Bir Grup Heterosiklik Bileşiğin Hidrazit ve Hidroksamik Asit Türevlerinin Sentezi ve Biyolojik Aktivitelerinin Araştırılması
Proje no. 277 · Durum: Kapanmış · 2017
Özet
<p>Inflammation is the body's defensive response to a stressful stimulus and is a necessary process for the healing and tissue regeneration. Although the main purpose of inflammation is to eliminate the damage in the body, when this response is not properly controlled, it can cause greater stress in the body and lead to the onset of various chronic diseases. Atherosclerosis, rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, cancer, type 2 diabetes are examples of these diseases.</p><p>Myeloperoxidase (MPO) is an enzyme in the immune system that mediates the destruction of microorganisms with the reactive products it creates. The activity of MPO takes place through two cycles called the "halogenation cycle" and the "peroxidation cycle". Both cycles begin with a common step in which hydrogen peroxide binds to the enzyme's active site. The main compound thought to be responsible for the antimicrobial effect of the enzyme is hypochlorous acid (HOCl) and is formed during the halogenation cycle. On the other hand, various reactive free radical compounds ocur during the peroxidation cycle.</p><p>MPO exerts its effect on the immune system in structures called phagolysosomes. However, in recent years, it has been revealed that MPO and its reactive products spill into extracellular fluids for some reasons that are not yet fully understood and cause many diseases due to the damage on the host biomolecules. It causes development of chronic inflammation, and diseases, so MPO inhibition has become an interesting therapeutic strategy.</p><p>In this dissertation, a group of 2(3H)-Benzoxazolone derivatives that potential MPO inhibitors were designed and synthesized, their biological activities were studied and their possible interaction with the enzyme was evaluated by molecular modeling studies.</p><p>The 2(3H)-Benzoxazolone ring, that has been previously reported in the literature with its MPO inhibitory activity, was chosen as the pharmacophore structure, and hydrazide and hydroxamic acid functional groups, which were determined to be effective in terms of MPO inhibitory activity in previous studies, were also included in the</p><p>VI</p><p>molecular design. It is planned to connect hydrazide and hydroxamic acid functional groups via the methylene bridge over the nitrogen atom on the 2(3H)-Benzoxazolone and 5-chloro-2(3H)-Benzoxazolone rings. In order to evaluate the structure-activity relationships from a wider perspective, acyl hydrazone and methyl hydroxamate functional groups are also included in the study.</p><p>The structures of the compounds were confirmed by IR, 1H NMR, 13C NMR, Mass Spectroscopical techniques and elemental analysis studies.</p><p>The inhibitory activities of the synthesized compounds on the chlorination and peroxidation cycle of the MPO enzyme were determined by taurine-chloramine and Ampleks Red experiments, respectively. In addition, the IC50 concentrations of the most active compounds were determined, and the "Guaiacol oxidation test" was performed to evaluate the enzyme affinity of these derivatives. In addition, the HOCl scavenging activity of these compounds was also determined.</p><p>According to obtained data, C21 namely N'-[(furan-2-yl)methylene]-2-(2,3-dihydro-5-chloro-2-oxobenzoxazol-3-yl)acetohydrazide was found as the most active compound with an IC50 value of 0.42 ± 0.06 μM.</p><p>Molecular modeling studies were carried out in order to determine possible interactions of the compounds with the enzyme. Docking studies were performed for the compounds selected by % inhibition screening study and different binding states with the enzyme active site were determined. In addition, molecular dynamics (MD) simulations created for C21, the most active derivative of the series, were investigated for further understanding the behavior of the molecule in the receptor site.</p><p>In conclusion, this study revealed that 2(3H)-Benzoxazolone and 5-chloro-2(3H)-Benzoxazolone derivatives carrying hydrazide functional group are promising structures in terms of MPO inhibitory activity and can be a good starting point for new studies to be carried out in this field.</p><p>Keywords; 2(3H)-Benzoxazolone, hydrazide, hydroxamic acid, acyl hydrazone, inflammation, myeloperoxidase</p>