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Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as 1H NMR, 13C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a, 3e, 3f, 3g, 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC50 value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC50 = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC50 = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies.

Phortress is an anticancer prodrug, which has active metabolite (5F-203) being potent agonist of the aryl hydrocarbon receptor (AhR). The 5F-203 switches on cytochrome P450 CYP1A1 gene expression and thus exhibits anticancer activity. In this study, it is aimed to obtain new phortress analogues by bioisosteric replacement of benzothiazole core in the structure to benzoxazole ring system. Synthesis of compounds (3a-3p) were performed according to literature methods. Their structures were elucidated by IR, 1H NMR, 13C NMR, 2D-NMR and HRMS spectroscopic methods. Cytotoxicity (MTT), inhibition of DNA synthesis and flow cytometric analysis assays were applied to determine anticancer activity of the compounds on colon (HT-29), breast (MCF7), lung (A549), liver (HepG2) and brain (C6) carcinoma cell types. When compared reference agent doxorubicin, compounds 3m and 3n displayed very attractive anticancer effect against carcinogenic cell lines. Due to structural similarity to phortress, biotransformation studies for 3m and 3n were examined by LCMS-IT-TOF system and probable metabolites of these compounds were determined. Induction potential of these compounds on CYP1A1/2 enzymes was also investigated to clarify possible mechanism of action. Interaction modes between CYP1A1 enzyme and compound 3n or its some metabolites were investigated by docking studies. In conclusion, findings of these study indicate that compounds 3m and 3n possess significant anticancer activity, probably with the same mechanism of action to Phortress.

WOS: 000425198100005, PubMed ID: 29248751, In the recent works, it was shown that numerous thiazolylhydrazine derivatives display hMAO inhibitory activity in the range of micromolar concentration. Hence, in the present study a new series of new thiazole-hydrazines (3a-3n) were designed, synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro flurometric method. The enzyme inhibition assay revealed that most of the synthesized compounds have selective inhibition potency against hMAO-A. The compounds 3f and 3h showed promising hMAO-A inhibition with an IC50 values of 0.012 mu M and 0.011 mu M and significant selectivity indexes of 1214 and 1601 towards hMAO-A, respectively. The mechanism of hMAO-A inhibition of compounds 3f and 3h was investigated by Lineweaver-Burk graphics and reversible-competitive inhibition of hMAO-A was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 3h was found as non-cytotoxic and non-genotoxic. Theoretical calculation of ADME properties suggested that synthesized compounds may have a good pharmacokinetic profile. The docking study of compound 3f and 3h revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound

WOS: 000388544600081, PubMed ID: 27783974, Donepezil (DNP), an acetylcholinesterase (AChE) inhibitor, is one of the most preferred choices in Alzheimer diseases (AD) therapy. In the present study, 38 new DNP analogues were synthesized. Structures of the synthesized compounds (1-38) were elucidated by IR, H-1 NMR, C-13 NMR and HRMS spectroscopic methods and elemental analysis. Inhibitory potential of the compounds on cholinesterase enzymes was investigated. None of the compounds displayed significant activity on butyrylcholinesterase (BChE) enzyme. On the other hand, compounds 26-29 indicated important inhibitory activity on AChE enzyme. Kinetic studies were performed in order to observe the effects of the most active compounds on substrate-enzyme relationship. Cytotoxicity studies and theoretical calculation of pharmacokinetic properties were also carried out to get an information about toxicity and pharmacokinetic profiles of the compounds. The compounds 26-29 were found to be nontoxic at their effective concentrations against AChE. A good pharmacokinetic profile was predicted for these compounds. Docking studies were performed for the most active compounds 26-29 and interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds