Ete ei REGULATIONS US RELa Dg OF B. PHARM. MEDICINAL CHEMISTRY-IIA Practical Book of PHARMACOLOGY - Ill As Per PCI Regulations THIRD YEAR B. PHARM. Semester - VI Dr. Rupesh K. Gautam M4 Pharm, Ph,0, (Praznscob wy Amiocian P o Coordinator. Og klomatio Care, (Gepsrimnt at Pharmaceiy MM Sera corm ‘SavopurAmmbala ~Indiae 134007 Price ? 40.00 NIRALI AKASHAN oe [Nao7a)Acknowledgement It is a matter of great pride and immense pleasure to extend our sincere regards and deepest sense of gratitude towards management of Sinhgad Technical Education Society, Pune, Hon’ble Prof. M. N, Navale (Founder President), Hon'ble Dr. (Mrs.) Sunanda M. Navale (Founder Secretary) and Management of JSS Academy of Higher Education & Research, Mysuru_ for their continuous encouragement, constructive criticism and invaluable support for the publication of this book It is a pleasure moment for all of us to gratefully acknowledge the constant co-operation of Principals, colleagues and friends of both pharmacy colleges for their inspiration, help and guidance, which provided us confidence during writing of this book We cordially acknowledge our family members (Spouse and children) who have not only endured but also encouraged, assisted and inspired throughout our writing endeavor. The authors extend their due thanks to publishers Mr. Dineshbhai K. Furia and Mr. Jigneshbhai C. Furia of Nirali Prakashan, Pune, for their excellent support in the production of this book in a record time period. We express our heartfelt thanks to Mrs, Roshan Khan, Mrs. Varsha Bodake, Mr. Akbar Shaikh, Miss Chaitali Takle and other supporting staff members of Nirali Prakashan, for their helpful suggestions and skilful supervision which helped us to mould the text in a beautiful book. Last but not least, we would like to dedicate this book to our beloved parents, whose love and blessings provided us tremendous emotional support and the zeal to work hard towards our goal Dr. Sanjay G. Walode Dr. Chandan R. 8.Preface As per the need of students and instructors, we have been engaged in writing and compiling the data based on Pharmacy Council of India regulated syllabus. It gives us immense pleasure to introduce ‘Text book of Medicinal Chemistry-II" in continuation with “Text book of Medicinal Chemistry-I". This book has been designed and arranged to provide the basic knowledge of chemistry, classification, mechanism of action and uses of the drugs mentioned in the course of study. The content is focused on synthesis and structure activity relationship of drugs which enable determination of chemical group responsible for evoking a target biological effect in the organism The contents of the book are structured as per Pharmacy Council of India regulated syllabus and will be more useful to undergraduate students pursuing carrier in Pharmaceutical Sciences in India Book is written in a simple and comprehensive manner along with the structure, schematic diagrams and tables that clearly demonstrate core concept of Medicinal Chemistry. The authentic text of the book will definitely furnish exhaustive information to the students with impressively and user-friendly style. We will be grateful to all the students, teachers and readers for their constructive suggestions to improve the quality of content of this book. The suggestions from all the readers will be highly appreciated and will be incorporated in the next edition. Dr. Sanjay G. Walode Dr. Chandan R. S.Syllabus [10 Hours] ‘amine, receptors and their distribution in the human body. H-Antagonists: Diphenhydramine hydrochloride’, Dimenhydrinate, Doxylamines succinate, Clemastine fumarate, Diphenylphyraline hydrochloride, Tripelenamine hydrochloride, Chlorcyclizine hydrochloride, Meclizine hydrochloride, Buclizine hydrochloride, Chlorpheniramine maleate, Triprolidine hydrochloride*, Phenidamine tartrate, Promethazine hydrochloride’, Trimeprazine tartrate, Cyproheptadine hydrochloride, Azatidine maleate, Astemizole, Loratadine, Cetirizine, Levocetirizine Cromolyn sodium H2-Antagonists: Cimetidine’, Famotidine, Ranitidine. Gastric Proton Pump Inhibitors: Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole. Anti-Neoplastic Agents: Alkylating Agents: Meclorethamine*, Cyclophosphamide, Melphalan, Chlorambucil Busulfan, Thiotepa. Antimetabolites: Mercaptopurine’, Thioguanine, Fluorouracil, Floxuridine, Cytarabine, Methotrexate, Azathioprine. Antibiotics: Dactinomycin, Daunorubicin, Doxorubicin, Bleomycin. Plant Products: Etoposide, Vinblastin sulphate, Vincristin sulphate. Miscellaneous: Cisplatin, Mitotane UNIT- IL [10 Hours] Anti-Anginal: Vasodilators: Amyl nitrite, Nitroglycerin*, Pentaerythritol tetranitrate, Isosorbide dinitrite*, Dipyridamole. Calcium Channel Blockers: Verapamil, Bepridil hydrochloride, Diltiazem hydrochloride, Nifedipine, Amlodipine, Felodipine, Nicardipine, Nimodipine. Diuretics: Carbonic anhydrase inhibitor Dichlorphenamide. Thiazides: Chlorthiazide*, Hydrochlorothiazide, Hydroflumethiazide, Cyclothiazide, Acetazalamide*, Methazolamide, Loop diuretics: Furosemide*, Bumetanide, Ethacrynic acid. Potassium sparing Diuretics: Spironolactone, Triamterene, Amiloride, Osmotic Diuretics: Mannitol Anti-hypertensive Agents: Timolol, Captopril, Lisinopril, Enalapril, Benazepril hydrochloride, Quinapril_ hydrochloride, Methyldopate hydrochloride,* Clonidine hydrochloride, Guanethidine monosulphate, Guanabenz acetate, Sodium nitroprusside Diazoxide, Minoxidil, Reserpine, Hydralazine hydrochlorideUNIT- It [10 Hours] Anti-arrhythmic Drugs: Quinidine sulphate, Procainamide hydrochloride, Disopyramide phosphate*, Phenytoin sodium, Lidocaine hydrochloride, Tocainide hydrochloride, Mexiletine hydrochloride, Lorcainide hydrochloride, Amiodarone, Sotalol Anti-Hyperlipidemic Agents: Clofibrate, Lovastatin, Cholesteramine and Cholestipol Coagulant and Anticoagulants: Menadione, Acetomenadione, Warfarin*, Anisindione, clopidogrel. Drugs used in Congestive Heart Failure: Digoxin, Digitoxin, Nesiritide, Bosentan, Tezosentan. UNIT- IV [08 Hours] Drugs acting on Endocrine System: Nomenclature, Stereochemistry and metabolism of steroids. Sex Hormones: Testosterone, Nandralone, Progestrones, Oestriol, Oestradiol, Oestrione, Diethy| stilbestrol Drugs for Erectile Dysfunction: Sildenafil, Tadalafil. Oral Contraceptives: Mifepristone, Norgestrel, Levonorgestrel. Corticosteroids: Cortisone, Hydrocortisone, Prednisolone, _Betamethasone, Dexamethasone. Thyroid and Antithyroid Drugs: L-Thyroxine, L-Thyronine, Propylthiouracil, Methimazole UNIT-V [07 Hours] Antidiabetic Agents Insulin and its preparations Sulfonylureas: Tolbutamide*, Chlorpropamide, Glipizide, Glimepiride. Biguanides: Metformin Thiazolidinediones: Pioglitazone, Rosiglitazone, Meglitinides: Repaglinide, Neteglinide. Glucosidase inhibitors: Acrabose, Voglibose. Local Anesthetics: SAR of Local anesthetics Benzoic Acid Derivatives: Cocaine, Hexylcaine, Meprylcaine, Cyclomethycaine, Piperocaine. Amino Benzoic acid Derivatives: Benzocaine*, Butamben, Procaine*, Butacaine, Propoxycaine, Tetracaine, Benoxinate. Jocaine/Anilide derivatives: lignocaine, Mepivacaine, Prilocaine, Etidocaine Miscellaneous: Phenacaine, Diperodon, Dibucaine.* oanContents 1. Antihistaminic Agent 11-134 11 Introduction 11 12 Histamine 12 1.2.1 Biosynthesis, Storage, Release and Metabolism of Histamine 12 1.2.2 Histamine Receptors 14 13. Antihistaminic Agents 4s 1.3.1 Mechanism of Action of Antihistaminic Agents 15 13.2. Classification of Antihistaminic Agents 15 13.3. General Structure of Antihistaminic Agents 16 14 First-Generation or Classical Antihistamines 16 14.1 Aminoalkylether Derivatives (Ethanolamines) 16 142 Ethylenediamine Derivatives 1.10 143 Piperazine Derivatives (Cyclizines) 111 144 Propylamine Derivatives 113 145 Phenothiazine Derivatives 115 146 Imidazoline Derivatives 116 147 Piperidine Derivatives 117 148 Dibenzocycloheptenes 117 149 Miscellaneous Drugs 119 15 Second-Generation or Non-Sedating Antihistamines 120 1.6 Drugs Acting On Peptic Ulcer Disease (PUD) 122 16.1 Histamine H.-Receptor Antagonists 123 1.6.2 Proton Pump Inhibitors 1.25 * synthesis 128 + Exercise 129 2. Antineoplastic Agents 2.1-2.21 2.1 Introduction 21 2.2. General Categories of Neoplasm (Cancer) 2 2.3 The Cell Cycle 22 24 Classification of Antineoplastic Agents 24 2.5 Alkylating Agents 25 2.6 Antimetabolites 28 2.7 Antibiotics 212 2.8 Plant Products 215 2.9 Miscellaneous Antineoplastic Agents 216 * synthesis 217 + Exercise 2183. Anti-Anginal Drugs 3.1-3.20 3.1 Introduction al 3.2 Factors Affecting Myocardial Oxygen Delivery al 3.3 Classification of Angina 32 34° Antianginal Drugs 34 3.4.1 Classification of Anti-anginal Drugs 34 35 Vasodilators 34 3.5.1 Nitro-vasodilators or Organic Nitrates 34 3.5.2. Mechanism of Action of Organic Nitrates a4 35.3 Effects of Nitro-vasadilators a5 354 Tolerance, Dependence and Adverse effects with Nitro-vasodilators 3.6 35.5 Examples of Nitro-vasodilators 36 3.6 Calcium Channel Blockers 38 3.6.1 Mechanism of Action of Calcium Channel Blockers 39 3.6.2 Types of Calcium Channel 3.10 3.6.3 Classification of Calcium Channel Blockers 311 3.64 Pharmacological Importance of Calcium Channel Blockers 3.1 3.6.5 Selectivity of Blockade 32 3.6.6 Advantages of Calcium Channel Blockers 3.12 3.6.7 Examples of Calcium Channel Blockers 3.12 3.7 B-Adrenergic Blockers in the Treatment of Angina 3.17 3.8 Miscellaneous Antianginal Drugs 3.17 © Synthesis 3.18 + Exercise 3.18 4. Diuretics 4.1-4.20 Introduction 41 Physiology of Nephron System in Urine Production 42 Pharmacology of Diuresis Process 43 Classification of Diuretics 43 44.1 Carbonic Anhydrase Inhibitors 45 44.2 Thiazide and Thiazide like Diuretics a7 44.3 Loop Diuretics or High Ceiling Diuretics 410 44.4. Potassium-Sparing Diuretics 413 445 Osmotic Diuretics 415 + Synthesis 4.16 + Exercise 4175. Anti-Hypertensive Agents 5.1-5.15 5.1 _ Introduction to Anti-Hypertensive Agents 51 5.2 Mechanism of Action of Antihypertensive Agents 53 5.3 Classification of Antihypertensive Agents 54 5.4 Antihypertensive Drugs 55 + Synthesis 5.13 + Exercise 5.13 6. Anti-Arrhymthic Agents 6.1-6.17 61 Introduction 61 6.2. Mechanism of Arthythmias 63 63. Classification of Arrhythmia 64 64 Classes of Anti-Arrhythmic Drugs 64 64.1 Class-I Anti-Arrhythmic Drugs 64 64.2. Class-Il Anti-Arrhythmic Drugs 6.10 64.3 Class-Ill Anti-Arrhythmic Drugs 611 644 Class IV Anti-Arrhythmic Drugs 6.13 + Synthesis 614 * Exercise 14 7. Anti-Hyperlipidemic Agents 7.1-7.13 7.1 Introduction 71 7.2 Sources of Lipids 71 7.3. Types of Lipoproteins 73 7.4 Types of Hyperlipidemia 74 7.5 Pathological Investigation 75 7.6 Anti-Hyperlipidemic Agents 75 7.6.1 HMG CoA Reductase Inhibitors (Statins) 76 7.6.2. Fibrates/Fibric Acid Derivatives (Activators of Lipoprotein Lipase) 77 7.6.3 Bile Acid Sequectrants 79 7.6.4 Inhibitors of Lipolysis 7:10 7.65 Cholesterol Absorption Inhibitors TAL © Exercise TazCoagulants and Anticoagulants 81-812 8.1 Coagulants 81 8.11 Mechanism of Coagulation 82 81.2 Pro-Coagulants 84 813 Coagulant Drugs 84 82 Anticoagulants 85 82.1 Classification of Anticoagulants 86 83 Parenteral Anticoagulants 86 83.1 Indirect Thrombin Inhibitors 86 83.2 Direct Thrombin Inhibitors 88 83.3. Indirect Factor - Xa Inhibitors 8s 84° Oral Anticoagulants 88 8.4.1 Vitamin K Epoxide Reductase Inhibitors 88 8.4.2. Direct Factor-Xa Inhibitors 89 8.4.3 Direct Thrombin Inhibitor 89 85 Anticoagulant Drugs 8.10 © Exercise 811 9. Drugs used in Congestive Heart Failure 9.1-9.11 91 Introduction ot 9.2 Symptoms of CHF 92 9.3 Physiology of Cardiac Muscle Contraction 92 9.4 Pathophysiology of Cardiac Performance 93 9.5 Compensatory Mechanisms in CHF 94 96 Drugs Used to Treat CHF 94 9.7 Cardiac Glycosides 9.6 9.8 Brain Natriuretic Peptide (BNP) 98 9.9 Endothelin Antagonists 99 9.9.1 Classification of Endothelin Antagonists 99 © Exercise 9.10 10. Drugs Acting on Endocrine System 10.1 - 10.40 10.1 Introduction 10.1 10.2 Pituitary Hormones 10.11. 10.3 104 105 10.6 107 108 10.9 10.2.1 Anterior Pituitary Hormones (Adenohypophyseal Hormones) 10.2.2 Posterior Pituitary Hormones (Neurohypophyseal Hormones) 10.2.3 Melanotropins or Melanocyte-Stimulating Hormone (MSH) Steroids 10.3.1 Biosynthesis of Steroids 10.3.2 Steroid Hormone Mechanism of Action Sex Hormones Drugs for Erectile Dysfunction 10.5.1 Factors Lowering the Risk of Getting Erectile Dysfunction Oral Contraceptives 10.6.1 Oral Contraceptive Drugs 10.6.2 Male Contraceptive Corticosteroids 10.7.1 Corticosteroid Drugs Thyroid Hormone and Antithyroid Agents 10.8.1 Synthesis, Storage and Release of Thyroid Hormones 10.8.2 Biological Actions of Thyroid Hormones 10.8.3 Metabolism of Thyroid Hormones 10.8.4 Thyroid Disorders Antithyroid Agents 10.10 Thyroid Drugs Antidiabetic Agents ut 112 113 114 © Exercise Introduction Types of Diabetes Symptoms of Diabetes Insulin and its Preparations 11.4.1 Types of Insulin 114.2 Insulin Preparations 11.4.3 Mechanism of Action of Insulin 11.4.4 Physiologic Actions of Insulin i1- 10.3 10.5 10.6 10.6 109 10.10 10.11 10.17 10.18 10.19 10.21 10.22 10.23 10.24 10.28 10.29 10.31 10.31 10.32 10.34 10.35 10.37 11.16 11 a 12 113 1s 115 116 17115 Sulfonylureas 116 Biguanides 117 Thiazolidinediones 118 Meglitinides 119. Glucosidase Inhibitors © Synthesis + Exercise 12. Local Anesthetics 121 Introduction 12.2 Historical Development of Local Anesthetics 123 Chemistry of Local Anesthetics 124 Structure activity Relationship of Local Anesthetics 12.5 Nerve Conduction Physiology of Local Anesthetics 12.6 Factors affecting Local Anesthetic Activity 12.7 Ideal Properties of Local Anesthetics 12.8 Classification of Local Anesthetics 12.9 Benzoic Acid and Aniline Derivatives with Local Anesthetic Activity 12.10 Lipophilic-Hydrophobic Balance of Local Anesthetics 12.11 Homologous Series of Local Anesthetics 12.12 Benzoic Acid Derivatives 12.13 Amino Benzoic Acid Derivatives 12.14 Lidocaine/Anilide Derivatives 12.15 Miscellaneous + Synthesis + Exercise Index 118 qi qa 4142 11.13 12.15 12.15 12.1-12.20 124 121 12.2 12.2 123 124 125 125 125 127 12.7 128 12.10 12.13 12.14 12.15 12.17 11-13Chapter ... 1 ANTIHISTAMINIC AGENTS + LEARNING OBJECTIVES ¢ After completing this sub-unie the students should be able © Tostudy biosyrtisis, storage, release and metabolism of histamine. © Tostudy different histamine receptors and pharmaceutical action om its stimulation © Tostudy classification an mechanism of action of antiistaminie agents, © To study structure activity relationship of various classes of antifistaminic agents. © Tostusiy she dings acting on peptic ulcer disease. © To study the drugs acting on proton puntp. © Tostudy various antikistaminic drugs with their MOA and uses. © Toleare she synthetic pathways of some selective amifistaminic drugs 1.1 INTRODUCTION Autacoid is a term derived from Greek words: autos means self and akos means healing substance or remedy. These are varied substances produced by a broad variety of cells in the body. These substances generally act locally at the site of synthesis and release and having intense biological activity. As, these compounds are typically produced locally, act locally and are metabolized locally, they are also called as ‘local hormones’. However, they differ from hormones in two important ways - hormones are produced by specific cells, and are transported through circulation to act on distant target tissues whereas the effects of autacoids are primarily local, though large quantities can be produced and moved into circulation, Autacoids are involved in a number of physiological and pathological processes and even serve as transmitters or modulators in the nervous system, but their role at many sites is not precisely known. A number of useful drugs act by modifying their action or metabolism. Autacoids can have a variety of different biological actions, including modulating the activities of smooth muscles, glands, nerves, platelets and other tissues. chijitMedicinal Chemistry - It Antihistaminic Agents The autacoids are classified as, Amine autacoids - i.e, Histamine, 5-Hydroxytryptamine (Serotonin). Lipid derived autacoids - i.e., Prostaglandins, Leukotrienes, Platelet activating factor. Peptide autacoids - i.e, Plasma kinins (Bradykinin, Kallidin), Angiotensin In addition, cytokines (interleukins, TNFa, GM-CSF etc) and several peptides like gastrin, somatostatin, vasoactive intestinal peptide and many others may be considered as autacoids. 1.2 HISTAMINE Histamine, (histos-tissue) meaning ‘tissue amine’ is a -imidazolylethylamine derivative that is present in essentially all mammalian tissues. Histamine is an organic nitrogenous compound involved in local immune responses and is produced by basophils and by mast cells found in nearby connective tissues. It acts as a neurotransmitter (chemical messenger) for the brain, spinal cord, and uterus, The major physiological actions of histamine are centered on the cardiovascular system, nan-vascular smooth muscle, exocrine glands and the adrenal medulla. Histamine is involved in most of the allergic and . NH hypersensitivity reactions and also in the regulation of py gastric acid secretion which leads to the development of pa important classes of drug useful in the treatment of mw ON symptoms associated with allergic and gastric hyper Bip (108) secretory disorders. Histamine Histamine is chemically, [2-(imidazol-4-yl)ethylamine]. At 4" position of an imidazole ring, the methylene groups of the aminoethyl side chain are designated by a and B. Nitrogen at 3” position of imidazole is designated as pros (x) N, whereas nitrogen at 1* position is termed as tele (1). The side chain nitrogen is distinguished as N% 4.2.4 Biosynthesis, Storage, Release and Metabolism of Histamine Histamine is synthesized in granules in mast cells and in white blood cells (leukocytes) called basophils from the decarboxylation of the naturally occurring amino acid S-histidine. The reaction is catalyzed by pyridoxal phosphate dependent enzyme L-histidine decarboxylase or aramatic amino acid decarboxylase Biosynthesis of Histamine: H HO. ° a ‘OPO, Ry NH, Hy: y NH, H wel 00H Pyridoxal phosphate —/ ds Histidine decarboxylase 7 ‘Aromatic amino acid 7 we decarboxylase 12 cha|i2Medicinal Chemistry - I Antihistaminic Agents Once formed, protein-complexed histamine is stored in mast cells and basophilic granulocyte and released by exocytosis in response to a wide variety of immune (antigen and antibody) and non-immune (bacterial products, xenobiotics, physical effects, and cholinergic effects) stimuli. Hypersensitivity reaction of histamine is initiated by the interaction of an antigen-Ige complex with the membrane of a histamine storage cell. This interaction triggers activation of intracellular. phosphokinase-C, leading to accumulation of inositol-1,4,5-triphosphate, 1,2-diacylglycerol and elevation of intracellular Ca‘*. Voltage-gated calcium channels may be opened by activation of ion channels permeable to Na‘ and K' ions. On released, histamine is rapidly metabolized in vivo to nearly inactive metabolites by two major pathways: N-methylation, and oxidation. Methylation is catalyzed by the intracellular enzyme histamine-N-methyl transferase, yields an inactive metabolite. A portion of the N-methylated metabolite is oxidized sequentially via monoamine oxidase and then via aldehyde oxidase to the corresponding N-methylimidazole acetic acid. Oxidation is catalyzed by diamine oxidase (histaminase). A small amount of this acid intermediate is converted to the corresponding riboside, an unusual metabolite. Metabolism of Histamine: NH) V4 Histamin-N-methyl Histamine Diamine oxidase transferase (Histaminase) NH, os 7 WA awa f He imidazole acetic acid N-Methyhistamine PRT Monoamino oxidase a Aidehyde oxidase ° Ho = OH On ON Zo OH WS ONG nc 7 HO OH N-Methylimidazole acetic acid imidazole acetic acid riboside cha|13Medicinal Chemistry - I Antihistaminic Agents 1.2.2 Histamine Receptors The physiological effects of released histamine are mediated by specific cell-surface receptors. There are two kinds of histamine receptors, H; and Hz. Among these, H:-receptors have been detected in mammalian brain, smooth muscle of the bronchi, gut, uterus, cardiovascular system, adrenal medulla, endothelial cells and lymphocytes. Structurally H,-receptor possesses several important features that distinguish it from the Hy receptor. Hi receptor contains seven hydrophobic trans-membrane domains characteristic of most G-protein receptors. Pharmacological action of H; receptor stimulation: 1. Dilation of capillary and arterioles: (@) Increases diffusion of plasma protein and fluid into extracellular fluid ie. flush, flair and wheel (urticaria), (b) If vasodilation occurs in skin, it leads to edema and skin rashes with itching. {© If cranial blood vessels dilated, it leads to vascular headache. (d) Increased permeability in lungs leads to asthma (asphyxia) 2. Contraction of smooth muscles: {@) Bronchial contraction leads to deficiency in breathing. (b) Contraction of smooth muscles of gastrointestinal tract leads to nausea, vomiting, epigastric distress and diarrhea 3. Increased nasal and lachrymal secretion: It separates from H; receptor. H2-receptors have been detected in a wide variety of tissues (myocardial cells and acid-secreting [parietal] cells of the gastric mucosa) and mediate the gastric acid secretory actions of histamine, H:-receptor has the general characteristics of a G-protein-coupled receptor with non-essential N-glycosylation sites in the N-terminal region. Pharmacological action of H2 receptor stimulation 1. Stimulation of oxyntic cells of stomach leads to increased secretion of hydrochloric acid which results into peptic ulcer. 2. Cardiac stimulation leads to increased heart rate In 1987, Hj-receptor was discovered which appears to exist only in the central nervous system. The H;-receptor is proposed to function as a neural auto receptor (presynaptic) serving to modulate histamine synthesis and release in the CNS. Subsequently a new membrane receptor, H, has been discovered during 2000, plays an important role in the regulation of immune system. H; receptors are located in the intestinal tissue, spleen, thymus and immune active cells, such as T-cells, neutrophils and eosinophils. chijiaMedicinal Chemistry - Il Antihistaminic Agents 1.3 ANTIHISTAMINIC AGENTS: The term antihistamine is usually referred to drugs that antagonize the actions of histamine at H:-receptors rather than H2-receptors. H:-receptor antagonists, referred as the first generation or classical are related structurally and are non-specific with varied pharmacological activities that contribute towards therapeutic applications and adverse reactions. The first-generation H,-antihistamines are useful and effective in the treatment of allergic responses (eg,, hay fever, rhinitis, urticaria, and food allergy). These agents also have effects at cholinergic, adrenergic, dopaminergic and serotonergic receptors. The first-generation H,-antihistamines shows the central adverse effects such as sedation, drowsiness and decreased cognitive ability, whereas peripheral side effects include blurred vision, dry mouth, urinary retention and constipation. Other observed side effects include appetite stimulation, muscle spasm, anxiety, confusion, tremor and tachycardia. Among all the side effects, CNS depression is the most common and so pronounced that some of these agents with short durations of action are used as over the counter sleep aids. To overcome the adverse effect of H;-receptor antagonists, a number of second- generation or non-sedating antihistamines have been developed and introduced which bear some structural resemblance with first-generation agents, but have been modified to be more specific in action and limited in their distribution profiles Hy-receptar antagonists inhibit gastric acid secretion induced by histamine. Thus they are used to treat gastric and duodenal ulcers 1.3.1 Mechanism of Action of Antihistaminic Agents An Hi-antagonist acts by competitively inhibiting the action of histamine on the tissues containing H1-receptors. It binds to the receptor and blocking the activation of the receptor by histamine. It shows the effect opposite to histamine, As these drugs readily cross the blood-brain barrier, sedation is the common side effect associated with H.-antagonists and therefore some of these drugs such as diphenhydramine and doxylamine are used to treat insomnia. Antihistamines have no effect on rate of histamine release nor do they inactivate histamine. 1.3.2 Clas: (A) First-Generation or classical a 1. Amino alkyl ether derivatives (Ethanolamines): Diphenhydramine hydrochloride, Dimenhydrinate, Doxylamine succinate, Clemastine fumerate, Diphenylpyraline hydrochloride. 2. Ethylene diamine derivatives: Tripelennamine hydrochloride. 3. Piperazine derivatives (Cyclizine): Chlorcyclizine hydrochloride, Meclizine hydrochloride, Buclizine hydrochloride 4, Propylamine derivatives: Chlorpheniramine maleate. chajis ication of Antihistaminic AgentsMedicinal Chemistry - Il Antihistaminic Agents 5. Phenothiazine derivatives: Promethazine hydrachloride, Trimeprazine tartrate. 6. Imidazoline derivative: Antazoline hydrochloride. 7. Piperidine derivatives: Thenalidine tartrate. 8. Debenzocycloheptenes: Cyproheptadine hydrochloride, Azatadine maleate. 9. Miscellaneous drugs: Triprolidine hydrochloride, Phenindamine tartrate, Cromolyn sodium. (8) Second-Generation or non-sedating anti Cetirizine, Levocetirizine, Loratadine Astemizole, Fexofenadine tamines: 1.3.3 General Structure of Antihistaminic Agents + Hrantihistamines can be represented by a general structure of two aromatic groups linked through a short chain to a tertiary aliphatic amine. Ar, R, XN a Spacer ]—N An Nr, * The aromatic groups (Ar, Ar.) usually are phenyl or substituted phenyl, thienyl or pyridyl * The aromatic groups are attached to the 'X’ group, which is, = anitrogen atom in the ethylene diamines. = acarbon atom in the alkyl amines or — a carbon attached to an ether oxygen atom in the ethanolamine ether series. * The spacer usually is 2-3 carbons in length and it may be in a ring, may be branched and may be saturated or unsaturated, * The 'R’ groups attached to the aliphatic amine usually are simple alkyl groups, generally methyl or occasionally aralkyl groups. 1.4 FIRST-GENERATION OR CLASSICAL ANTIHISTAMINES 1.4.1 Aminoalkylether Derivatives (Ethanolamines) This class of compounds essentially has the following general structure: Structure Activity Relationship of Aminoalkylether: © The aminoalkylether antihistamines are characterized by the presence of a CHO connecting moiety 'X’ and * Two or three carbon atom chain as the linking moiety between the diary! and tertiary amino groups. * Most of compounds in this series are simple N,N-dimethylethanolamine derivatives ch1j16Medicinal Chemistry - IL Antihistaminic Agents Some compounds such as clemastine and diphenyl pyraline differ from this basic structural pattern. In these compounds, = The basic nitrogen moiety and some part of the carbon chain are in the form of heterocyclic ring system and — There are 3 carbon atoms between the ‘O’ and ‘N’ atoms. Diphenhydramine was found to be the first clinically useful member of the ethanolamine derivatives containing simple diphenyl groups and serves as the prototype. Substitution of -CH; or -OCH; or -Cl or -Br at para position on one of the phenyl ring of diphenhydramine leads to the better activity and less side effects than diphenhydramine. Replacement of one of the phenyl rings of the diphenhydramine with a 2-pyridyl group as in doxylamine, enhances oral antihistaminic activity by two times. Most of the aminoalkylethers are optically active in which S-enantiomers are predominantly active. Adverse Effect: As most of the tertiary aminoalkylethers have ability to penetrate the blood-brain barrier, drowsiness is common side effect associated with these drugs and can be exploited in over the counter sleeping aids. The gastro intestinal side effects of aminoalkylethers antihistamines are relatively low compared with the ethylene diamine antihistamines Metabolism: Most of the aminoalkylethers antihistamines are extensively metabolized by the pathways including N-oxidation and successive oxidative N-dealkylation followed by amino acid conjugation of the resultant acid metabolites. 1. Diphenhydramine Hydrochloride: + HCl CH, Diphenhydramine hydrochloride Diphenhydramine hydrochloride is chemically, 2-(diphenylmethoxy)-N,N-dimethyl ethanamine hydrochloride It is an ethanolamine and first-generation histamine antagonist with anti-allergic activity. It competitively blocks H;-receptors, thereby preventing the actions of histamine on bronchial smooth muscles, capillaries, and gastrointestinal (GI) smooth muscles. chiji7Medicinal Chemistry - Il Antihistaminic Agents Uses: © Diphenhydramine hydrochloride has a potent antihistaminic action and is recommended in various allergic conditions. + It is administered either orally or parenterally in the treatment of urticaria and seasonal rhinitis. + It also exhibits anti-dyskinetic, antiemetic, antispasmodic, antitussive and sedative properties. ‘+ Because of drowsiness as most common side effect, it is used in over the counter as sleep-aid products. 2. Dimenhydrinate: 6 OL i H Ho ocH QU I Le Y Dimenhydrinate * _ Dimenhydrinate is 8-chlorotheophylline salt of diphenhydramine. ‘+ Ibis chemically 8-chlorotheophylline,2-(diphenyimethoxy)-N,N-dimethyl ethylamine. * It is an ethanolamine and first-generation histamine antagonist with anti-allergic activity. ‘* It competitively blocks H.-receptors, thereby preventing the actions of histamine on bronchial smooth muscles, capillaries, and gastrointestinal (GI) smooth muscle. Uses: ‘+ Dimenhydrinate is recommended for the nausea of motion sickness and for hyper ‘emesis gravidarum (nausea of pregnancy). 3. Doxylamine Succinate: }C—OCH,CH,N: s, CH, + COOH Doxylamine succinate * Doxylamine succinate is a pyridine derivative histamine H,-antagonist with pronounced sedative properties © Itis chemically, 2-{a-[2-(dimethylamino)ethoxy]-o-methylbenzyl]pyridine; succinate. CH, chijisMedicinal Chemistry - It Antihistaminic Agents + It competitively blocks the histamine H, receptor and manages the allergic and anaphylactic responses caused by actions of histamine on bronchial and gastrointestinal smooth muscles, and on capillaries, + Doxylamine succinate is used for allergic conjunctivitis due to inhalant allergens (like pollens and dust) + It is also used in seasonal and perennial allergic rhinitis and in the treatment of urticaria 4. Clemastine Fumerate: al cH, H OCH,CH, e pe 4 Clemastine fumerate + Clemastine fumerate is chemically, 2-[2-[1-(4-chlorophenyl)-1-phenylethoxylethy!]-1- methylpyrrolidine hydrogen fumarate * It is a synthetic ethanolamine with anticholinergic, sedative, and histamine Hy antagonistic properties. + It competitively blocks the histamine H,-receptor and prevents the symptoms that are caused by histamine on bronchial and gastrointestinal smooth muscles and on capillaries. + Clemastine fumerate has significant antihistamine and antimuscarinic activity. + Ithas moderate sedative properties. * It is used for the symptomatic relief of allergic conditions such as rhinitis, urticaria, conjunctivitis and in pruritic (severe itching) skin conditions. 5. Diphenylpyraline Hydrochloride: Diphenylpyraline hydrochloride ch1ji9Medicinal Chemistry - I Antihistaminic Agents Uses: Diphenylpyraline hydrochloride is chemically, _4-(diphenylmethoxy)-1-methyl- piperidine hydrochloride. It is structurally related to diphenhydramine with the aminoalkyl side chain incorporated in a piperidine ring. Diphenylpyraline hydrochloride is a potent antihistaminic agent It is also effective for use in seasonal and perennial allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis due to inhalant allergens and foods 1.4.2 Ethylenediamine Derivatives This class of compounds essentially has the following general structure: A UR N—CH,cH—N ne Nr Structure Activity Relationship of Ethylenediamine Derivatives: The ethylenediamine antihistamines are characterized by the presence of a nitrogen connecting atom ‘x’ and Two-carbon atoms chain as the linking moiety between the key diaryl and tertiary amino moieties. All compounds in this series are simple diarylethylenediamines except antazoline, in which ~The terminal amine and a portion of the carbon chain are included as part of an imidazoline ring system ~ Itdiffers significantly in its pharmacological profile. Ni yr 7 I W. cH, | cy" Antazoline Phenbenzamine (prototype) was the first clinically useful member of this class. Replacement of the pheny! moiety of phenbenzamine with a 2-pyridyl system gives tripelennamine, more effective histamine receptor blocker, Bs pus Hs ort cH, nC “y* LNCH,CH,t nt CH, NCHLCHNG cH. co? AT Tripelennamine Methapyriene ohn chi} 110Medicinal Chemistry - II Antihistaminic Agents © Substitution of -OCHs, -Cl or ~Br at para position of phenyl group further enhances activity. * Replacement the benzyl group of tripelennamine with a 2-thienylmethyl-group provides methapyrilene, a potent H; antihistaminic agent. * Replacement of tripelennamine’s 2-pyridyl group with a pyrimidinyl moiety with p-methoxy substitution gives thozylamine, a potent H:-antihistaminic agent. * In all of these compounds the aliphatic or terminal amino group is significantly more basic than the nitrogen atom bonded to the diaryl moiety. 1. Tripelennamine Hydrochloride: ae pe NCHCHNC Hel Tripelennamine hydrochloride © Tripelennamine hydrochloride is chemically, 2-[benzyl [2-(dimethylamino) ethyl] amino] pyridine monohydrachloride. * Its an ethylenediamine derivative with an antihistaminergic property. * It competitively blocks central and peripheral histamine H; receptors. * It is metabolized in humans by N-glucuronidation, N-oxidation and pyridyl oxidation followed by phenol glucuronidation Uses: ‘+ Tripelennamine hydrochloride is a potent antihistaminic agent. * Itis also effective far use in seasonal and perennial allergic thinitis, vasomotor rhinitis, allergic conjunctivitis due to inhalant allergens and foods. 1.4.3 Piperazine Derivatives (Cyclizines) This class of compounds essentially has the following general structure: tH-H NOR x Structure Activity Relationship of Piperazine Derivatives (Cyclizines): * The piperazines or cyclizines can alsa be considered as ethylenediamine derivatives or cyclic ethylenediamines because the connecting group (CHN), the carbon chain (-CH,~CH,) and terminal tertiary nitrogen are part of piperazine moiety. chijiitMedicinal Chemistry - I Antihistaminic Agents * Both nitrogens in these compounds are aliphatic and thus display comparable basicities. + Para substitution of -Cl at position ‘X’ is important for optimal activity. + The piperazine derivatives are moderately potent antihistaminics with a lower incidence of drowsiness. + The piperazine derivatives are moderately potent antihistaminics with a low incidence of drowsiness. + These agents have slow onset and long duration of action. * These agents have peripheral and central antimuscarinic activity, which may be responsible for the antiemetic and anti-vertigo effects. + These agents also act on the medullary chemoreceptor trigger zone, therefore are more useful as anti-emetics and anti-nauseants and in the treatment of motion sickness. 1. Chlorcyclizine Hydrochloride: cr G 1 / \ cH h—cH,- He! UY Chloreyetizine hydrochloride * Chlorcyclizine hydrochloride is chemically, 1-(p-chloro-a-phenylbenzyl)-4- methylpiperazine; manohydrochioride. + Itisa histamine H,-antagonist with low sedative action, but frequent gastrointestinal invitation. Uses: + Chlorcyclizine hydrochloride is useful in the symptomatic relief of asthma, urticaria, hay fever, rhinitis and certain other allergic conditions. 2. Meclizine Hydrochloric | ch | NcHy +2HCI Meelizine hydrochloride + Meclizine hydrochloride is chemically, 1-(p-chloro-a-phenylbenzyl)-4-(m-methyl- benzyl) piperazine; dihydrochloride. cha] 12Medicinal Chemistry - Il Antihistaminic Agents * It differs from chlorcyclizine in having an N-(m-methylbenzy!) group in place of the N-methyl group. © It blocks the H;-histamine receptor and prevents the symptoms that are caused by histamine activity. © Itexerts its antiemetic effects by its anticholinergic actions or due to a direct effect on the medullary chemoreceptive trigger zone. ‘+ Meclizine hydrochloride is a moderately potent antihistaminic. © It is used primarily as an anti-nauseant in the prevention and treatment of motion sickness. ‘+ It is also used in the treatment of nausea and vomiting associated with pregnancy, vertigo and radiation sickness. 3. Buclizine Hydrochloride: O"™NG ie Oo poorer a Buclizine hydrochloride + Buclizine hydrochloride is chemically, 1-(p-tertbutylbenzyl)-4-(p-chloro-a- phenylbenzy!) piperazine; dihydrochloride. * It blacks the Hy histamine receptor and prevents the symptoms that are caused by histamine activity. + It exerts its anti-emetic effect by blocking the muscarinic and hista the vomiting center of the CNS. + It also prevents activation of the chemo receptor trigger zone (CTZ) and may reduce nausea and vomiting, 1e receptors in Uses: Buclizine hydrochloride has antihistaminic and antiemetic properties. It is used primarily in the treatment of nausea and vomiting associated with vertigo and motion sickness. 4.4.4 Propylamine Derivatives This class of compounds essentially has the following general structure: chi| 113Medicinal Chemistry - It Antihistaminic Agents +The propylamine antihistamines structurally contain a carbon chain of two additional carbons linking with the key tertiary amino and diarylpharmacophore moieties. ‘+ Propylamine with this saturated carbon connecting moiety are commonly referred to as the pheniramines. + All of the pheniramines consist of a phenyl and a 2-pyridyl aryl group and a terminal dimethyl amino moiety. ‘+ Substitution with Cl or -Br at para-postion of phenyl ring increases the activity by 20-50 times with longer duration of action. + All pheniramines are chiral molecules. Among isomers, 5-stereoisomer, exclusively possesses antihistaminic activity. + Pheniramines are primarily metabolized by mono- and di-N-dealkylation followed by complete oxidation of terminal amino moiety and glycin conjugation, Uses: ‘+ The antihistamines in this group are most active Hi antagonists and used in the treatment of alleray as over the counter. * [tis most extensively used until selective second generation antihistaminic appeared ‘* These agents produce less sedation than the other classical antihistamines. + They have little antiemetic action. * They also exhibit significant anti-cholinergic activit 1. Chlorpheniramine Meleate: ci He—cooH chor cy HC—cooH Chiorpheniramine maleate * Chlorpheniramine meleate is chemically,2-[p-chloro-a-[2-(dimethylamino) ethyl] benzyl] pyridine; maleate Chlorination of pheniramine in the para position of the phenyl ring increases activity by 10 times with no appreciable change in toxicity, + [tacts as a competitive histamine H,-receptor antagonist + Italso has anticholinergic activity with mild sedative effects. + Chlorpheniramine meleate is a histamine Hy-receptor antagonist used in allergic reactions, + Itis used in treatment of hay fever, rhinitis, urticaria and asthma. chaiseMedicinal Chemistry - I Antiistaminic Agents 1.4.5 Phenothiazine Derivatives This class of compounds essentially has the following general structure: = CH. SH ———> yD H.C tf Cysteamine 4-Hydroxy Dimethyl-N-cyanoimino methyl-S-methy! dithiocarbonate imidazole H NH Hc Ye H,C—H,C—S—H, HC YN’ * H Cimetidine Multiple Choice Questions: 1. Which one of the following is Histamine Hi, Receptor antagonist ? (@) 4-(5-H dibenzofad] cyclohepten- -ylidene}-1-ethylpiperidine hydrochloride b) 3-(5-H dibenzo[a,d] cyclohepten-5-ylidene)-1-propylpiperidine hydrachloride (©) 4(5-H dibenzola,d] cyclohepten-5-ylidene)-1-methylpiperidine hydrochloride (d) 4-(5-H dibenzofa.d] cyclohepten-S-ylidene)-1-butylpiperidine hydrochloride chaj1.29Medicinal Chemistry - Il Antihistaminic Agents a, 10. i. Which of the following is a pharmacological action of histamine? (@) Capillary constriction (b) Stimulation of gastric secretion (© Elevation of blood pressure (d) Skeletal muscle paralysis Histidine is a heterocyclic amino acid which on heating alone is decomposed to produce (a) Imidazole (b) Histamine (© Propionic (d) Ammonia Cetrizine as an antihistaminic agent has low sedative potential due to one of the following reasons. Identify that reason (2) Ithas a chiral center. (b) It has high log P value. (© Ithas high polarity (d) It has low molecular weight. Proton pump inhibitors like omeprazole and lansoprazole contain the following ring system: (@) Pyrimidine (b) Benzimidazole (0) Benzothiazole (d) Oxindole The antihistamine that is also an antiemetic is (@) Cetirizine (b) Pyrilamine (© Promethazine (d) Loratidine Non-sedative antihistamines include (@) Cyclizine (b) Cetirizine (© Loratidine (d) Astemizole For a molecule to exhibit antihistaminic activity, the distance between the aryl and aliphatic N should be (@) 5-6A (b) 454 (© 3-4A (d) 6-7A Antihistamine synthesized starting from phthalide is (@) Promethazine (b) Cyclizine (© Cetirizine {d) Doxylamine Which of the following statements about histamine is not correct? (@) Itis a bronchodilator. (b) Large scale release of it may cause a fall in blood pressure (© Large scale release of it may cause a fall in blood volume. (d) Histamine release contributes to the symptoms of anaphylaxis. The separation of the ring and the side chain nitrogen should be ......... carbon for optimal H antagonist activity. (@) 2 (b) 3 o4 @s ch 2) 130Medicinal Chemistry - Il Antihistaminic Agents 12. 13. 14. 15. 16. 17. 18. 19. Histamine is formed from histidine by (@) Oxidation (b) Reduction (0 Deamination (d) Decarboxylation The drug belonging to proton pump inhibitor class is (@) Cimetidine (b) Diphenhydramine (Q. Omeprazole (d) Meclizine Which one of the following states regarding H, antihistamines is correct? (a) Second generation Hj antihistamines are relatively free of adverse effects. (b) The motor coordination involved in driving an automobile is not affected by the use of first generation Hy antihistamines (© H: antihistamines can be used in the treatment of acute anaphylaxis. (d) Both first and second generation H, antihistamines readily penetrate the blood brain barrier. Which of the following statements about histamine is correct? (a) Histamine is stored in peripheral nerve endings. (b) Histamine is released from mast cells following an allergic challenge (Q_ Histamine is a vasoconstrictor. (d) Histamine is an essential arnino aci Which of the following activities occurs following the stimulation of Hz receptors? (2) Vasodilation (b) Uterine contraction (© Bronchial smooth muscle contraction (d) Enhanced secretion of hydrochloric acid in the stomach Which of the following statements about serotonin is correct? (a) 5-HT, receptors are found on nerve endings and are stimulatory. (b) 5-HT2 receptors are found on smooth muscle and are stimulatory. (© 5-HT; receptors are found on smooth muscle and are inhibitory. (d) Cyproheptadine is a highly selective antagonist of 5-HT, receptors. Which of the following is the most frequent side effect of H; antihistamines that is less common with second generation antihistamines? (@) Decreased appetite (b) Sedation (0) Bradycardia (d) increased appetite Cimetidine is synthesized fram (@) 4-Hyroxy ethyl-S-methyl imidazole (b) 4-Nitro-5-methyl imidazole (© 4-Amino-S-methyl imidazole (d) 4-Hyroxy methyl-5-methy| imidazole h1| 131Medicinal Chemistry - Il Antihistaminic Agents 20. 21. 22. 23, 24, 25. 26. 2 28. Which of these is not an antihistaminic drug? (a) Dimenhydrinate (b) Levacetirizine (©) Cyclizine (d) Piroxicam Which of the following statements concerning bradykinin is not true? (a) It is generated by the action of the enzyme kininase. (b) The substrate for its generation is kininogen, a plasma globulin. (©) Itis inactivated by the loss of its C-terminal arginine, (d) It is a potent vasodilator. Which of the following histamine receptor blocking drugs is used in the treatment of stomach ulcers? (a) Chlorpheniramine (6) Loratadine (9) Famotidine (d) Azelastine Which of the following drugs belongs to non-sedative antihistaminic class? (a) Chlorpheniramine meleate (b) Buclizine hydrochloride (©) Cetirizine (d) Azatadine Maleate Imidazoline containing antihistaminic agent iS... (a) Chlorpheniramine meleate (b) Antazoline hydrochloride (©) Promethazine hydrochloride (d) Buclizine hydrachloride The most appropriate starting materials for the synthesis of Diphenhydramine BTS cxsesc (a) Benzophenone and N,N-Dimethyl aminoethanol (b) Benzhydrol and N,N-Dimethyl aminoethanol (©) Dipheny! ether and N,N-Dimethyl aminoethanol (d) Diphenyl amine and 2-chloro ethanol Which one of the following antihistaminic drugs is a basic ether? (a) Pheniramine (b) Triprolidine HCI (©) Diphenhydramine HCI (d) Promethazine HCl Cetirizine is chemically (a) 2-[4-[(4-chlorophenyl)phenylmethyi)- 1-piperazinyljethoxy propionic acid. (b) 2-[4-[(4-chlorophenylphenylmethyll- 1-piperazinyl]methoxy acetic acid (0) 2-[4-[(4-chlorophenyl)phenylmethyl)- 1-piperazinyljethoxy acetic acid (d) 2-[4-{(4-chloropheny)phenylethyl]- 1-piperazinyllethoxy acetic acid The antihistaminic agent with diphenyl methyl group is (a) Methdilazine (b) Meclizine (©) Pheniramine () Diphenhydramine Ch 1/132Medicinal Chemistry - I Antihistaminic Agents 29. Chlorpheniramine is chemically, 30. 31. 32. 33. 34, -[2-(dimethylamino) ethyl] benzyl] pyrazine -[2-(dimethylamino) ethyl] benzyl] pyridine (©) 2-{p-Chloro-c-{2-(dimethylamino) ethyl] benzyl] piperidine (d) 2-[p-Chloro-c-[2-(diethylamino) ethyl] benzyl] pyridine Which of the following eicoasanoids is released from platelets and promotes their aggregation? (a) PGL (©) LTB (b) TXA: (d) LTC, 2-(diphenyl methoxy)-N,N-dimethyl ethanamine is chemical name of (a) Cyclizine (©) Chlorpheniramine 10-[2-(Dimethylamino) propyl] phenothiazine is chemical name of (a) Promethazine (©) Diphenhydramine Chlorpheniramine meleate is a antihistaminic drug belonging to the class (a) Ethylene diamine derivatives (©) Amino alkyl ether analogs Diphenhydramine is chemically... (d) Phenindamine (o) Meclizine (d) Trimeprazine (a) 2-(diphenyl methoxy)-N,N-dimethyl ethanamine (b) 2-(diphenyl ethoxy)-N,N-dimethyl ethanamine (©) 2-(diphenyl methoxy)-N,N-diethyl ethanamine (d) 2-(diphenyl ethoxy)-N,N-diethyl ethanamine (b) Diphenhydramine (b) Cyclic basic class analogs (d) Propyl amines Answers: 1 | 2b) | 3) | 4@ | 50) | 6 | 7@ | &@ | %) | 101) 11 (©) | 12. (d) | 13. | 14.(@) | 15. (b) | 16. (a) | 17. (b) | 18. (b) | 19. (d) | 20. (d) 21 (a) | 22. | 23.) | 24. (b) | 25.(b) | 26.0) | 27.(€) | 28 (b) | 29.(b) | 30.(b) 31.(b) | 32. (a) | 33.(d) | 34. (a) Short-Answer Questions: 1. Define autacoid? Explain different types of autacoid 2. Write a short note on histamines. ch 1/133Medicinal Chemistry - IL Antihistaminic Agents Give structure activity relationship of aminoalkylether antihistamines Explain biosynthesis, storage, release and metabolism of histamines. Write in detail about histamine receptors. Give structure activity relationship of Phenothiazine antihistamines. Write pharmacological actions of H, and H; receptor stimulation. Define antihistaminic agent. Give a brief classification of antihistaminic agent. Define antihistaminic agent? Write mechanism of action of antihistaminic agent. ‘Write general SAR of antihistaminic agent. Give structure activity relationship of ethylenediamine antihistamines. Write a brief note on second generation antihistaminic agents Write a brief note on histamine H,-receptor antagonists. Write a brief note on proton pump inhibitors. cha /134.2 Chapter ANTINEOPLASTIC AGENTS ¢ LEARNING OBJECTIVES ¢ After completing this sub-unit the students should be able: © Tostuy the definition and different types of neoplasm. © Dostudy various phases of cell cyte © Tostualy classification and mechanism of action of antineoplastic agents. © Tostualy different classes of antineoplastic agents with its MOA. © Gostuily various antineoplastic drugs with their MOA and uses © Tolears the synthetic patizoays of some selectie antineoplastic agents. _2.4 INTRODUCTION The body is made up of trillions of cells that grow, divide, and die in an orderly fashion. This regulated process is controlled by the DNA machinery within the cell. When a person is growing up, the cells of the body rapidly divide, but once adulthood is reached, cells generally only divide to replace worn-out, dying cells or to repair injured cells Neoplasm or tumor is the uncontrolled, abnormal growth of cells or tissues in the body. Neoplasm can be benign or malignant, Benign neoplasms do not grow aggressively, do not invade the surrounding body tissues, and do nat spread throughout the body. Malignant neoplasms, on the other hand, tend to grow rapidly, invade the tissues around them, and spread, or metastasize, to other parts of the body. A malignant tumour may grow even when it has impoverished its host and source of nutrition; it still retains the potentiality for further proliferation The word “tumor” is often used to describe the actual swelling or other physical appearance of a neoplasm. The word” cancer” is often confused with neoplasm, but only malignant neoplasms are truly cancers. If cancer left untreated, these cancerous cells continue to rapidly divide and multiply in an uncontrolled and abnormal way. The tumor becomes larger and may eventually invade surrounding tissues or spread to other distant parts of the body via the bloodstream or lymphatic system. If many organs or a vital organ such as the brain or liver is extensively damaged by the cancer, then death will occur. ch2|21Medicinal Chemistry - Il Antineoplastic Agents 2.2 GENERAL CATEGORIES OF NEOPLASM (CANCER) © Carcinoma: This cancer begins in the skin or tissues that line internal organs. * Leukemia: This form affects tissues that make blood, such as the bone marrow. Large number of abnormal cells are produced in the bone marrow which then enters the bloodstream, + Lymphoma: This refers to cancer that originates in the immune system. * Sarcoma: This develops in bone fat, muscle, blood vessels, cartilage, bone or other types of connective tissues * Cancer of the central nervous system: This form of cancer originates in the tissues of the spinal cord and brain Neoplasm can be diagnosed by varius tests such as radiographs (X-rays), blood tests, and ultrasound examinations. A biopsy, taking a tissue sample from the neoplasm for examination under a microscope, is usually necessary to confirm the diagnosis and helps to determine if the neoplasm is benign or malignant. Additional biopsies of other tissues, such as lymph nodes, may be necessary to determine how far a malignant neoplasm (cancer) has spread The treatments available for treating malignant cancer include surgery, chemotherapy and radiotherapy. However, once metastasis has occurred, the patient prognosis is so poor that treating the multiple sites affected is not usually viable. 2.3 THE CELL CYCLE The basic differences between cancer cells and normal cells are uncontrolled cell proliferation, decreased cellular differentiation, ability to invade surrounding tissue, and ability to establish new growth at ectopic sites. Proliferation rates vary widely with the cell type. Development and homeostasis in multicellular organism are controlled by processes of cell division, differentiation and death. In the adult, the steady-state number of differentiated cells is maintained by a balance between cell proliferation and cell death. Cell death is a complex and actively regulated process known as apoptosis. Apoptosis is a defined process of cell shrinkage, membrane blebbing, and nuclear condensation. It differs from necrosis, the cell death induced by severe cellular injury, which is characterized by swelling and lysis. Cancer can be considered as a failure of cells to undergo apoptosis. A life cycle of cell begins with the organism's formation, is followed by growth and development, and finally ends in death. Individual cells also have life cycles. ch2|22Medicinal Chemistry - I Antineoplastic Agents Fig. 2.1: The cell cycle A series of events takes place in the cell’s life, The time taken to complete a cell cycle is not same for all the cells, It is different in plants, in animal embryos and in human cells. In human cell cycle takes around 16 hours. Cells in humans that are needed for repair, growth or replacement like skin and bone cells, constantly repeat the cycle. Most of the life cycle of eukaryotic cells (a cell with nucleus) is spent a period of growth and development called as interphase 'T (95%). Some cells in the body such as nerve cells and muscle cells are always in interphase and no longer divide, whereas skin cell copies its genetic material and prepares for cell division during interphase. Even though the cell is at rest during interphase, there are still many things going on to prepare the cell for its next division. The different phases are as follows: State Phase _| Abbreviation Description Quiescent Gap 0 Go A resting phase. Interphase Gap 1 G Cell increases in size. Synthesis s DNA replication occurs (genetic material is copied). Gap 2 G Cell continues to increase in size. Cell division | Mitosis M Cell separates the two copies of DNA and completes the division process ta form two complete cells is the process in which the nucleus divides to form two identical nuclei. Each new nucleus is identical to the one it came from. Mitosis is described as a series of phases or steps such as prophase, metaphase, anaphase and telophase. Ch 2) 23Medicinal Chemistry - Antineoplastic Agents Prophase Metaphase Anaphase Telophase Fig. 2.2: Different phases of mitosis 1. Prophase: During prophase, the pairs of chromatids are fully visible when viewed under a microscope. The nucleolus and nuclear membrane disappear. Two small structures called centrioles move to opposite ends of the cell. Between the centrioles, threadlike spindle fibers begin to stretch across the cell. Plant cells also from spindle fibers during mitosis but do not have centrioles. 2. Metaphase: In metaphase, the pairs of chromatids line up across the center of the cell. The centromere of each pair usually becomes attached to two spindle fibers - one from each side of the cell. 3. Anaphase: In anaphase, each centromere divides and the spindle fibers shorten. Each pair of chromatids separates, and chromatids begin to move to opposite ends of the cell. The separated chromatids are now called chromosomes. 4, Telophase: In the final step, telophase, spindle fibers start to disappear, the chromosomes start to uncoil, and a new nucleus forms, Most of the anticancer drugs block the biosynthesis or transcription of nucleic acids or prevent cell division by interfering with mitotic spindles. Cells in the DNA synthesis or mitosis phases are highly susceptible to these agents. In contrast, cells in the resting state are resistant to many agents. 2.4 CLASSIFICATION OF ANTINEOPLASTIC AGENTS {a) Alkylating agents: Mechlorethamine, Cyclophosphamide, Melphalan, Chlorambucil, Busulfan, Thiotepa. (b) Antimetabolites: Mercaptopurine, Thioguanine, Fluorouracil, Floxuridine, Cytarabine, Methotrexate, Azathioprine. (© Antibiotics: Dactinomycin, Daunorubicin, Doxorubicin, Bleomycin. (d) Plant products: Etoposide, Vinblastin sulphate, Vincristin sulphate. (@) Miscellaneous: Cisplatin, Mitotane. ch2|24Medicinal Chemistry - I Antineoplastic Agents 2.5 ALKYLATING AGENTS The term ‘alkylating agents’ is applied to compounds which, in a sense, alkylate the substance with which they react, by joining it through a covalent bond. + Aklylating agents directly damage DNA and prevent the cancer cells from undergoing metastasis or cell division. * They have a chemical structure that contains a bi-functional nitrogen mustard moiety which includes two reactive alkyl groups * These groups can cyclize in an aqueous environment to form a highly electrophilic “immonium ion” that can covalently bind to any nucleophilic compound, including the N-7 nitrogen position on guanine, which therapeutically is a major site of action. * They can produce a cross-linking of DNA when bath alkyl groups react with pairs of guanine residues in DNA (intrastrand or interstrand) * Cross-linking of DNA ultimately results in breaks of the DNA sequence, and cell death, Alkylating agents can also react chemically with other cellular components containing nucleophilic groups (sulfhydryl, amino, hydroxyl, carboxyl and phosphate groups). Although alkylating agents are not cell cycle specific, rapidly dividing cells are most susceptible to their effects. These drugs work in all phases of the cell cycle and are used to treat many different cancers, including cancers of the lung, breast, and ovary as well as leukemia, lymphoma, Hodgkin disease, multiple myeloma, and sarcoma. 1. Mechloretha: CH,CH,C! Ho-f CH,CH,C! Mechlorethamine Mechlorethamine is chemically, 2, 2-dichlora-N-methyldiethylamine. * It is a biological alkylating agent that exerts its cytotoxic effects by forming DNA adducts and DNA interstrand crosslinks, thereby rapidly inhibiting proliferating cells. * The aziridinium ion formed from mechlorethamine in body fluids is highly reactive + Ttacts on various cellular components within minutes of administration. * Mechlorethamine is effective in Hodgkin's disease, chronic leukemias, lung cancer and polycythemia vera + Mechlorethamine in combination with other agents like vincristine, procarbazine and prednisone is considered as the treatment of choice for most of the neoplasms. * The most serious toxic reaction associated with mechlorethamine is bone marrow depression, which results in leukopenia and thrombacytopenia * The side effects like nausea and anorexia persist for long ch2|25Medicinal Chemistry - I Antineoplastic Agents 2. Cyclophosphamide: Oy, 7 SHEN Oia NH ene ‘Cyclophosphamide * Cyclophosphamide is chemically, N, N-bis (2-chlorcethyl) tetrahydro-2H- 2-oxazaphosphorin-2-amine-2-oxide. * It is a precursor of an alkylating nitrogen mustard antineoplastic and immuno- suppressive agent that must be activated in the liver to form the active aldophosphamide * It is believed to work by interfering with the duplication of DNA and the creation of RNA * It destroys proliferating lymphoid cells and has greater effect on B-cells than on T-cells * It has advantages over other alkylating agents in that, it is active orally and parenterally and can be given in fractionated doses over prolonged periods * Cyclophosphamide is effective against acute leukemia, chronic lymphocytic leukemia and multiple myeloma, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma * In combination with other chemotherapeutic agents, it is found to cause radical cure in acute lymphoplastic leukemia in children and also in Burkitt's lymphoma. * Common side effects associated with cyclophosphamide include low white blood cell counts, loss of appetite, vomiting, hair loss (Alopecia), and bleeding from the bladder. 3. Melphalan: ch-cH,cH, HN cise =c001 cHCH,CH, 2 NH Melphalan Melphalan is chemically,4-[bis (2-chloroethyl) amino}-L-phenylalanine. It is an alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer (Melphalan). The dextro isomer (Medphalan) is toxic to bone marrow, but little vesicant action and is potential carcinogen. Uses: * Melphalan is active against multiple myeloma, * Itis also active against breast, testicular, and ovarian carcinoma * Nausea and vomiting are infrequent common side effects associated with melphalan, but alopecia occurs. ch2|26Medicinal Chemistry - Il Antineoplastic Agents 4, Chlorambuci CICH;CHa > CH,CH,CH,COOH CICH,CH; Chiorambuci + Chlorambucil is chemically, 4-[p-bis (2-chloroethy!) amino] phenyl] butyric acid + Itis alkylating nitrogen mustard that is used as an antineoplastic. + Itacts most slowly and is the least toxic. Uses: + Chlorambucil is used in treatment of Hodgkin's disease, lymphosarcoma, primary microglobulinemia and chronic lymphocytic leukemia, + It is rarely used in severe autoimmune conditions including rheumatoid arthritis, uveitis [an inflammation of the middle layer of the eye (uvea)] and nephrotic syndrome 5. Busulfan: 9° 9° H,C—S—O—CH,CH,CH,Ct Oo ° Busulfan + Busulfan is chemically, 1, 4-di (methane sulfonyloxy) butane. * It is an alkylating agent having a selective immunosuppressive effect on bone marrow. Uses: + Busulfan is broadly used in the treatment of granulocytic leukemia, * Itisalso used in the palliative treatment of chronic myeloid leukemia. + Itis used in preparative regimens for bone marrow transplantation in patients. * The toxic effect associated with busufan is depletion of thrombocytes which may lead to hemorthage. * The rapid destruction of granulocytes can cause hyper uricemia which might results in kidney damage. 6. Thiotepa: Thiotepa ‘+ Thiotepa is chemically, N,N’, N’ -triethylenethio-phosphoramide. * Itisa very toxic alkylating antineoplastic agent. ch2|27Medicinal Chemistry - I Antineoplastic Agents Uses: ‘* Thiotepa is used in the treatment of carcinoma of breast, ovaries, colon-rectum and rectum, + Ibis found to be useful in the treatment of malignant lymphomas and bronchogenic carcinomas. + Itis used to control intracavity effusions resulting from neoplasms. * [tis used as an insect sterilant. ‘* Thiotepa is highly toxic to bone marrow, and blood counts are necessary during therapy. 2.6 ANTIMETABOLIT! Antimetabolites are compounds that prevent the biosynthesis or use of normal cellular metabolites. These agents interfere with DNA and RNA growth by substituting the normal building blocks of RNA and DNA. These agents damage cells during the phase when the cell's chromosomes are being copied. They are commonly used to treat leukemias, cancers of the breast, ovary, and the intestinal tract, as well as other types of cancer. 1, Mercaptopurine: Uses: SH no ] ‘NH Aw Mercaptopurine Mercaptopurine is chemically, o-mercapto-6-purine It is a purine analogue and not active until it is anabolized to the phosphorylated nucleotide. Phosphorylated nucleotide competes with endogenous ribonucleotides for enzymes that convert inosinic acid into adenine and xanthine based ribonucleotides. Furthermore, phosphorylated nucleotide is incorporated into RNA, where it inhibits further RNA synthesis. One of its main metabolites of 6-mercaptopurine is 6-methyl mercaptopurineribo- nucleotide, which also is a potent inhibitor of the conversion of inosinic acid into purines. Mercaptopurine is metabolized by S-methylation followed by 8-hydroxylation. It also is oxidized to 6-thiouric acid. Mercaptopurine is used primarily for treating acute leukemia, ch2|28Medicinal Chemistry - Il Antineoplastic Agents * It also possesses an immune-suppressive property, and is used to treat autoimmune diseases as a corticosteroid-sparing agent. * The chief toxic effect associated with mercaptopurine is leukopenia. Thrombocytopenia and bleeding occur with high doses. Thioguanine: s Hy S LS NSN HN! Ny Thioguanine * Thioguanine is chemically, 2-aminopurine-6-thiol. * It is @ purine analog, which converts by hypoxanthine-guanine phosphoribosy| transferase into a nucleotide form that inhibits a number of reactions in RNA and DNA synthesis, including the activity of | phosphoribosy! pyrophosphate amidotransferase, the initial enzyme involved in purine biosynthesis. + Thioguanine is metabolized to methylthioguanine, thiouric acid, methylthioxanthine, and thioxanthine. Uses: * Thioguanine is used in treating acute leukemia, especially in combination with cytarabine. * The chief toxic effect associated with thioguanine is delayed bone marrow depression, resulting in leucopenia, thrombocytopenia and bleeding, Fluorouracil: Fluorouracil * Fluorouracil is chemically, 5-fluoro-2, 4 (1H, 3H)-pyrimidinedione or 2, 4- fluoropyrimidine. joxo-5- * It is metabolized into 5-fluorodeoxyuridine-5’-monophosphate (FUMP), which blocks the synthesis of thymidylic and hence of deoxyribonucleic acid (DNA). * It also converted into fiuorouridine triphosphate which is incorporated into RNA and DNA directly. * It is extensively metabolized in the liver and the main metabolite is dihydrafluorouracil ch2|29Medicinal Chemistry - IL Antineoplastic Agents + Parenteral administration usually produces toxic effects like leukopenia. + It may produce gastrointestinal hemorrhage which may be fatal. + Stomatitis, diarhea, nausea, and vomiting are the common side effects associated with fluorouracil along with alopecia and dermatitis. Uses: + Fluorouracil is used in management of carcinoma of the breast, colon, pancreas, rectum, and stomach in patients who cannot be cured by surgery or other means. 4. Floxuridine: ° H F. ye a, Floxuridine © Floxuridine is chemically, 5-fluoro-1-[(2R,45,5R)-4-hydroxy-5-(hydroxymethyl)oxolan- 2-yllpyrimidine-2,4-dione. « _Itis a pyrimidine analog of antimetabolite antineoplastic agent. + As floxuridine is metabolized rapidly to fluorouracil, it shows similar toxic reactions as fluorouracil Uses: « Floxuridine is used to treat hepatic metastases of gastrointestinal adenocarcinomas and for palliation in malignant neoplasm of the liver and gastrointestinal tract. 5. Cytaral CH,OH Cytarabine © Cytarabine is chemically, _0-amino-4-arabinofurannosyl-1-ox0-2-dihydro-1,2- pyrimidine. ch 2|210Medicinal Chemistry - 11 Antineoplastic Agents * Itis a pyrimidine nucleoside antimetabolite. * It acts by induction of the enzyme nucleotidase into DNA and inhibits polymerization via termination of strand synthesis. * By the action of the enzyme deoxycytidine kinase, cytarabine undergoes the anabolism to the triphosphorylaled nucleotide, which acts as competitive inhibitor of DNA polymerase after incorporation to DNA chains. It is ‘S’ phase specific. * Itis orally inactive, as it undergoes deamination by the action of the enzyme cytidine deaminase to inactive uracil arabinoside. * Cytarabine is useful in acute granulocytic leukemia of adults and found to be more effective when combined with thioguanine and daunorubacine. © It is also used for other acute leukemias of adults and children. ANS 9 OY I | NH. A sc NH 6. Methotrexate: Methotrexate * Methotrexate is chemically N-[4-[[(2, 4-diamino-6-pteridiny!) methyl] methylaminol benzoyl]-L-glutamic acid, * It acts by binding tightly and inhibiting the enzyme dihydrofolate reductase (DHFR), and thus prevents effectively the conversion of deoxyuridylate to thymidylate, that ultimately blocks the synthesis of new DNA required for the cellular replication. + Itis specific for the ‘S’ phase of the cell cycle. Uses: * Methotrexate is preferably used for the treatment of acute lymphocytic leukemia. * It is perpetually used in combination chemotherapy for palliative management of lung cancer, breast cancer and epidermoid cancers of the head. * As it enters the CNS, it is used in the treatment and prophylaxis of meningeal leukemia. Ch2| 211Medicinal Chemistry - IL Antineoplastic Agents HoN. ~~ as Azathioprine 7. Azathioprine: * Azathioprine is chemically, 6-[1-methyl-4-nitromidazole-5 yl] thio] purine ‘+ Its well absorbed when taken orally and converted extensively to 6-thioinasinic acid that predominantly serves as an antimetabolite to inhibit synthesis of adenine and guanine, + Italso gets converted to thioguanine, which is ultimately incorporated into both DNA and RNA to give rise to the formation of defective nucleic acids and finally helps in inhibition of cell mitosis * The chief toxic effects associated with azathioprine are hematological, such as leucapenia, anemia and thrombocytopenia. ‘* The main use of azathioprine is as an adjunct for the management and prevention towards the rejection of renal homotransplants. 2.7 ANTIBIOTICS These drugs are not like the antibiotics used to treat infections. They work by changing the DNA inside cancer cells to keep them away from growing and multiplying, 1. Dactinomycin (Actinomycin D): Sar Sar. we Life ete uP Leva D-Val 9 D-Val 2 LThF \ o: CH, CH, Dactinomycine ¢h2| 212Medicinal Chemistry ~ Il Antineoplastic Agents * Dactinomycin (Actinomycin D) was first isolated in 1940 by Waksman and Woodruff from a species of Streptomyces (Sparvullus). * It is chemically, 2-amina-4,6-dimethyl-3-oxo-1-N,9-N-bis[(3R,65,7R,10S,16S)-7,11,14- trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propan-2-yl)-8-oxa-1,4,11,14-tetrazabicyclo [14.3.0] nonadecan-6-yl]phenoxazine-1,9-dicarboxamide * Ibis found to be active against adenocarcinoma strains. * The mechanism of action of dactinomycin is as a nucleic acid synthesis inhibitor, and protein synthesis inhibitor. * It binds to DNA and inhibits RINA synthesis (transcription), with chain elongation. * actinomycin is used in the treatment of solid tumors in children and choriocarcinoma in adult women. * tis also used in the treatment or rhabdomyosarcoma. * It has also been used to inhibit immunological response particularly the rejection of renal transplants. 2. Anthracycline Antibiotics: Anthracyclines (daunorubicin and doxorubicin) are anti-tumor antibiotics that interfere with enzymes involved in copying DNA during the cell cycle. They are widely used for a variety of cancers. Hc: NH, HO Daunorubicin = R= CH, Doxorubicin = R = CH,OH (a) Daunorubicin: * Daunorubicin is a very toxic anthracycline amino glycoside antineoplastic isolated from Streptomyces coeruleorubidus and Streptomyces peucetius. * It is chemically, (8S-cis)-8-acetyl-10-{(3-amino-2,3,6-trideoxy)-c- 1-lyxohexano- pyranosyljoxy|-7, 8, 9, 10-tetrahydro-6, 8, 11-trihydroxy-10-methoxy-5,12-Naphtha- cenedione. ¢h2|213