Barkın Berk

Synthesis and antimycobacterial activity of some phthalimide derivatives

Structurally modified phthalimide derivatives were prepared through condensation of phthalic and tetrafluorophthalic anhydride with selected sulfonamides with variable yields. All compounds were screened for their antimycobacterium activity against Mycobacterium tuberculosis H37Ra (ATCC 25177) using a micro broth dilution technique. The fluorinated derivatives (compounds 2c, 2d, 2f and 2h) had antimycobacterium activity comparable with classical sulfonamide drugs. The minimum inhibitory concentration (MIC) of compounds 2c, 2d, 2f and 2h was greater than that of isoniazid (MIC<0.02 μg/mL) and in vitro activity was greater than that of pyrazinamide, another first line antimycobacterium drug (MIC 50-100 μg/mL). The new compounds could be considered new lead compounds in the treatment of multi-drug resistant tuberculosis.

Studies on non-steroidal inhibitors of aromatase enzyme; 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives

Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects. Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition. In this study, 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC50 values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC50:0.42 nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site.

Molecular Modelling and Compound Activity of The Escherichia Coli and Staphylococcus Aureus DNA Gyrase B ATPase Site

Development of new treatment ligands that can distinguish Escherichia coli (E. coli) from Staphylococcus aureus (S. aureus) is important because of bacterium multiple drug resistance. High-throughput virtual screening (HTVS), dockingscoring and receiver operating characteristic curves are essential components of computational methods used in designing potential new ligands. Here, we investigated the E. coli and S. aureus DNA gyrase B active site; amino acid, water molecule, and ligand interactions using crystallographic data and HTVS to determine potential hits. Trial and test sets were prepared from the 5000 and 50000 compounds of the ZINC databases with known E. coli and S. aureus DNA gyrase B ATPase inhibitor molecules. Trial sets were evaluated and screened by determining the contribution of water molecules to interactions. Data analysis led to the identification of novel interaction patterns, which were screened over a test set; 20 maximum scored compounds were identified and further tested against the novobiocin standard with gel-based E. coli and S. aureus supercoiling assays. The highest scoring N’-(1-naphthylcarbonyl)-2, 1, 3-benzothiadiazole-5-carbohydrazide structure showed selective inhibition with E. coli and S. aureus DNA gyrase B ATPases. We determined that in terms of selectivity, some water molecules have a major impact on amino acid-ligand interactions.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed medication in the management of pain, inflammation, and fever. They exert their therapeutic activity by non-selectively inhibiting cyclooxygenase-derived prostaglandin synthesis1-2. This mechanism of action is inherently responsible for their gastrointestinal (GI) 3-7, renal 8-10 and hepatic 11-13 side effects observed in ABSTRACT