Meric Koksal

Cancer Cell Cytotoxicities of 1-(4-Substitutedbenzoyl)-4-(4-chlorobenzhydryl)piperazine Derivatives

A series of novel 1-(4-substitutedbenzoyl)-4-(4-chlorobenzhydryl)piperazine derivatives 5a–g was designed by a nucleophilic substitution reaction of 1-(4-chlorobenzhydryl)piperazine with various benzoyl chlorides and characterized by elemental analyses, IR and 1H nuclear magnetic resonance spectra. Cytotoxicity of the compounds was demonstrated on cancer cell lines from liver (HUH7, FOCUS, MAHLAVU, HEPG2, HEP3B), breast (MCF7, BT20, T47D, CAMA-1), colon (HCT-116), gastric (KATO-3) and endometrial (MFE-296) cancer cell lines. Time-dependent cytotoxicity analysis of compound 5a indicated the long-term in situ stability of this compound. All compounds showed significant cell growth inhibitory activity on the selected cancer cell lines.

Analgesic and antiinflammatory activities of some new Mannich bases of 5-nitro-2-benzoxazolinones.

In this study, the synthesis of a novel series Mannich bases of 5-nitro-3-substituted piperazino-methyl-2-benzoxazolinones are described. The structures attributed to compounds 3a-3k were elucidated using IR,1H-NMR spectroscopic techniques besides elemental analysis. The compounds were examined for their in vivo antiinflammatory and analgesic activities in two different bioassays, namely, carrageenan-induced hind paw edema and p-benzoquinone-induced abdominal constriction tests in mice, respectively. In addition, the ulcerogenic effects of the compounds were determined. Among the tested derivatives most promising results were obtained for the compounds bearing electron-withdrawing substituents (F, Cl, COCH3) in the ortho/para position of the phenyl nucleus on the piperazine ring at 3 position of benzoxazoli-none moiety (3a, 3b, 3c, 3d, 3h). The analgesic activities of all compounds are higher than their antiinflammatory activities. Antiinflammatory inhibitory ratios for all compounds were above 30% for the last two measurements. Because of this compounds 3a, 3b, 3c, 3d deserve attention and may be considered for further evaluation.

Synthesis and in vitro Evaluation of Novel Indole-Based Sigma Receptors Ligands.

To investigate the molecular features involved in sigma (σ) receptors binding, a series of compounds based on indole scaffolds were synthesized and their chemical structures were confirmed by 1H‐NMR, IR, and elemental analysis. Their affinity toward σ1 and σ2 receptor subtypes was evaluated. 1‐{[4‐(2‐phenylethyl)piperazin‐1‐yl]methyl}‐3‐methyl‐1H‐indole 3b had a high affinity to σ1 receptors, while three compounds, 1‐{3‐[4‐(substitutedphenyl)piperazin‐1‐yl]propyl}‐1H‐indole derivatives 4a–c had shown high affinity and selectivity for σ2 receptors. Cytotoxicity of the compounds was demonstrated on cancer cell lines from liver (HUH7), breast (MCF7), and colon (HCT‐116) cancer cell lines. Compound 1c (3‐{[4‐(3,4‐dichlorobenzyl)piperazin‐1‐yl]methyl}‐1H‐indole) showed significant cell growth inhibitory activity on the selected cancer cell lines.

Synthesis and characterization of some new 2(3H)-benzoxazolones with analgesic and antiinflammatory activities

The synthesis, characterization and pharmacological activities of a new series of (6-difluorobenzoyl)-5-methyl-3-benzoylmethyl-2(3H)-benzoxazolone and 5-methyl-3-(2-hydroxyl-2-phenylethyl)-2(3H)-benzoxazolone are described. Antiinflammatory activity was investigated by the carrageenin-induced paw oedema test and analgesic activity by acetic acid writhing and hot plate tests in mice. Among the synthesized compounds, compound 3e 6-(2,5-difluorobenzoyl)-3-(4-bromobenzoylmethyl-2(3H)-benzoxazolone was found to be the most promising compound for analgesic activity. Reduced compounds (4a–4d) displayed considerable anti-inflammatory activity compared to the other derivatives.

Synthesis and anti-inflammatory activities of novel 5-(3,4-dichlorophenyl)-3-[(4-substitutedpiperazin-1-yl)methyl]-1,3,4-oxadiaxole-2(3H)-thiones.

To synthesize a new series of 5-(3,4-dichlorophenyl)-3-[(4-substitutedpiperazin-1-yl)methyl]-1,3,4-oxadiaxole-2-thiones for their anti-inflammatory activity.The title compounds synthesized by Mannich reaction of prepared 5-(3,4-dichloro-phenyl)-1,3,4-oxadiazole-2-thione and appropriate substituted piperazine derivatives. The structures of the compounds were confirmed by IR, NMR and elemental analyses. The newly synthesized compounds were evaluated for their anti-inflammatory and ulcerogenic activities.Most of the compounds were found to have significant anti-inflammatory profile in carrageenan footpad edema test. The compounds showed anti-inflammatory activity ranging from 30.6% to 57.8% inhibition.The compounds 5b, 5f, 5i, 5p and 5r showed most prominent anti-inflammatory activity with low gastric ulceration incidence than the reference drug indomethacine. These compounds could serve as lead molecules for further modifications.

5-(3,4-DICHLOROPHENYL)-3-{(4-(2-PYRIDYL)PIPERAZINE-1-YL)METHYL}- 1,3,4-OXADIAZOLE-2(3H)-ONE: SYNTHESIS, CHARACTERIZATION, X-RAY AND DFT STRUCTURES

Abstract5-(3,4-Dichlorophenyl)-3-{[4-(2-pyridyl)piperazine-1-yl)]methyl}-1,3,4-oxadiazole-2(3H)-one C18H17Cl2N5O2 (3) is synthesized and characterized by IR, 1H NMR, 13C NMR, elemental analyses, single-crystal X-ray diffraction, and the molecular structure is also optimized at the B3LYP/6-31G(d,p) level using density functional theory (DFT). All data obtained from the spectral studies support the structural properties of 3. The molecules are linked principally by C-H…O hydrogen bonds involving carbonyl atoms and carboxylate O atoms, forming R22(16) and R42 (20) rings that link to give a one-dimensional network of molecules. An extensive two-dimensional network of C-H…O hydrogen bonds and π…π interactions are responsible for crystal stabilization.

Synthesis and cytotoxic activity of novel 3-methyl-1-[(4-substitutedpiperazin-1-yl)methyl]-1H-indole derivatives.

A series of novel 3-methyl-1-[(4-substitutedpiperazin-1-yl)methyl]-1H-indoles (3a-l) were synthesized and their cytotoxicities were analyzed against 3 different human cell lines, including liver (HUH7), breast (MCF7) and colon (HCT116). The Mannich reaction of 3-methylindole (1) with 4-substitutedpiperazines (2) and formaldehyde resulted to the 3-methyl-1-[(4-substitutedpiperazin-1-yl)methyl]-1H-indoles (3a-l) in 38-69% yields. The investigation of anticancer screening revealed that the tested compounds showed comparable activity to the reference drug 5-fluorouracil and compounds 3g, 3h, 3i and 3k, had lower 50% inhibition (IC50) concentration than reference drug. Moreover, the cytotoxic effect of the most potent compound 3h on HUH7 and MCF7 cells through apoptosis was visualized by Hoechst staining and compared with paclitaxel, which is a mitotic inhibitor acting on microtubules. The morphological features of apoptosis were observed as condensed and fragmented nuclei that are similar to paclitaxel.

Synthesis, characterization and anti-inflammatory activity of new 5-(3,4-dichlorophenyl)-2-(aroylmethyl) thio-1,3,4-oxadiaxoles.

Several 5-(3,4-dichlorophenyl)-2-(aroylmethyl)thio-1,3,4-oxadiazoles were synthesized and characterized by elemental analyses, IR and nuclear magnetic resonance spectra. All compounds were evaluated for anti-inflammatory activity by determining their ability to provide protection against carregeenan-induced edema in rat paw. In addition, ulcerogenic activity was determined. The anti-inflammatory data scoring showed that compounds 5e, 5f and 5g, at the dose of 100 mg/kg, exhibited anti-inflammatory activity, which for compound 5f was comparable to that of the reference drug indometacin (CAS 53-86-1).

Synthesis and Evaluation of Analgesic, Anti-Inflammatory and Antioxidant Activities of New 6-Acyl-3-alkyl-5-methyl-2 (3H) -benzoxazolones

A new series of 6-acyl-3-alkyl-5-methyl-2(3H)-benzoxazolones have been obtained starting from 5-methyl-2(3H)-benzoxazolone. All the compounds have been characterized by IR, 1H-NMR and mass spectroscopy. The new compounds were screened for analgesic and anti-inflammatory activities and ulcerogenic effect. The in vitro antioxidant capacity of the synthesized compounds were tested by the nitric oxide radical scavenging assay. Most of the compounds showed antiinflammatory activity. Among them, 3-[4-(4-fluorophenyl)piperazinomethyl] -6-(3-chlorobenzoyl)-5-methyl-2(3H)-benzoxazolone (3j) was found more potent than the reference drug indometacin (CAS 53-86-1) with 41.66% decrease in edema. Compared with the control, some of the compounds exhibited analgesic effects. Similar to the anti-inflammatory activity results, compound 3j showed the highest analgesic profile with 48.56% inhibition. No active hemorragic focus was observed in the microscopic evaluation in the ulcerogenic effect studies of the tested compounds. 6-(3-Chlorobenzoyl)-5-methyl-2(3H)-benzoxazolone (2b) and 3-[4-(4-fluorophenyl-piperazino)methyl]-6-(3-chlorobenzoyl)-5-methyl-2(3H)-benzoxazolone (3j) showed nearly maximum antioxidant activity compared to ascorbic acid (CAS 50-81-7) with IC50 values of 27.6 and 30.1 microg/mL, respectively.

Some Novel Mannich Bases of 5-(3,4-Dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one and Their Anti-Inflammatory Activity

Non‐steroidal anti‐inflammatory drugs (NSAIDs), which are widely used for the treatment of rheumatic arthritis, pain, and many different types of inflammatory disorders, cause serious gastrointestinal (GI) side effects. The free carboxylic acid group existing on their chemical structure is correlated with GI toxicity related with all routine NSAIDs. Replacing this functional group with the 1,3,4‐oxadiazole bioisostere is a generally used strategy to obtain an anti‐inflammatory agent devoid of GI side effects. In the present work, a novel group of 5‐(3,4‐dichlorophenyl)‐1,3,4‐oxadiazole‐2(3H)‐one Mannich bases were synthesized and characterized on the basis of IR, 1H NMR, and elemental analysis results. The target compounds were first tested for cytotoxicity to determine a non‐toxic concentration for anti‐inflammatory screening. Anti‐inflammatory effects of the compounds were evaluated by in vitro lipopolysaccharide (LPS)‐induced NO production and in vivo carrageenan footpad edema with ulcerogenic profile. In LPS‐induced RAW 264.7 macrophages, most of the compounds showed inhibitory activity on nitrite production while compounds 5a, 5h, and 5j exhibited the best profiles by suppressing the NO production. To evaluate the in vivo anti‐inflammatory potency of the compounds, the inflammatory response was quantified by increment in paw size in the carrageenan footpad edema assay. The anti‐inflammatory data scoring showed that compounds 5a–d, 5g, and 5j, at the dose of 100 mg/kg, exhibited anti‐inflammatory activity, which for compound 5g was comparable to that of the reference drug indomethacin with 53.9% and 55.5% inhibition in 60 and 120 min, respectively.