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  3. Investigating the anti-inflammatory effects of newly synthesized N-aryl phthalamide derivatives

Investigating the anti-inflammatory effects of newly synthesized N-aryl phthalamide derivatives

Number of pages: 123 File Format: word File Code: 32048
Year: 2012 University Degree: Master's degree Category: Medical Sciences
Tags/Keywords: Anti-inflammatory effect - Anti-inflammatory effects - carrageenan - COX - Cyclooxygenase - Mefenamic acid - N-aryl phthalimide derivatives - Non-steroidal anti-inflammatory drugs - Prostaglandin
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  • Summary of Investigating the anti-inflammatory effects of newly synthesized N-aryl phthalamide derivatives

    Dissertation

    To receive the degree of Doctor of Pharmacy

    Persian summary

    A group of N-arylphthalimide derivatives were evaluated for anti-inflammatory activity. Non-steroidal anti-inflammatory drugs are considered as analgesic and anti-inflammatory, and their primary mechanism is enzyme inhibition. cyclooxygenase. Cyclooxygenase is a key enzyme in the production of prostaglandin and thromboxane, and these cyclooxygenase products are important mediators in pain, fever, and inflammation.

    In this project, the Carrageenan induced rat paw edema test is used to measure the anti-inflammatory response of new N-arylphthalimide derivatives.

    Edema through subcutaneous injection of 0.1 ml The carrageenan solution dissolved in normal saline is applied to the sole of the rat's right foot half an hour after gavage of different doses of derivatives (test), and then the thickness of the sole of the foot, from the inner to the outer part, is measured by a digital caliper at a time interval of 0.5, 1, 2, 3, 4, and 5 hours after the injection of carrageenan, and the edema is measured by changes in the thickness of the sole of the foot before and after the injection of carrageenan.

    The anti-inflammatory effect is calculated by the percentage of edema inhibition by the following formula:

    : changes in sole thickness before and after injection (control group)

    : changes in sole thickness before and after injection (test group)

    Of course, we also have a group as a control group that only injects carrageenan into the soles of the mice and we check the diameter of the inflammation at 0.5, 1, 2, 3, 4 and 5 hours.

    The other group, which is the standard group, includes 5 compounds (diclofenac, indomethacin, aspirin, ibuprofen and mefenamic acid). It is given orally to mice.

    .

    Chapter One

    Overview

    The necessity and importance of the topic

    Efforts to obtain new anti-inflammatory drugs with the aim There is an increase in efficiency and a decrease in side effects. Cyclooxygenase "COX" is an enzyme that catalyzes the synthesis of prostaglandin from arachidonic acid "A.A". Therefore, inhibiting the activity of this enzyme stops the production of prostaglandins, and inhibiting prostaglandins causes the occurrence of analgesic and anti-inflammatory effects. COX-1 is found in most normal cells and tissues and is responsible for the synthesis of prostanoids, which plays a role in maintaining the normal physiology of the digestive mucosa, kidney, and also regulating platelet activity. It only comes into action when there is tissue damage and inflammation. For that reason, the synthesis of phthalimide derivatives has been considered to increase the analgesic and anti-inflammatory effects. Phthalimide has been investigated with the possible effect of simultaneously inhibiting cyclooxygenase and lipoxygenase. These pharmacophore groups are aimed at increasing therapeutic effects and reducing side effects. rtl;"> 

    The second chapter

     

    Examining the texts and studies of others in this field

     

     

     

    Part I: Examining the Texts

     

     

    2-1-1. Introduction

    Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used compounds in the treatment of pain and inflammation.The history of the use of non-steroidal anti-inflammatory drugs (NSAIDs) by humans goes back to 3500 years ago. (5) These drugs are among the most widely used drug categories and are primarily used in the treatment of pain and inflammation, especially rheumatoid arthritis. The first NSAID (aspirin) that is still in use has been introduced as medicine for more than a century. (6) The molecular mechanism of aspirin and other NSAIDs was first clarified in the 1970s and it was found that these drugs exert their anti-inflammatory effect by inhibiting the enzyme cyclooxygenase (COX). The cyclooxygenase enzyme catalyzes the synthesis of PGG2 from arachidonic acid and its conversion to PGH2, which is the precursor of all prostanoids.

    This mechanism of action of NSAIDs well explains the beneficial anti-inflammatory, antipyretic and analgesic effects as well as side effects on the digestive system. Unfortunately, patients who use NSAIDs for a long time suffer from the problem of gastrointestinal damage and, in severe cases, bleeding and gastrointestinal ulcers. Other side effects of these drugs in some patients include kidney dysfunction, prolonged bleeding time, and severe contraction of respiratory smooth muscles. (7)

    Inhibition of cyclooxygenase enzyme by nonsteroidal anti-inflammatory drugs, in addition to inhibiting the synthesis of protective prostaglandins (COX-1 products), also increases the metabolism of arachidonic acid in the lipoxygenase pathway. In a study conducted on human osteoblast cells, it was found that the long-term use of a COX inhibitor called NS398 increases the level of LTB4 by 4 times the initial value. (8)

    Regarding the role that leukotrienes have in pain and inflammation processes, the increase of these compounds while using NSAIDs, in addition to reducing the analgesic and inflammatory effects of these drugs, causes an increase in side effects, especially gastrointestinal complications of these drugs.

    For example, leukotrienes such as LTC4 have constrictive effects on the vessels of the gastric mucosa, thereby reducing blood flow in this area and causing tissue damage.

    LTB4 also increases tissue damage by stimulating the infiltration of leukocytes to the damaged area in the mucosal tissue and by releasing Proteases and free radicals and degranulation of inflammatory cells cause tissue necrosis. (9) In addition, kinins, neuropeptides and histamines are also released at the site of tissue damage. Stimulation of the membrane of neutrophils also leads to the production of free radicals derived from oxygen. Superoxide anion is made through the reduction of molecular oxygen and is able to stimulate the production of other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these substances with arachidonic acid leads to the production of chemotactic substances and perpetuates the inflammation process. inhibit lipoxygenase), or have superoxide scavenger properties, can have stronger therapeutic effects and less side effects. (11 and 12).

     

    2-1-2. History

    From ancient times to the 19th century, combinations of plant materials containing salicylate, especially the bark of the willow tree, were used to treat fever and pain. (13) The active component of the bark of the willow tree is a bitter glycoside called salicin, which is converted into glucose and salicylic acid by hydrolysis. (14)

    In 1875, sodium Salicylate was introduced as an antipyretic to treat rheumatoid fever. (15) After proving the anti-inflammatory effects of acetylsalicylic acid, this compound was introduced to the medical world in 1899 under the name of aspirin. This compound is still widely used in the treatment of pain, fever and inflammation. In the following decades, several other NSAIDs such as phenylbutazone (1949), indomethacin (1963) and ibuprofen (1969) were developed, but the discovery of the mechanism of action of these drugs remained unknown until 1971. (16)

    In this year, Sir John Vane introduced cyclooxygenase enzyme as the common molecular target of all these compounds.

  • Contents & References of Investigating the anti-inflammatory effects of newly synthesized N-aryl phthalamide derivatives

    List:

     

     

    Persian summary.. 1

    Chapter one: General

    1- 1. Necessity and importance of the topic.. 3

    1- 2. Purpose.. 3

    Chapter two: review of other texts and studies in this field

    Part one: Review Texts 2-1-1. Introduction.. 5

    2-1-2. History.. 7

    2-1-3. Inflammation.. 7

     

    2-1-3-1. Symptoms of inflammation..9

    2-1-3-2. mediators of inflammation..9

    2-1-3-3. Inflammatory response..9

    2-1-4. Eicosanoids..11

    2-1-4-1. Definition.. 11

    2-1-4-2. Structure and biosynthesis..11

    2-1-5. Cyclooxygenase pathway..14

    2-1-5-1. Prostaglandins..18

    2-1-5-1-1. History.. 18

    2-1-5-1-2. Building.. 18

    2-1-5-2. Biological effects of prostanoids. 19

    2-1-5-2-1. The role of prostanoids in the process of pain and inflammation. 21 2-1-6-3. Cyclooxygenase enzyme and its isoforms. 21 2-1-5-3-1. Biochemical structure of cyclooxygenase enzyme isoforms. 22 2-1-5-3-2. Three-dimensional structure of cyclooxygenase enzyme. 23

    2-1-5-3-3. The active site of cyclooxygenase. 25

    2-1-5-3-4. Comparison of the active site of cyclooxygenase cox-1 and cox-2. 27

    2-1-5-3-5. Comparison of cox-1 and cox-2 in relation to cyclooxygenase inhibitors. 29

    2-1-5-3-6. Investigating the crystal structure of cox-1 enzyme complex and inhibitor. 30

    2-1-5-3-7. Investigation of the crystal structure of cox-2-inhibiting enzyme complex. 31

    2-1-6. Cyclooxygenase inhibitors. 33

    2-1-6-1. Classical inhibitors (non-selective). 34

    2-1-6-1-1. Structural classification of cyclooxygenase enzyme non-selective inhibitors. 34

    2-1-6-1-1-1. Salicylates.. 38

    2-1-6-1-1-2. Arylalkanoic acids. 39

     

    2-1-6-1-1-3. N-aryl anthranilic acids (phenamates). 40

    2-1-6-1-1-4. Enoic acids (oxicams). 41

    2-6-1-2. Cyclooxygenase inhibition mechanism by non-selective inhibitors. 42 2-1-6-1-3. Therapeutic applications of non-selective cyclooxygenase inhibitors. 43 2-1-6-1-3-1. Anti-inflammatory activity of non-steroidal anti-inflammatory drugs. 43

    2-1-6-1-3-2. Antipyretic effects of non-steroidal anti-inflammatory drugs. 44

    2-1-6-1-3. Side effects of non-selective cyclooxygenase enzyme inhibitors. 44

    2-1-6-1-4-1. Gastrointestinal complications. 45

    2-1-6-1-4-2. Skin complications: 47

    2-1-6-1-4-3. Kidney complications: 47

    2-1-6-1-4-4. Liver complications: 48

    2-1-6-1-4-5. Effects of non-steroidal anti-inflammatory drugs on platelets. 48

    2-1-6-1-4-6. Photosensitivity reaction:   48

    2-1-6-2. Selective COX2 inhibitors.  48

    2-1-6-2-1. Structural classification of cox-2 selective inhibitors.  49

    2-1-7. Lipoxygenase pathway.. 50

    2-1-8-1.  Leukotrienes.. 50

    2-1-7-1-1. Biosynthesis.. 51

    2-1-7-1-2. Biological effects of leukotrienes.  54

    2-1-7-1-3. The effects of leukotrienes in the inflammation process.  55

    2-1-7-2. Leukotriene inhibitors:  56

    2-1-7-2-1. Antioxidants: 56 2-1-7-2-2. Iron chelators:  57

    2-1-7-2-3. Competitive inhibitors:  58

    .  59 FLAP. Inhibitors of 2-1-7-2-4

    2-1-7-2-5. Leukotriene receptor antagonist:  60

    2-1-8. Non-enzymatic pathways.  61

    2-1-8-1. Isoprostane pathway.. 61

    2-1-8-2. Malondialdehyde.. 64

    2-1-8-4.3 Hydroxynonenal 4-Hydroxynonenal.  65

    2-1-8-4. The role of superoxide and nitric oxide in inflammatory processes.  66

    Part Two: Studies by others in this field

    2-2-1. Review the studies of others in this field. 70

    2-2-2. Simultaneous COX/LOX inhibitors:  71

    2-2-2-1. Modified NSAIDs:  71

    2-2-2-2. Derivatives of N-aryl phthalimides: 71 Chapter 3: Materials and methods 3-3. Pharmacological steps. 76 3-3-1. Animals. 76 3-3-2. Preparation of samples for pharmacological tests.  76

    3-3-3. Anti-inflammatory effects..   77

    3-3-5. Statistical analysis of data. 78

    Chapter four: results

    Chapter five: discussion and conclusion

    Discussion and conclusion.  94

     

    English abstract. 99 references.

    None.

    Source:

     

    Fiorucci S, Meli R, Bucci M. Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy? Biochem. Pharmacol. 2001; 62 (11): p. 1433-1438

    2) Garavito R.M. The cyclooxygenase-2 structure: new drugs for an old target? Nat. Struct. Biol. 1996;3 (11):p.897-901

    3) Fosslien E. Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal system. Ann. Clin. Lab. Sci. 1998; 28 (2): p. 67-81

    4) Hallas J, [et al]. Nonsteroidal anti-inflammatory drugs and upper gastrointestinal bleeding, identifying high-risk groups by excess risk estimates. Scand J Gastroenterol. 1995; 30: p.438-444

    5) Warner TD, Mitchell J.A. Cyclooxygenase-3: Filling in the gaps towards a COX continuum. Proc. Natl. Acad. Sci. 2002; 99:p.13371-13373

    6) Pairet M, Ryn JV. COX-2 inhibitors. In: Milestones in Drug Therapy. First edition. 2004. p. 1-14

    7) Dannhardt G, Keifer W. Cyclooxygenase inhibitors: current status and future prospects. Eur. J. Med. Chem. 2001; 36:p.109-126

    8) Gilory DW, Tomlinson A, Willoughby DA. Cyclooxygenase may contribute to the resolution of inflammation. Eur. J. pharmacol. 1998; 355:p.211-217

    9) Scott G. Stewart, Marta E. Polomska, anti inflammatory a new analog thalidomide. 2002; 28:p.2375-2382

    10) Foegh ML, Ramwell PW. The eicosanoids: prostaglandins, thromboxanes, leukotrienes, and related compounds. Frust DE, Munster T. Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics and drugs used in gout. In: Katzung, Basic & Clinical Pharmacology. New York: McGraw-Hill; 2001. pp. 311-325, 596-623

    11) Gelott F, Laufer S. Anti-inflammatory drugs: New multitarget compounds to face an old problem. The dual inhibition concept. Pharmacol. Res. 2001;43:429-436

    12) Funk CD. Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology. Science. 2001; 294 (5548):p.1871-1875

    13) Nies AS, Gresser M.J. Cyclooxygenase-2 inhibitors. Adv. Pro. Chem. 2001;56, p.115-141

    14) Borne RF. Nonsteroidal anti-inflammatory agents. In: Williams DA. LemkeTL, Foye's Principal of Medicinal Chemistry. Philadelphia: Lippincott Williams & Wilkins; 2002.p. 751-793

    15) Roberts LJ, MorrowJ D. Analgesic-antipyretic and anti-inflammatory agents and drugs employed in the treatment of gout. In: Hardman, LG. Limbird, LE. Goodman Gilman, A. eds. Goodman & Gilman's Pharmacological Basis Of Therapeutics. New York: McGraw-Hill; 2001. p. 687-731

    16) Dannhardt G, LauferS. Structural approaches to explain the selectivity of COX-2 inhibitors.Curr.Med.Chem.2000;7:p.1101-1112

    17) Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature. 1971; 231: 232-235

    18) Fu JY, [et al]. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J. Biol. Chem. 1990; 265: p. 16737-16740

    19) Ristimaki A, Narko K, Hla T. Down-regulation of cytokine-induced cyclooxygenase-2 transcript isoforms by dexamethasone: evidence posttranslational regulation. Biochem. J. 1996;318:p. 325-331

    20) Griag CR, Stitzel RE. Modern Pharmacology. 3rd ed. London: Little and Brown company, Boston; 1990. PP. 509,517,521-522

    21) Bowman WC, Rand MJ. Text book of pharmacology. 2nd ed. Oxford: Blackwell Scientific publication; 1980. PP. 5-6, 10-21

    22) Rang HD, Dale MM. Pharmacology. Edinburg: Churchill living stone; 1987.pp.61-64, 451-453, 556-557, 588

    23) Sanderson JB. A system of surgery. 2 rd ed. Longmans: Green and co; 1871.p.121

    24) Spector WG, Willoughby DA. The inflammatory response. Bacteriological reviews. 1963; 27: p.

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