Eugenol, timol ve karvakrol uzantılı yeni ranolazin türevlerinin sentezi
Synthesis of new ranolazine derivatives with eugenol, thymol and carvacrol extensions
Yazar: BEGÜM OSMANOĞULLARI
Danışman: PROF. DR. MUSTAFA ZENGİN
Sakarya Üniversitesi / Fen Bilimleri Enstitüsü / Kimya Ana Bilim Dalı / Organik Kimya Bilim Dalı
Derece: Yüksek Lisans, 2024
Konu: Kimya = Chemistry

Özet:
Tüm dünyada kardiyovasküler hastalık yaygınlaşmaya başlamıştır. Özellikle de koroner kalp hastalığı ciddi sorunlar ortaya çıkarmaktadır. Bu sorunların önümüzdeki on yılda da bu sayıların artacağı öngörülmektedir. Günümüzde kalp hastalığı tedavi yöntemlerinin gelişmesine rağmen hala iskemik kalp hastalığına sahip olan hastaların semptomları tamamen kontrol altına alınamamaktadır.Klasik anti anjinal tedavi yöntemleriyle sorunlarını çözemeyen hastalar için yeni geliştirilen alternatif ilaç yöntemleri kullanılmaya başlanmıştır. Bu yeni alternatif ilaçlardan birisi de ranolazindir. Ranolazinin en önemli özelliklerinden biri diğer anti anjinal ilaç çeşitlerinden farklı etki mekanizmasına sahip olmasıdır.
Bu çalışmada ranolazin türevlerinin seçilmesinin nedeni yeni tıbbi tedavi seçeneklerinden ranolazinin diğer anti anjinal ilaçlardan farklı olması ve geliştirilmesine ihtiyaç duyulmasıdır. Literatürde ranolazin türevleri ile ilgili çeşitli çalışmalar yapılmıştır. Ancak timol , karvakrol ve eugenol eklentili türevlerine rastlanmamıştır.Tıp ve ilaç kimyası için önemli bir bileşik olan ranolazinin yeni türevlerine ihtiyaç olduğu gözlenmiştir.
Ranolazinin iskelet yapısında fenolik bileşikler olan guaikol bulunmaktadır. Bu tez çalışmasında guaikol yerine doğal fenolik bileşikler olan eugenol , timol ve karvakrol kullanılarak yeni ranolazin türevlerinin sentezi gerçekleştirilmiştir.Tez çalışmasında kullanılan doğal fenolik bileşikler inflamasyonu azaltma, alerjik reaksiyonları önleme, pıhtılaşmayı önleme, virüs enfeksiyonlarını önleme, mikroorganizmaların aktivitesini engelleme ve anti diyabetik gibi önemli özelliklere sahiptir. Karvakrol bileşiği bu özelliklerin yanı sıra ayrıca da oksidasyon hızını yavaşlatma özelliğine de sahiptir.Yapılan çalışmalarda karvakrolün kanserin oluşumunu ve hücrelerin anormal büyümeyi engellediği bulunmuştur. Timol bileşiği sayılan genel özelliklerinin yanında ayrıca antifungal yani mantar enfeksiyonlarını önleyici özelliğe de sahiptir. Fenolik bileşikler, kan damarlarının sağlığını koruyarak, LDL kolesterolü azaltarak ve kan basıncını dengeleyerek kalp sağlığını destekler. Bu tez çalışmasında kullanılan yöntem doğal fenolik bileşikler olan çıkış bileşikleri eugenol, karvakrol ve timol, epiklorohidrin ile muamele edilerek epoksitlerine çevrildi. Daha sonra piperazin ile oksiran halkasının açılması sağlanarak oksiproponolamin türevleri elde edildi. Diğer taraftan, 2,6-dimetilanilin bileşiği kloroasetil klorür ile muamelesinden 2-kloro-N-(2,6-dimetilfenil)asetamit elde edildi. Son basamakta elde edilen bileşikler reaksiyona sokularak hedeflenen türevler elde edilerek nihai ürünler kolon kromotografisi kullanarak saflaştırıldı. 1H ve 13C NMR'ı ve kütle spektroskopisi ile karakterize edildi. Böylelikle yeni ranolazin türevlerinin sentezi literatüre eklenmiş oldu.

Abstract:
KAH or coronary artery disease is a common condition caused by atherosclerosis, leading to reduced blood flow and myocardial ischemia. It is the leading cause of death worldwide, including in Turkey. KAH can be classified in two clinical groups: stable and unstable. While most research focuses on strategies for managing acute coronary syndromes, the burden of KAH also includes chronic stable angina, which can lead to significant disability. Despite advances in revascularization techniques, many patients with KAH are still struggling with symptoms that cannot be adequately treated. Therefore, medical treatment remains an important element in the management of stable coronary patients. Cardiovascular disease is on the rise around the world. Coronary heart disease in particular can cause serious problems. These problems are predicted to increase over the next decade. Today, despite the development of heart disease treatment methods, the symptoms of patients who still have ischaemic heart disease cannot be completely controlled, and newly developed alternative medicine methods have begun to be used for patients whose problems cannot be solved by classical anti-inflammatory treatment methods. One of these new alternative medicines is ranolazine. One of the most important features of ranolazine is that it has a different mechanism of action from other types of anti- anginal drugs.The antianginal drugs used in coronary heart patients are classified into four groups; nitrate and nitrites, calcium channel blockers, beta blockers and other drugs (ivabradin, nicorandil, trimetazidine, ranolazine, etc.). Antianginal drugs such as beta-blockers, nitrates and calcium channel blockers are widely used to improve the quality of life of patients with stable coronary artery disease. These drugs work by reducing myocardial oxygen consumption or by dilating blood vessels to reduce myocardial tension and increase blood flow. However, they can also cause changes in heart rate, myocardial contractility, and blood pressure.Ranolazine is a drug used to treat angina in patients with chronic stable coronary artery disease. Anti-anginal treatments provide more oxygen to the heart muscles that receive insufficient oxygen as a result of a heart attack. At the same time, it reduces heart rate, reduces the workload and oxygen consumption of heart muscles, or improves heart function by improving the energy efficiency of heart cells. These medications can be used alone or in combination to effectively control angina symptoms and improve the quality of life of patients with this condition several options are available to tailor treatment to individual patient needs. In the choice of treatment, the clinical condition of the patient should be taken into account in order to optimize the mechanism of action of the drug, safety profile and symptom control, and to improve the quality of life. The main drugs used for treating myocardial ischemia and angina pectoris include nitrates and nitrites, β-adrenoreceptors blockers, and Ca 2+ channel blockers. These medications help alleviate chest pain and improve blood flow to the heart by targeting different mechanisms involved in myocardial ischemia and angina pectoris. Specific drugs used for treatment include nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, atenolol, methop rolol, propranolol, nadolol, verapamil, diltiazem, nifedipine, nicardipine, papaverine, and dipyridamole. Ranolazine is a drug whose mechanism of action is different from that of classical antianginal drugs and was approved in 2006 for the treatment of stable coronary artery disease. In myocardium, ATP needs are met in three ways. The first way is anaerobic glycolysis, an inefficient ATP production method that ends with pyruvate production. It is rarely used in myocardium, but in cases of ischemic its effectiveness may increase. Pyruvate can join the tricarboxylic acid cycle or turn into lactate. Lactate formation leads to acidosis and adverse effects on myocardial cells. Fatty acid oxidation meets most of the myocardium's ATP needs. This method is more energy efficient compared to glucose oxidation; that is, each mole produces more ATP for carbon dioxide. Glucose oxidation is more oxygen efficient than fatty acid oxidation, producing more ATP with the same amount of oxygen. In myocardial ischaemia, it may be beneficial to shift ATP production from fatty acid oxidation to glucose oxidation. This is the mechanism of action of ranolazine; by inhibiting beta-oxidation of fatty acids, it shifts ATP production in the myocardium to glucose oxidation, thereby protecting the myocardium from ischaemia. Ranolazine in ischaemia glucose from the oxidation of fatty acids under the influence of oxygen. Oxidation produces a more oxygen-efficient ATP, i.e. cardiac work is produced with less oxygen. Ranolazine is thought to increase glucose oxidation indirectly by inhibiting fatty acid beta-oxidation, which in turn activates the PDH enzyme. Looking at the farmo- kinetics of ranolazine, it reaches its maximum plasma concentration 4-6 hours after oral intake. It should be taken twice a day and will reach a steady state within three days. Its absorption is not influenced by food. Oral bioavailability is 30-55% and 65% is bound to plasma proteins. The effective plasma concentration of ranolazine for the treatment of angina is 2-6 μmol/L. It is metabolised in the liver by CYP3A4 at a rate of 75-85%. Ranolazine is a P-glycoprotein inhibitor. It is not recommended to be used with strong CYP3A inhibitors (such as ketoconazole, diltiazem, verapamil, macrolides, HIV protease inhibitors, and grapefruit juice). It increases digoxin levels by 1.4-1.6 times.
The reason for choosing ranolazine derivatives in this study is that ranolazine from new medical treatment options is different from other anti-anginal drugs and needs to be developed. Several studies have been conducted in the literature on the derivatives of ranolazine. However, no additional derivatives of thymol, carvacrol and eugenol have been found.It has been observed that new derivatives of ranolazine, an important compound for medicine and drug chemistry are needed. In the skeletal structure of ranolazine is guaikol, which are phenolic compounds. In this dissertation study, the synthesis of new ranolazine derivatives was carried out using eugenol, thymol and carvacrol, which are natural phenolic compounds, instead of guaikol.Natural phenolic compounds used in the dissertation study reduce inflammation, prevent allergic reactions, prevent clotting, it has important properties such as preventing viral infections, blocking the activity of microorganisms and anti- diabetic. In addition to these properties, the carvacrol compound also has the ability to slow down the rate of oxidation, and studies have shown that carvacrol prevents the formation of cancer and the abnormal growth of cells. In addition to the general properties of the thymol compound, it also has the ability to be antifungal, i.e. prevent fungal infections. Phenolic compounds support heart health by maintaining the health of blood vessels, reducing LDL cholesterol and balancing blood pressure. Carvacrol, thymol and eugenol, the natural phenolic compounds used in the thesis study, are also effective compounds in preventing or fighting diseases such as heart disease and some cancers due to radical-induced stress. The synthesis of new ranolazine derivatives was carried out with a four-digit synthesis phase. In the first step, oxirane compounds were obtained by reacting carvacrol, eugenol and thymol compounds with epichlorohydrin.Colon chromotography was applied to purify the products in the  hand. In the second step, a reaction was carried out to open the oxirane ring with piperazine using piperazine molecules, which become oxiranes of carvacrol, eugenol and thymol compounds. Methanol was used as the solvent. Acetal amide was obtained by dissolving acetic acid with dimethylaniline as an intermediate and adding chloroacetyl chloride. The product was formed in solid white form. In the fourth step, a clamping reaction was carried out by reacting the piperazine-opened eugenol oxirane, carvacrol oxirane and thymol oxirane compounds with the acetylamide compound synthesised in the intermediate step. The final products of the docking reaction with eugenol, carvacrol and thymol were purified from impurities by column chromatography and characterised by 1H and 13C NMR and mass spectroscopy. Thus, the synthesis of new ranolazine derivatives was added to the literature.