《有机化学》课程教学资源（参考书籍）Principles of Organic Medicinal Chemistry, by Rama Rao Nadendla

1 Introduction to medicinal chemistry 2 General priciples of drug action 3 Physico chemical properties of organic medicinal agents 4 Chemistry of prodrugs 5 Drug metabolism 6 General anesthetics 7 Sedative-hypnotic drugs 8 Psychoactive drugs 9 Antiepileptic agents 10 Cholinergic and anticholinergic drugs 11 Adrenergic drugs 12 Adrenoreceptor blocking drugs 13 Skeletal muscle relaxants 14 Antihistamines 15 Narcotic analgesics 16 Narcotic antagonists 17 Antitussives 18 Non-steroidal antiinflammatory drugs 19 Local anesthetics 20 Diuretics 21 Hypoglycemic agents 22 Thyroid and antithyroid drugs

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C-8—N-CHEMI\TITLE.PM5 3 Principles of Organic Medicinal Chemistry is concerned with chemistry, synthesis, structure activity relationships, properties and uses of drugs of carbon compounds. This book has primarily been written with the aim of meeting the needs and interests of undergraduate and graduate pharmacy course according to syllabi of various Indian Universities. The book is a concise form covering all newer drugs will help the readers to a great extent. Though several books are available on medicinal chemistry, the material in most of them is present in a diffused form or highly specialized. In the ever expanding knowledge of the chemistry of drugs it is very difficult to go through the various textbooks, journals, and pharmacopoeias. The major objective of writing this book is to present the information in a lucid, condensed and cohesive form, to cater specially the needs of undergraduate and graduate students of pharmacy. It is impossible to express my indebtedness to those authors of various books, articles and monographs mentioned in bibliography, which became a major source of information for writing this text. I wish to recall my gratitude to Sri Y.V. Anjaneyulu, Chairman, Chalapathi Education Society, Guntur, members of Siddhartha Academy, Vijayawada, staff members of Chalapathi Institute of Pharmaceutical Sciences, Guntur, and Principal and staff members of KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada for their kind cooperation. I am also wish to acknowledge indebtedness to all who have assisted with the completion of the book. The cooperation of publishers, Messrs New Age International (P) Limited and publishers is very much appreciated in bringing out this book. The contribution that I received by sustained cooperation of my wife and daughter cann’t be ignored. I have made every effort to avoid printing errors. However, despite best efforts, some might have crept in inadvertently. I shall be oblished if these are brought to my notice. Constructive suggestions, comments and criticism on the subject matter of the book will be gratefully acknowledged, as they will certainly help to improve future editions of the book. It is hoped that the book will be received favorably as an effective text book by both students and teachers of pharmacy, science and medical scientists. Author

C-8—N-CHEMI\TITLE.PM5 4 1. Introduction to medicinal chemistry ........................................................................... 1 2. General priciples of drug action ................................................................................... 3 3. Physico chemical properties of organic medicinal agents ........................................ 14 4. Chemistry of prodrugs ................................................................................................ 31 5. Drug metabolism......................................................................................................... 41 6. General anesthetics .................................................................................................... 52 7. Sedative-hypnotic drugs ............................................................................................. 61 8. Psychoactive drugs...................................................................................................... 77 9. Antiepileptic agents .................................................................................................. 102 10. Cholinergic and anticholinergic drugs .................................................................... 121 11. Adrenergic drugs ....................................................................................................... 149 12. Adrenoreceptor blocking drugs ................................................................................ 170 13. Skeletal muscle relaxants ........................................................................................ 180 14. Antihistamines .......................................................................................................... 184 15. Narcotic analgesics ................................................................................................... 211 16. Narcotic antagonists ................................................................................................. 225 17. Antitussives ............................................................................................................... 229 18. Non-steroidal antiinflammatory drugs ................................................................... 232 19. Local anesthetics ....................................................................................................... 249 20. Diuretics .................................................................................................................... 259 21. Hypoglycemic agents ................................................................................................ 270 22. Thyroid and antithyroid drugs ................................................................................. 282 Practice Questions ..................................................................................................... 290 References .................................................................................................................. 315 Index .......................................................................................................................... 317

The subject of medicinal chemistry explains the design and production of compounds that can be used for the prevention, treatment or cure of human and animal diseases. Medicinal chemistry includes the study of already existing drugs, of their biological properties and their structure-activity relationships. Medicinal chemistry was defined by IUPAC specified commission as “it concerns the discovery, the development, the identification and the interpretation of the mode of action of biologically active compounds at the molecular level”. Medicinal chemistry covers the following stages: (i) In the first stage new active substances or drugs are identified and prepared from natural sources, organic chemical reactions or biotechnological processes. They are known as lead molecules. (ii) The second stage is optimization of lead structure to improve potency, selectivity and to reduce toxicity. (iii) Third stage is development stage, which involves optimization of synthetic route for bulk production and modification of pharmacokinetic and pharmaceutical properties of active substance to render it clinically useful. Medicinal chemistry is the application of chemical research techniques to the synthesis of pharmaceuticals. During the early stages of medicinal chemistry development, scientists were primarily concerned with the isolation of medicinal agents found in plants. Today, scientists in this field are also equally concerned with the creation of new synthetic compounds as drugs. Medicinal chemistry is almost always geared toward drug discovery and development. Medicinal chemists apply their chemistry training to the process of synthesizing new pharmaceuticals. They also work on improving the process by which other pharmaceuticals are made. Most chemists work with a team of scientists from different disciplines, including biologists, toxicologists, pharmacologists, theoretical chemists, microbiologists, and biopharmacists. Together this team uses sophisticated analytical techniques to synthesize and test new drug products and to develop the most cost-effective and eco-friendly means of production. 1 Introduction to Medicinal Chemistry 1

A very broad definition of a drug would include “all chemicals other than food that affect living processes.” If the affect helps the body, the drug is a medicine. However, if a drug causes a harmful effect on the body, the drug is a poison. The same chemical can be a medicine and a poison depending on conditions of use and the person using it. Another definition would be “medicinal agents used for diagnosis, prevention, treatment of symptoms, and cure of diseases.” Contraceptives would be outside of this definition unless pregnancy was considered a disease. All drugs have the potential for producing more than one response. Some adverse drug responses which are unavoidable are appearing at therapeutic doses are termed as side effects. Incontrast, adverse drug effects appearing at extreme drug doses are described as toxic effects. Drugs can be classified according to various criteria: 1. By origin—sources of drugs Drugs may be obtained from 1. Plants 2. Animals 3. Minerals or 4. Microorganisms. The drugs may also be semisynthetic or synthetic compounds. The sources of drugs are summarized as follows: A. Synthetic. Most of the drugs in use today are synthetic in origin. Such drugs are chemically pure and it is easy to maintain supply line. Ex. : Aspirin, Paracetamol. B. Natural. There are number of natural sources. They are: (a) Plants. A number of plant based drugs such as vincristine, taxol, digoxin, quinine, reserpine, ergotamine, ephedrine, colchicine etc. are still a part of standard therapy. Most of these don’t have any synthetic substitutes. Several other plant products are used in formulations that are sold across the counter in several countries. (b) Animal. Some modern drugs continue to be derived from animal sources because the synthesis of such chemicals is very cumbersome and expensive. Ex. : Gonadotrophins, heparin, insulin, thyroid extracts and enzymes. (c) Microorganisms. Following the accidental discovery of penicillin from a mould in 1928 and its successful use in chemotherapy in 1940, a large number of antibiotics 2 General Principles of Drug Action 3

4 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY C-8—N-CHEMI\CHE2-1.PM5 have been discovered from a variety of soil fungi and some bacteria. These drugs form the most important group of chemotherapeutic agents used against infective diseases. Ex. : Penicillin, Streptomycin, Tetracycline. (d) Minerals. Minerals or mineral-containing medicated springs have been in use since time immemorial. Several such hot water springs with medicinal value are popular in India. Ex. : Rajgrin (Bihar), Sahashradhara (Dehradun). Minerals of medicinal value are iron, calcium, magnesium, aluminium, sodium, potassium etc. C. Semi-synthetic. In some cases, especially with complex molecules, the synthesis of a drug may be very difficult or expensive and uneconomical. At the same time, the ones derived from natural sources may be impure. In these cases semisynthetic processes are used. Ex. : 6-Aminopenicillanic acid is obtained from the fungus Penicillium chrysogenum. D. Biosynthetic. Several drugs are complex polypeptides. It is difficult to obtain these drugs in pure form from natural sources and are very expensive to synthesize in the laboratory. Ex: Biosynthetic human insulin, interferon, erythropoietin, hepatitis vaccine. Amongst all these, synthetic drugs are used most widely because of their inexpensiveness, ease of quality control, mass production and therapeutic efficacy. The synthetic drugs are prepared by chemical processes. Ex: Chloroquine, acetylsalicylic acid, chlorpromazine, ephedrine etc. 2. By Action According to similarity of drug effects: Ex: marijuana and atropine both increase heart rate and cause dryness of the mouth. Thus, marijuana would be classified as atropine-like drug. 3. By therapeutic use These drugs mainly affect the normal dynamic processes of the body. They are; (i) Anti-arrhythmics (ii) Antianginals (iii) Vasodialators (iv) Anti-hypertensives (v) Cardiotonics (vi) Hypocholesteric agents (vii) Antiallergic agents (viii) Drugs acting on GIT (ix) Drugs influence renal function (x) Drugs acting on central nervous system (xi) Drugs acting on peripheral nervous system 4. By site of drug action Ex: Alcohol is a depressant drug because of its depresant CNS action. This system is limited when a drug has an effect at several body sites (e.g., the CNS stimulant cocaine also has local anesthetic (pain reducing) effects

GENERAL PRINICPLES OF DRUG ACTION 5 C-8—N-CHEMI\CHE2-1.PM5 5. By Chemical Structure Drugs are classified according to the chemical moiety or functional group. They may be further subclassified as: (i) Hydrocarbons (ii) Halogenated compounds (iii) Alcohols (iv) Carboxylic acids (v) Phenols (vi) Nitro compounds (vii) Amides (viii) Amines (ix) Sulphonamides, sulphones, stilbenes, thioureas, ureides etc. Most drugs can be administered by a variety of routes. The choice of appropriate route in a given situation depends both on drug as well as patient related factors. Drugs my be administered locally or systemically. The drugs administered through systemic routes are intended to be absorbed into blood and distributed all over the body. 1. Oral/swallowed. Oral ingestion is the oldest and commonest mode of drug administration. Most drugs in this route of administration are absorbed in small intestine. Full stomach delays absorption (e.g. alcohol). Several drugs may subject to first-pass metabolism by liver (Ex: Aldosterone, corttsol, acetyl salicylic acid). The drug candidates may undergo extensive metabolism before reaching target receptors. It is safer, more convenient, noninvasive, often painless, the medicament need not be sterile and so cheaper. Both solid dosage forms and liquid dosage forms can be given orally. 2. Oral/sublingual. The tablet or pellet containing the drug is placed under the tongue or crushed in the mouth and spread over the buccal mucosa. In this mode of administration fast systemic absorption is observed which, bypass gastrointestinaltract entry. It avoids absorption and first-pass metabolism in the liver and is useful for those likely to vomit from swallowed medication. 3. Rectal. Here the drugs are absorbed directly from the rectum. It partially avoids first-pass metabolism by liver and also for those likely to vomit and lose swallowed medication. Certain irritant and unpleasant drugs can be put into rectum as suppositories or retention enema for systemic effect. Ex: Aminophylline, indomethacin, paraldehyde, diazepam, ergotamine, and few other drugs are some times given rectally. 4. Epithelial. In this technique drugs are absorbed through the skin. This route is useful for those likely to vomit (e.g. nicotine patch). Highly lipid soluble drugs can be applied over the skin for slow and prolonged absorption. The drug bypasses the liver by this route of administration. The drug can be incorporated in an ointment and applied over specified area of skin.

6 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY 5.Inhalation.Volatile oils and gases are given by inhalation ex:general anesthetic, amylnitrite.The drugs enter the bloodstream very rapidly from the lungs.Here no absorption or first-pass metabolism problems occur.This route is potentially dangerous because it is so fast and direct. 6.Parenteral route.Parenteral administration refers to administration by iniection into tissue fluid or blood without having to cross the intestinal m osa.This route employed even in unconscious,uncooperative or vomiting patient.The imp routes are subcutaneous (SC);intramuscular(IM):intravenous (IV).The rate of absorption depends on blood flow through injection site.SC or IM exert effects more quickly than oral administration.IV is the fastest route and most certain in terms of obtaining desired concen- tration of drug in blood plasma. SITES OF DRUG ACTION 1.Enzyme inhibition.Drugs act within the cell by modifving normal biochemical reac. tions.Enzyme inhibition may be reversible or non-reversible;competitive or non-competitive. Antimetabolites may be used which mimic natural metabolites. 2.Drug-Re epterinteractinD ugs act on the cell membrane by phy 。1 11 no A rece of the cell ith which a d interacts to produce its been identifed with rts of proteins and nucleic acids.In most cases.the chemical nature of the receptor re. 3.Nor ecific interactions.Drugs act exclusively by ph hysical means outside of cells s of sk d ga trac MODE OF DRUG ACTION ntiohemicalaphys ogical hanis s by which the cn duc es a response ng orga arewithcel con he nd the of One major problem of pharmacology is that no drug produces a single effect.The pri- mary effect is the desired therapeutic effect.Secondary effects are all other effects beside the desired effect which may be either beneficial or harmful.Drugs are chosen to exploit differ abonc proc s and any aonormal may b rence in action and The biological effects observed after a drug has been administered are the result of interaction between that chemical and some part of the organism.Mechanisms of drug action

6 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY C-8—N-CHEMI\CHE2-1.PM5 5. Inhalation. Volatile oils and gases are given by inhalation ex: general anesthetic, amylnitrite. The drugs enter the bloodstream very rapidly from the lungs. Here no absorption or first-pass metabolism problems occur. This route is potentially dangerous because it is so fast and direct. 6. Parenteral Route. Parenteral administration refers to administration by injection into tissue fluid or blood without having to cross the intestinal mucosa. This route can be employed even in unconscious, uncooperative or vomiting patient. The important parenteral routes are subcutaneous (SC); intramuscular (IM); intravenous (IV). The rate of absorption depends on blood flow through injection site. SC or IM exert effects more quickly than oral administration. IV is the fastest route and most certain in terms of obtaining desired concentration of drug in blood plasma. l. Enzyme inhibition. Drugs act within the cell by modifying normal biochemical reactions. Enzyme inhibition may be reversible or non-reversible; competitive or non-competitive. Antimetabolites may be used which mimic natural metabolites. 2. Drug-Receptor interaction. Drugs act on the cell membrane by physical and/or chemical interactions. This is usually through specific drug receptor sites known to be located on the membrane. A receptor is the specific chemical constituents of the cell with which a drug interacts to produce its pharmacological effects. Some receptor sites have been identified with specific parts of proteins and nucleic acids. In most cases, the chemical nature of the receptor site remains obscure. 3. Non-specific interactions. Drugs act exclusively by physical means outside of cells. These sites include external surfaces of skin and gastrointestinal tract. Drugs also act outside of cell membranes by chemical interactions. Neutralization of stomach acid by antacids is a good example It is important to distinguish between actions of drugs and their effects. Actions of drugs are the biochemicals, physiological mechanisms by which the chemical produces a response in living organisms. The effect is the observable consequence of a drug action. For example, the action of penicillin is to interfere with cell wall synthesis in bacteria and the effect is the death of bacteria. One major problem of pharmacology is that no drug produces a single effect. The primary effect is the desired therapeutic effect. Secondary effects are all other effects beside the desired effect which may be either beneficial or harmful. Drugs are chosen to exploit differences between normal metabolic processes and any abnormalities, which may be present. Since the differences may not be very great, drugs may be nonspecific in action and alter normal functions as well as the undesirable ones, this leads to side effects. The biological effects observed after a drug has been administered are the result of interaction between that chemical and some part of the organism. Mechanisms of drug action

GENERAL PRINICPLES OF DRUG ACTION 7 C-8—N-CHEMI\CHE2-1.PM5 can be viewed from different perspectives, namely, the site of action and the general nature of the drug-cell interaction. l. Killing foreign organisms. Chemotherapeutic agents act by killing or weakening foreign organisms such as bacteria, worms, and viruses. The main principle of action is selective toxicity, i.e. the drug must be more toxic to the parasite than to the host. 2. Stimulation and depression. Drugs act by stimulating or depressing normal physiological functions. Stimulation increases the rate of activity while depression reduces it. 3. Irritation. It is a non-specific action of a drug that can occur in all the body tissues. Certain drugs act by causing irritation. Ex: Drugs like senna and castor oil show their laxative effects by their irritant action on gastrointestinal tract. 4. Replacement. Drugs serve as replacement of essential body chemicals that are either absent or present in less than required quantity due to disease. Ex: Insulin is used in diabetes. Levodopa therapy in Parkinson’s disease. A drug act by virtue of its various properties like physical, chemical, physiological etc. The fundamental mechanisms of drug action can be distinguished into following categories. 1. Physical Properties A physical property of the drug is responsible for its action. (i) Taste. Bitter taste drugs increase the flow the hydrochloric acid reflexly in the stomach. Ex: Quassia, Chirata (ii) Mass. By increasing the bulk of drug in intestine produce laxative effect. Ex: Isapgol (iii) Adsorption. Certain drugs like kaolin adsorb water on to its surface and there by reduce gastric motility (iv) Radioactivity. The radioactive substances are commonly used to treat cancer. Ex: 125. 2. Chemical Properties The drugs react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc. Ex: (i) Aluminium hydroxide neutralizes acid in stomach (ii) Toxic heavy metals can be eliminated by chelating agents like EDTA, BAL, penicillamine etc. (iii) Oxidising agents are germicidal. 3. Through Enzymes Enzymes are very important targets of drug action because almost all biological reactions are carried out under the influence of enzymes. Drugs may either increase or decrease enzymatic reactions. Ex: (i) Adrenaline stimulates adenyl cyclase (ii) Pyridoxine acts as a cofactor and increases decarboxylase activity

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