H)-thione-5-yl)phenylhydrazono]-3-oxobutyrate (OXKT) was prepared as a pigment and its printability was investigated for use in printing. The OXKT was synthesised, characterised then printed on uncoated and gloss-coated papers and Bristol cardboard. Physical tests and spectrophotometric measurements were carried out to determine the technical characteristics of the printed ink. Additionally, print quality, ink density and gloss were evaluated. The results showed that the proposed ink with the OXKT compound had acceptable rub resistance. Also, the gloss and light fastness values exceeded the acceptable rates for the printing industry because of their colour differences. However, more research needs to be conducted to improve light performance. Nevertheless, it is still possible for use in applications that do not stipulate strict light fastness values.

Phase I and Phase II metabolic reactions are involved in the pharmacokinetic properties of drugs after administration. These reactions mainly aim to make drugs more polar and eliminate them safely. However, some of these metabolites have the potential to exhibit a toxicological effect. Industry and/or academia have to consider these metabolites in terms of their pharmacodynamic and pharmacokinetic properties. These metabolites are not only residual intermediates from the synthetic process of the main drug but also unique structures produced by metabolic enzymes in the human organism. Thus, metabolite synthesis by synthetic or semi-synthetic methods is a key feature in the pharmaceutical industry. In this review, synthetic methods of the metabolites from all known metabolic pathways are reviewed from the literature. It was observed that both synthetic and semi-synthetic methods require more attention as they are as important and complex as drug synthesis. Moreover, it showed that there was much more research available for Phase I than Phase II in the literature.

The aim of this study is to perform therapeutic drug monitoring for isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) in pediatric tuberculosis patients. The study was carried out in 3 different training-research hospitals in Istanbul, Turkiye between 2011 and 2012. The pediatric patients (aged <= 14 years) who initiated the standard primary anti-tuberculosis therapy were included in this study. The serum samples were collected 3 hours after the first medication doses were given on the 5th day of treatment. Chromatographic experiments were performed on an Agilent 1100 High-Performance Liquid Chromatography (HPLC) system, and the separation was carried out on a Nova-Pak C-18 (3.9x150 mm, 5 mu m, Merck) analytical column. In this HPLC method, the gradient elusion delivered 3% to 40% (v/v) acetonitrile in phosphate buffer was used, and diode array detector. Twenty-three children (60.9% male) patients were included with a mean age of 111.70 +/- 59.94 months. Plasma levels were measured sub-therapeutically for INH in 14, RIF in 10, and PZA in 5 patients, according to the normal range of adult patients. Maximum plasma concentrations after three hours were found between 0.53-14.02 mg/L for INH, 11.17-60.39 mg/L for PZA, 2.15-16.75 mg/ L for RIF. In conclusion, this method has been successfully applied to simultaneously determine RIF, INH, and PZA plasma levels in pediatric tuberculosis patients. RIF and INH plasma levels were found to be lower in pediatric patients with tuberculosis compared to target range of adult patients.

In this study, a series of 1,3,4-thiadiazole (1b-9b) and 1,2,4-triazole-3-thione (1c-9c) derivatives were synthesized. The reaction proses was carried out with the cyclocondensation of suitable 1,4-disubstituted thiosemicarbazide derivatives (1a-9a). The structures of the synthesized compounds were confirmed by the data obtained from elemental analysis, HPLC, UV, IR, H-1-NMR and MS spectra. All of the compounds were tested for their cytotoxic activities against L929 fibroblast cells by MTT method. It was determined that the tested compounds 1a-9a, 1b-9b and 1c-9c were not cytotoxic at the studied concentrations (5.0 mu g/mL and 10.0 mu g/mL) in L929 cell lines. Compounds 1a-c, 2a-c, 3a-c, 4a-c, 5a-c and 8a-c showed increased growth inhibition whereas compounds 6a-c, 7a-c and 9a-c showed decreased growth inhibition on L929 cell lines

In the present study, a series of 4(3H)-quinazolinone derivatives (5a-f) were synthesized through the cylization reaction of substituted 1,3,4-thiadiazoles containing an aromatic primary amin and anthranilic acid in the presence of acetic anhydride and acetic acid. The structures of the synthesized compounds were confirmed by elemental analysis, IR, H-1-NMR and mass spectroscopic (5b and 5f) methods. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) using a modification of Ellman's spectrophotometric method. Compounds 2-methyl-3-{4-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]phenyl} quinazolin-4(3H)-one (5b) and 2-methyl-3-{4-[5(cyclohexylamino)-1,3,4-thiadiazol-2-yl]phenyl} quinazolin4(3H)-one (5d) can be identified as promising anticholinesterase agents due to their inhibitory effect when compared with donepezil as a reference drug.

In the present study, several 2-(4-aminophenyl)-5-substituted amino-1,3,4-thiadiazoles (2a-l) and their coupling products, 2,3,4-pentanetrione-3-[4-(5-alkyl/arylamino-1,3,4-thiadiazole-2-yl)phenyl]hydrazones (3a-j) were synthesized in good yields and characterized by UV, IR, H-1-NMR, mass and elemental analysis. Antitubercular activity of the synthesized compounds was determined in vitro using the BACTEC 460 Radiometric System against Mycobacterium tuberculosis H37Rv at 6.25 mu g/mL. The antimycobacterial data of screened compounds indicated that 2-(4-aminophenyl)-5-(4-chlorophenyl)amino-1,3,4-thiadiazole 2f demonstrated the highest inhibition.

Accepted: 15.12 .201

BACKGROUND:Taking into account the improvement in insecticidal activity by the inclusion of fluorine in the hydrazone moiety, the authors synthesized new 4-fluorobenzoic acid hydrazides and 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazoles, substituting a phenyl group or a heteroaryl ring carrying one or two atoms of F, Cl and Br, and investigated their biting deterrent and larvicidal activities against Aedes aegypti for the first time.RESULTS:The compound 3-acetyl-5-(4-fluorophenyl)-2-[4-(dimethylamino)phenyl]-2,3-dihydro-1,3,4-oxadiazole (17) produced the highest biting deterrent activity (BDI = 1.025) against Ae. Aegypti, followed by 4-fluorobenzoic acid [(phenyl)methylene] hydrazide (1). These activity results were similar to those of N,N-diethyl-meta-toluamide (DEET), which showed a proportion not biting of 0.8-0.92. When compounds 1 and 17 were tested on cloth worn on human volunteers, compound 1 was not repellent for some volunteers until present in excess of 500 nmol cm(-2) , while compound 17 was not repellent at the highest concentration tested (1685 nmol cm(-2) ). In the larvicidal screening bioassays, only compounds 10, 11, 12 and 17 showed 100% mortality at the highest screening dose of 100 ppm against Ae. aegypti larvae. Compounds 11 and 12 with LD50 values of 24.1 and 30.9 ppm showed significantly higher mortality than 10 (80.3 ppm) and 17 (58.7 ppm) at 24-h post-treatment.CONCLUSION:The insecticidal and biting deterrent activities were correlated with the presence of a halogen atom on the phenyl or heteroaryl substituent of the hydrazone moiety.

3,4-Disubstituted-2,4-dihydro-5H-1,2,4-triazole-5-thiones were synthesized by a new one-pot, two-step synthesis method which was demonstrated to be superior than the current synthesis methods. The new method involves addition of alkyl/aryl isothiocyanates to substituted hydrazides in ethanol following the refluxing process of intermeadiate in 4N sodium hydroxide solution. According to our new synthesis procedure, reaction has gone to completion within 6 hours by higher product yields and reduced solvent usage.

ABSTRACT: Novel derivatives of substituted hydrazone (2a-e), 2-pyrazoline-5-one (3a-e, 4ae) and 2-isoxazoline-5-one (5a-e) derivatives possessing 1,3,4-thiadiazole moiety were synthesized and evaluated for their antitubercular activity. The highest inhibitions were observed with the synthesized compounds are 87% for 3-methyl-4-[4-(5-cyclohexylamino- 1,3,4-thiadiazole-2-yl)phenylhydrazono]-2-isoxazoline-5-one (5b) and 86% for ethyl 2-[4-(5-cyclohexylamino-1,3,4-thiadiazole-2-yl)phenylhydrazono]-3-oxobutirate (2b). Compounds 2b and 5b could be a good initial point to develop new lead compound. KEY WORDS: 1,3,4-thiadiazole, 2-pyrazolin-5-one, 2-isoxazoline-5-one, hydrazone and antitubercular activity

This study describes the synthesis of novel 1-(alpha,alpha-diphenyl-alpha-hydroxy) acetyl-4-substitutedthiosemicarbazide (2a-k), [5-(substitutedamino)-1,3,4-thiadiazole-2-yl](diphenyl) methanol (3a-b) and 3-[hydroxy(diphenyl)methyl]-4-(nonsusbtituted/substituted)-2,4-dihydro-5H-1,2,4-triazole-5-thione derivatives (4a-c) and evaluation of their cytotoxic activities. In the course of the syntheses benzilic acid methyl ester was reacted with hydrazine hydrate in absolute ethanol to afford benzilic acid hydrazide (1). Reaction of 1 with appropriate alkyl/arylisothiocyanates gave 1-(alpha,alpha-diphenyl-alpha-hydroxy) acetyl-4-substitutedthiosemicarbazide (2a-k). [5-(substitutedamino)-1,3,4-thiadiazole-2-yl](diphenyl) methanol derivatives (3a-b) were obtained by cyclization of 2a and 2c with concentrated sulphuric acid. On the other hand, 3-[hydroxy(diphenyl)methyl]-4-(nonsusbtituted/substituted)-2,4-dihydro-5H-1,2,4-triazole-5-thione (4a-c) were obtained by cyclization of 2c, 2d and 2g with 2N NaOH. The structures of the new compounds were confirmed by the data obtained from elemental analysis, HPLC, UV, IR, 1H-NMR, 13C-NMR, HSQC and MS spectra. Compounds 2a, 2c-k, 3b and 4b were selected for cytotoxic screening by using HEK293 cell line of MTT assay. The highest inhibition were confirmed as 50.23% at 10 mg/ml for the compound 1-(alpha,alpha-diphenyl-alpha-hydroxy) acetyl-4-cyclohexylmethylthiosemicarbazide (2e).

Azo compounds are extensively used for colouring food, drink, pharmaceuticals, cosmetics, textiles and printing inks. Publications in the literature have shown that azo dyes can pose threats to public health by metabolic and chemical oxidation and reduction reactions. In the present study, the in vivo and in vitro biotransformation of ethyl 4-[(2-hydroxy-1-naphthyl)azo]benzoate, an azo compound which is structurally similar to 1-phenylazo-2-naphthol was studied to investigate its in vivo and in vitro metabolic products. For the in vitro biotransformation study, rat liver microsomal preparations fortified with NADPH as a co-factor were used. Three unidentified metabolic products were observed. For the in vivo biotransformation study, a concentrated solution of this substrate was given orally to female rats. After the administration of substrate, blood samples of rats are taken at certain intervals. The blood plasma were obtained by centrifuging blood samples. The cold acetonitrile was added to plasma to precipitate plasma proteins and plasma was centrifuged. The supernatant was evaporated at room temparature. The residue was reconstituted with acetonitrile and examined by the HPLC. The unchanged substrate together with the corresponding reduction and acetylation products were detected in plasma. However, no initial hydrolysis occurred in the ester moiety.

In this review, the synthesis and biological activities of 3-acyl- 2,3-dihydro-1,3,4oxadiazole derivatives are reported. Synthesis of 1,3,4-oxadiazolines via carboxylic acid hydrazide-hydrazones by using acetic anhydride or other cyclization agents establishes the peculiar basis of our work.

Various 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazoles (11–20) were prepared by the reaction of aryl substituted hydrazones of 4-fluorobenzoic acid hydrazide (1–10) with acetic anhydride. The structures of the synthesized compounds 11–20, were confirmed by UV, IR, 1H-NMR and mass spectroscopic methods. Antifungal evaluation of the hydrazide–hydrazones 1–10 and corresponding 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazoles 11–20, against clinical and standard Candida pathogens have been performed by using agar diffusion to indentify the active compounds, which were later subjected to a broth microdilution assay to justify the activity level in terms of minimum inhibitory concentrations (MIC). 4-Fluorobenzoic acid [(5-bromothiophen-2-yl)methylene]hydrazide, showed the highest inhibitory activity against Candida albicans (MIC: 125 μg/ml), and when compared with ketoconazole. In addition, bioauthographic antifungal activity against plant pathogenic fungi such as Colletotrichum, Botrytis, Fusarium, and Phomopsis was conducted. 4-Fluorobenzoic acid [(5-bromothiophen-2-yl)methylene]hydrazide was the most active analog against P. viticola with 91% inhibition at 30 μM after 144 h. Furthermore, known and the newly synthesized compounds were also screened through a panel of bioassays to determine their anti-inflammatory, cytotoxic, and antioxidant activities in mammalian cells. 3-Acetyl-5-(4-fluorophenyl)-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydro-1,3,4-oxadiazole, showed a strong inhibition of NF-κB-dependent transcription in SW1353 cells with IC50 value of 0.75 μg/ml. 4-Fluorobenzoic acid [(3-hydroxy-4-methoxyphenyl)methylene]hydrazide, and 3-acetyl-5-(4-fluorophenyl)-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydro-1,3,4-oxadiazole on intracellular ROS generation in PMA induced HL-60 cells demonstrated potent activity with IC50 values of 0.9 μg/ml. A strong inhibition of the activity of iNOS activity in LPS induced RAW 264.7 cells was observed for 3-acetyl-5-(4-fluorophenyl)-2-(4-hydroxyphenyl)-2,3-dihydro-1,3,4-oxadiazole with IC50 value of 0.3 μg/ml.

A series of novel triazene derivatives 1-3, 1a-3a were synthesized by the coupling of diazonium salts of amines (sulfaguanidine, sulfapyridine, sulfamethoxazole) with N-methylaniline / p-nitroaniline in acidic media. The structures of the synthesized compounds were confirmed by the spectral data (UV, IR, H-1-NMR, APCI-MS) and elemental analysis. The effects of all the compounds on A 549 and L 929 cell lines growth were investigated. The cytotoxic and antitumor activities of these compounds have not been in vitro aganist A 549 and L 929 cell lines.

Several isoxazolone derivatives were synthesized, starting from substituted 1,3,4-thiadiazoles and 1,2,4-triazole-3-thione. In the first part of the research, compounds 2-(4-aminophenyl)-5-alkyl/arylamino-1,3,4-thiadiazoles (4a-e) and 5-(4-aminophenyl)-4-substitude- 2,4-dihydro-3H-1,2,4-triazole-3-thiones (5a-c) were prepared from ethyl 4-aminobenzoate. In the second part, compounds, which were prepared by coupling the diazonium salts of aromatic primary amines with ethyl acetoacetat (6a-e, 7a-c) were cyclized with hydroxylamine hydrochloride and sodium acetate in ethanol and yielded 3-methyl-4-[2-{4-[5 alkyl/arylamino)-1,3,4-thiadiazol-2-yl] phenyl} hydrazinylidene] isoxazol-5(4H)-one (8a-e) 3-methyl- 4-[2-{4-[4-(4-alkyl/aryl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl] phenyl} hydrazinylidene] isoxazol-5(4H)-one (8f-g). The structures of the synthesized compounds were confirmed by elemental analysis (C, H, N, S), UV, IR, 1H-NMR and mass spectroscopic methods. Cytotoxicity of these compounds were evaluated by using HEK293 cell line of MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide] assay. The highest inhibitions were confirmed as % 45.72 for the compound 3-methyl-4-[2-(4-{5-[(4-methoxyphenyl) amino]-1,3,4-thiadiazol-2-yl} phenyl) hydrazinylidene] isoxazol-5(4H)-one (8e) and % 33.07 for the compound 3-methyl-4-[2-(4-{5-[(4-methylphenyl) amino]-1,3,4-thiadiazol-2-yl} phenyl) hydrazinylidene] isoxazol-5(4H)-one (8a).

A series of 3,5-dimethylpyrazole derivatives, structurally related to the previously described potent ameltolide analogues, were synthesized and evaluated for their anticonvulsant activity. Ten compounds were prepared by reacting the 4-amino-3,5-dimethylpyrazole with appropriate substituted carboxylic acids, benzoyl chlorides and benzaldehydes to obtain amide and imine derivatives. Initial anticonvulsant screening was performed using intraperitoneal pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizure tests in mice. Among the 10 tested compounds, N-[1-(4-methoxybenzoyl)-3,5-dimethylpyrazole-4-yl]-4-methoxybenzamide 2 and N-[1-(2,6-dichlorobenzoyl)-3,5-dimethylpyrazole-4-yl]-2,6-dichlorobenzamide 3 decreased seizure severity and the mortality rate in the PTZ test. Hence, compound 3 was tested in an animal model of absence epilepsy, Genetic Absence Epileptic Rats from Strasbourg (GAERS). There were no significant changes in the duration or number of spike-and-wave discharges in this model.