8 research outputs found
Bazı tiyazolilaminoasetiltiyoimidazol türevi bileşiklerin sentez biyolojik aktivite ve moleküler modellemeleri üzerine çalışmalar
No full textTez (yüksek lisans) - Anadolu ÜniversitesiAnadolu Üniversitesi, Sağlık Bilimleri Enstitüsü, Farmasötik Kimya Anabilim DalıKayıt no: 469260Trisiklik yapılardaki merkezi halkanın farklı yapısal varyasyonları, selektif siklooksijenaz 2 (COX-2) inhibisyonu için popüler bir araştırma alanı olmuştur. Aynı şekilde tiyazol türevlerinin de farklı farmakolojik aktivitelere sahip olduğu bilinmektedir. Bu çalışma kapsamında 1,5-disübstitüefenil-imidazol-2-tiyol ve N-tiyazol asetamit yapıları reaksiyona sokularak 9 tane yeni 2-[(1,5-disübstitüe fenil-1H-imidazol-2-il)tiyo]-N-tiyazol-2-il asetamit türevi elde edilmiştir (Bileşik 1-9). Sentezlenen bu bileşiklerin COX -1 ve COX-2 inhibisyon aktiviteleri, enzim denemeleri ile test edilmiş. Etkin bileşik aktif yöre arasındaki etkileşimler moleküler modelleme çalışmalarıyla aydınlatılmıştır
Design and synthesis of stable N-[2-(Aryl/heteroaryl substituted)ethyl] propanamide derivatives of (S)-ketoprofen and (S)-ibuprofen as non-ulcerogenic anti-inflammatory and analgesic agents
No full textThe carboxylic acid groups of (S) ketoprofen and (S) ibuprofen were brought into reaction with substituted ethylamine derivatives to form (S)-2-(4-isobutylphenyl)- and (S)-2-(3-benzoylphenyl)-N-[2-(aryl/heteroaryl substituted) ethyl]propanamide derivatives. Then, these sets were evaluated in terms of their in vivo anti-inflammatory and analgesic properties using the carrageenan-induced paw edema and p-benzoquinone-induced writhing models. Among the synthesized compounds, (S)-2-(4-isobutylphenyl)-N-[2-(pyrrolidin-1-yl)ethyl]propanamide (4f) showed the highest activity at the 100mg/kg dose inducing no gastric lesions when compared to the parent compound, ibuprofen. In vitro studies on chemical stability revealed that the amide derivative with the highest activity (4f) was chemically stable in simulated gastric (pH 1.2) and intestinal fluids (pH 7.4). In 80% v/v human plasma, the amide derivative was found to be stable against plasma hydrolases over the experimental period. The most active compound, (S)-2-(4-isobutylphenyl)-N-[2-(pyrrolidin-1-yl)ethyl]propanamide, was also studied in 10% rat liver homogenate (pH 7.4) to identify its release pattern as a prodrug
Potent ribonucleotide reductase inhibitors: Thiazole-containing thiosemicarbazone derivatives
No full textSAHIN, ZAFER/0000-0002-5976-676X; Berk, Barkin/0000-0001-6047-2796WOS: 000484830900001PubMed: 31475759The antioxidant, antimalarial, antibacterial, and antitumor activities of thiosemicarbazones have made this class of compounds important for medicinal chemists. in addition, thiosemicarbazones are among the most potent and well-known ribonucleotide reductase inhibitors. in this study, 24 new thiosemicarbazone derivatives were synthesized, and the structures and purity of the compounds were determined by IR, H-1 NMR, C-13 NMR, mass spectroscopy, and elemental analysis. the IC50 values of these 24 compounds were determined with an assay for ribonucleotide reductase inhibition. Compounds 19, 20, and 24 inhibited ribonucleotide reductase enzyme activity at a higher level than metisazone as standard. the cytotoxic effects of these compounds were measured on the MCF7 (human breast adenocarcinoma) and HEK293 (human embryonic kidney) cell lines. Similarly, compounds 19, 20, and 24 had a selective effect on the MCF7 and HEK293 cell lines, killing more cancer cells than cisplatin as standard. the compounds (especially 19, 20, and 24 as the most active ones) were then subjected to docking experiments to identify the probable interactions between the ligands and the enzyme active site. the complex formation was shown qualitatively. the ADME (absorption, distribution, metabolism, and excretion) properties of the compounds were analyzed using in-silico techniques.Anadolu University Scientific Research Projects CommissionAnadolu University [1609S624]Anadolu University Scientific Research Projects Commission, Grant/Award Number: 1609S62
Novel thiazole-piperazine derivatives as potential cholinesterase inhibitors
No full textSAHIN, ZAFER/0000-0002-5976-676X; Berk, Barkin/0000-0001-6047-2796WOS: 000485774300001Dementia is a cognitive disorder mostly associated with Alzheimer's disease (AD) in addition to being seen in many other diseases of the central nervous system (CNS). the limited number of drugs is not sufficient to provide adequate improvement to increase the quality of life of patients suffering from this symptom; therefore, all treatment options should be evaluated in detail. in this study, new molecules, [2-(4-(2/3/4-substituted phenyl)piperazin-1-yl)-4-phenylthiazol-5-yl][3/4-substituted phenyl]methanone derivatives (1-44), were obtained and analyzed in terms of their anticholinesterase activities. Kinetic mode and molecular interactions were also evaluated. An enzyme inhibition study was undertaken on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the Ellman method. Maestro program was used in molecular modeling studies. Forty-four compounds were evaluated on AChE and BChE enzymes at 10(-3) and 10(-4) concentrations. the inhibition concentrations were calculated as 0.268 mu M to 2.104 mu M for six compounds (4, 5, 16, 27, 37, and 38) on AChE. Compound 5 including the 4-methoxy substituent (IC50: 0.268 mu M) and compound 38 containing the 4-methoxy and 3-methyl substituents (IC50: 0.286 mu M) showed the highest AChE inhibitory activity. They were further examined in terms of hydrogen bonding with Arg296 and Ar-Ar interaction with Trp286. the activity of compound 5 was also assessed in mixed-type kinetic mode.Anadolu Universitesi [1610S656]Anadolu Universitesi, Grant/Award Number: 1610S65
Synthesis, characterization, COX1/2 inhibition and molecular modeling studies on novel 2-thio-diarylimidazoles
No full textHeterocyclic compounds with diaryl substituents have been a milestone approach for selective cyclooxygenase 2 (COX 2) inhibition by bioisosteric replacements and modifications. It is also known that thiazole derivatives have different pharmacological activities. In this study, nine novel 2-[(1,5-diphenyl-1H-imidazole-2-yl)thio]-N-(thiazole-2-yl)acetamide derivatives (Compound 1-9) were synthesized via the reaction of 1,5-disubstitued phenyl-imidazole-2-thiole and N-thiazole acetamide. The inhibitory effects of COX-1 and COX-2 enzymes were tested for the synthesized compounds. Enzyme-ligand interactions of the most active compound on COX subtypes were elucidated by molecular modeling studies. The percent inhibitory effect for compound 1, which is the naked derivative among all the compounds, was found to be the most active on COX-2 at 10 mu M concentration (C1(COX-2): 88%, SC-560(COX-2): 98.2%, C1(COX-1): 60.9%); whereas compound 9 showed the highest inhibitory effect and was found to be the most selective derivative on COX-1 isoenzyme (C9(COX-1): 85%, DuP-697(COX-1): 97.2%, C9(COX-2): 57.9%)
Thiazole-substituted benzoylpiperazine derivatives as acetylcholinesterase inhibitors
No full textWOS: 000453476000005PubMed ID: 30343499Hit, Lead & Candidate Discovery After acetylcholine is released into the synaptic cleft, it is reabsorbed or deactivated by acetylcholinesterase (AChE). Studies on Alzheimer's disease (AD) in the mid-20th century proved that cognitive dysfunctions are associated with cholinergic neurotransmission. Drugs, such as tacrine, rivastigmine, donepezil, and galantamine are known as acetylcholinesterase inhibitors. However, these drugs have limited use in advanced AD and dementia. Recently, the anticholinesterase activity of various heterocyclic-framed compounds, including piperazine derivatives, has been investigated, and compounds with similar effects to known drugs have been identified. The aim of this study was to design new donepezil analogs. In this study, 66 original piperazinyl thiazole derivatives were synthesized by the reaction of piperazine N '-benzoyl thioamides and bromoacetophenones to inhibit AChE. Biological activity was measured by the Ellman method. Compounds 35, 38, 40, 45, 57, and 61 showed a high inhibitory effect among the series (80.36%-83.94% inhibition), and donepezil had a 96.42% inhibitory effect. The IC50 values of compounds 35, 38, and 40, were calculated as 0.9767 mu M, 0.9493 mu M, and 0.8023 mu M, respectively. Compound 45 (IC50 = 1.122), Compound 57 (IC50 = 1.2130) and 61 (IC50 = 0.9193) also exhibited good activity on AChE. Molecular modeling studies were in agreement with the predictions. Trp286, Arg296, and Tyr341 were the key amino acids at the active site. Both donepezil and synthesized compounds seemed to interact with these residues.Anatolian University Scientific Research Projects Coordination Unit [1610S656]This project was financially supported by the Anatolian University Scientific Research Projects Coordination Unit 1610S656
Potent ribonucleotide reductase inhibitors: Thiazole-containing thiosemicarbazone derivatives
No full textThe antioxidant, antimalarial, antibacterial, and antitumor activities of thiosemicarbazones have made this class of compounds important for medicinal chemists. In addition, thiosemicarbazones are among the most potent and well-known ribonucleotide reductase inhibitors. In this study, 24 new thiosemicarbazone derivatives were synthesized, and the structures and purity of the compounds were determined by IR, H-1 NMR, C-13 NMR, mass spectroscopy, and elemental analysis. The IC50 values of these 24 compounds were determined with an assay for ribonucleotide reductase inhibition. Compounds 19, 20, and 24 inhibited ribonucleotide reductase enzyme activity at a higher level than metisazone as standard. The cytotoxic effects of these compounds were measured on the MCF7 (human breast adenocarcinoma) and HEK293 (human embryonic kidney) cell lines. Similarly, compounds 19, 20, and 24 had a selective effect on the MCF7 and HEK293 cell lines, killing more cancer cells than cisplatin as standard. The compounds (especially 19, 20, and 24 as the most active ones) were then subjected to docking experiments to identify the probable interactions between the ligands and the enzyme active site. The complex formation was shown qualitatively. The ADME (absorption, distribution, metabolism, and excretion) properties of the compounds were analyzed using in-silico techniques
Novel thiazole-piperazine derivatives as potential cholinesterase inhibitors
No full textDementia is a cognitive disorder mostly associated with Alzheimer's disease (AD) in addition to being seen in many other diseases of the central nervous system (CNS). The limited number of drugs is not sufficient to provide adequate improvement to increase the quality of life of patients suffering from this symptom; therefore, all treatment options should be evaluated in detail. In this study, new molecules, [2-(4-(2/3/4-substituted phenyl)piperazin-1-yl)-4-phenylthiazol-5-yl][3/4-substituted phenyl]methanone derivatives (1-44), were obtained and analyzed in terms of their anticholinesterase activities. Kinetic mode and molecular interactions were also evaluated. An enzyme inhibition study was undertaken on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the Ellman method. Maestro program was used in molecular modeling studies. Forty-four compounds were evaluated on AChE and BChE enzymes at 10(-3) and 10(-4) concentrations. The inhibition concentrations were calculated as 0.268 mu M to 2.104 mu M for six compounds (4, 5, 16, 27, 37, and 38) on AChE. Compound 5 including the 4-methoxy substituent (IC50: 0.268 mu M) and compound 38 containing the 4-methoxy and 3-methyl substituents (IC50: 0.286 mu M) showed the highest AChE inhibitory activity. They were further examined in terms of hydrogen bonding with Arg296 and Ar-Ar interaction with Trp286. The activity of compound 5 was also assessed in mixed-type kinetic mode
