Medicinal Chemistry-l Past Paper 2024-2025 PDF

Alamein International University PharmD Program Medicinal Chemistry-I Prof. Dr. Mona El Semary 1 If you can DREAM IT You can DO IT 2  INTRODUCTION TO MEDICINAL CHEMISTRY CHEMISTRY After completing this section, the student shoul...

Alamein International University PharmD Program Medicinal Chemistry-I Prof. Dr. Mona El Semary 1 If you can DREAM IT You can DO IT 2  INTRODUCTION TO MEDICINAL CHEMISTRY CHEMISTRY After completing this section, the student should be able to: 1. Understand what Medicinal Chemistry is? 2. Define, classify and give the appropriate nomenclature of drugs 3. Apprehend the physico-chemical properties in relation to biological action 4. Discuss the factors affecting physicochemical properties of the drug 5. Predict different drug targets in relation to biological action 6. Know the different forces of attraction responsible for drug-receptor interactions 7. Understand different stereochemical aspects of drugs 8. Understand and predict the different phases of drug metabolism 9. Apprehend and apply the prodrug concept 3 What is Medicinal Chemistry ? 4 Medicinal Chemistry: Medicinal chemistry is a chemistry-based discipline involving aspects of biological, medical and pharmaceutical sciences. It is concerned with: The discovery, design, identification and preparation of drugs The interpretation of their mode of action at the molecular level The construction of structure-activity relationships. The study of their metabolism 5 Definition a Drug: A drug is biologically active compound used for: Treating, curing or preventing diseases in humans or animals. Correcting or modifying physiological functions of the body. Simply: Drugs are compounds that interact with a biological system to produce a biological response. 6  Classifications of drugs 1. Classification According to the Origin into: Natural Synthetic Semi-synthetic materials Either complete These compounds obtained from synthesis or either cannot be both plant and synthesis of purely synthesized animal, naturally occurring or cannot be e.g. vitamins, compounds isolated from hormones, (e.g. morphine, natural sources in amino acids, atropine,steroids low cost. antibiotics, and cocaine) e.g. semi synthetic alkaloids, to reduce their penicillins. glycosides. cost. 7 2. Classification According to the Pharmacological Action: Since there is no certain (assured) relation between chemical structure and pharmacological activity therefore, it would be unreliable to arrange all drugs on the basis of their structures or origin. Thus, it is better to arrange the drugs according to their medicinal use. 8 Drugs can be classified according to their medicinal uses into two main classes: Pharmacodynamic agents: Drugs acting on the various physiological functions of the body (e.g. Antispasmodic, Antihypertenssives ,analgesics, sedatives and hypnotic etc.). Chemotherapeutic agents: Drugs which are used to fight pathogenises (e.g.sulphonamides, antibiotics, antimalarial, antiviral and anticancer agents etc.). N.B.  Drugs can be classified by their pharmacological effect, their chemical structure, their effect on a target system or their effect on a target structure. 9 Nomenclature of Drugs A Drug is identified by 4 kinds of names: 1. Code designation This name is given by the discoverer during the early stages of development. 2. Chemical Name (Nomenclature) This name describes the exact chemical structure of the drug. It is very specialized but long and difficult to be pronounced or understood by normal people. 10 3. Generic or Non Proprietary Name This name is chosen by official agencies e.g. FDA. It should be concise. 4. Trade, Brand or Proprietary Name This name is given to drug by the company that manufactures it. The drug may be marketed under different trade names either locally or in different countries. These names are usually registered as trademark. 11 Generic or Non Proprietary Name Diclofenac Chemical names: Sodium;2-[2-(2,6-dichloroanilino)phenyl]acetate (Potassium) Brand names: Voltaren Zipsor Cataflam, Cambia 12 N.B.  Clinically useful drugs have a trade (or brand) name, as well as a recommended international non-proprietary name.  Most structures produced during the development of a new drug are not considered for the clinic.  They are identified by simple codes that are specific to each research group. 13  DRUG DEVELOPMENT To discuss the topic of drug development we must understand the concept of 3 main ideas: Physico-Chemical Properties in Relation to Biological Action Drug Targets in Relation to Biological Action Drug Metabolism (Biotransformation) 14 Characteristics of drug molecules to exert their biologic effects 1- Soluble in and transported by the body fluids. 2- Pass various membrane barriers. 3- Escape excessive distribution into inert tissues. 4- Resist metabolism. 5- Penetrate the site of action where they orient and interact to give the action. These characteristics depend on: the physicochemical properties of the drug molecules (can be altered) and physicochemical properties of the biologic systems (fixed and complex). 15  Oral Intramuscular or Administration Subcutaneous Injection Gastrointestinal Tract TissueDepots Intravenous Receptors for Injection Desired Effects Drug Drug Drug Drug-metabolite Drug Serum albumin Systemic circulation Drug Drug metabolites Drug metabolites Conjugates -Drug metabolites Liver : site of most Bile Duct Intestine Kidney drug metabolism Execretion of soluble Feases conjugates 16  Basic Concepts LADME scheme ☺L = Liberation, the release of the drug from its dosage form. ☺A = Absorption, the movement of drug from the site of administration to the blood. ☺D = Distribution, the process by which drug diffuses or is transferred from the systemic circulation to body tissues. ☺M = Metabolism, the chemical conversion of drugs into eliminable compounds. ☺E = Excretion, the elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes. 17 18 Factors Affecting physicochemical properties of the drug 1. Solubility of drugs. 2. Partition coefficient. 3. Drug ionization state. 4. Chemical and metabolic stability. 19 a.Solubility of Drugs The drug must possess appropriate water solubility in order to be absorbed and reach the site of action. It must also have acceptable degree of lipid solubility to pass biological membranes. 20 Prediction of Water or Lipid Solubility Two concepts are taken in consideration in predicting water or lipid solubility: A. Hydrogen Bonding Functional group capable of donating or accepting a hydrogen bond will contribute to the overall water solubility of the compound, hence increasing the hydrophilic nature of the molecule. Conversely, functional group incapable of forming hydrogen bond will not enhance hydrophilicity will contribute to lipid solubility of the molecule. 21 So, the more hydrogen bonds, the greater is water solubility as long as no intramolecular hydrogen bonding is formed. Intramolecular hydrogen bonding would decrease water solubility and increase lipid solubility since fewer interactions with solvent occur. 22 Compounds containing more than 5 hydrogen bonds donating or accepting groups are poorly absorbed. 23  H O + d- HO N O d+ O H H O H H H O- Compounds with ionizable functional groups that produce a zwitterionic molecule have the potential to interact with each other rather than with water molecules and leading to water insoluble compounds. Zwitterion form of tyrosine 24  Zwitterion form of tyrosine A classical example is the amino acid tyrosine being capable of ionization, it is expected that tyrosine is very soluble in water, however, the basic alkylamine and carboxylic acid portions of the molecule can interact with each other producing a zwitterionic molecule with reduced water solubility. 25 B. Ion-Dipole Bonding This bond plays an important role in water solubility, and it is observed when dealing with organic salts. Ion-dipole bond is developed between either a cation or an anion and a dipole solvent such as water. Examples of ion-dipole bonds 26 C. Van der Waals forces This bond plays an important role in lipid solubility, and it is observed when dealing with nonpolar molecules (uncharged atoms/molecules). Van der Waals forces are the weakest intermolecular forces they are dependent on the distance between atoms or molecules. These forces arise from the interactions between uncharged atoms/molecules When the electron density around the nucleus of an atom undergoes a transient shift, Van der Waals forces will arise. 27 Factors Affecting physicochemical properties of the drug 1. Solubility of drugs. 2. Partition coefficient. 3. Drug ionization state. 4. Chemical and metabolic stability. 28. 2. Partition Coefficient It is a measure of the partition of a substance between a lipid (oil) and water. It is defined as the concentration ratio of a compound, as a neutral molecule, in an immiscible solvent and an aqueous phase. True partition coefficient is symbolized by PC or P. [HA − Organic] PC= [HA − Aqueous] Log P is a constant for the molecule. 29 Since PC is difficult to be measured in living systems; they are usually determined in vitro using n-octanol as the lipid phase and phosphate buffer pH 7.4 as the aqueous phase. n-Octanol / phosphate buffer system gives the most consistent correlations for drugs absorbed in gastrointestinal tract; oliveoil gives more consistent correlations for drugs crossing the blood-brain barrier. While chloroform gives values for buccal absorption (soft tissue in mouth). consistent 30 Factors Affecting physicochemical properties of the drug 1. Solubility of drugs. 2. Partition coefficient. 3. Drug ionization state. 4. Chemical and metabolic stability. 31 3. Drug Ionization State (Drug’s Pka) Most compounds used in medicine are either weak acids RCOOH or weak bases RNH2 and existing in both ionized and unionized forms. The unionized form of the drug is the diffusible and penetrates most membrane barriers. The degree of ionization is dependent on the pKa of the drug and the pH of body fluid in which it is 32 dissolved. Blood has a pH of 7.4, the stomach has a pH of 1 to 3, in the duodenum of small intestine,the pH is between 5 and 7 and it increases gradually until reaching a maximum of 8 in the colon. Basic compounds (RNH2) will not be so well absorbed in the stomach than acidic compounds (RNH2) since it is generally the unionised form of the drug which diffuses into the blood stream. 33  A simple way to calculate degree of Ionization Handerson-Hasselbach Equation It is used to predict the extent to which the drug ionizes. The equation can be generalized for weak acids and weak bases as follows: pH = pKa + Log Nonprotonated ( NP) protonated( P ) As pKa is a constant value; change in the pH of the medium will result in varied ratios between ionized and unionized forms (pH dependent) and NP = Molar concentration of nonprotonated form (proton acceptor form). P = Molar concentration of protonated form (proton donor form). 34  when pKa= pH; the compound will be 50% ionized. pH = pKa + Log Nonprotonated ( NP ) protonated( P ) An increase of pH by one unit from pKa will cause an acid (HA) (RCOOH) to become 90.9% in the ionized form (A-)( ) , and will cause a decrease in the ionization of basic drugs to 9.1 35  Nonprotonated ( NP ) pH = pKa + Log protonated( P) Nonprotonated ( NP ) Log = Zero protonated( P ) Log (NP) - Log (P) = Zero Log (NP) = Log (NP) 50% = 50% 36 Ion Trapping Ion trapping is the process of accumulation of drug ions on a side of the membrane. This happens when the pH of the environment and pKa of the drug favor drug ionization, thus preventing the drug from penetrating the membrane. Ion trapping of drugs is induced by a body fluid that has a pH different from that of blood as milk, vaginal secretion, prostatic secretion and fetus circulation. Basic drugs accumulate in acidic fluids and acidic drugs accumulate in basic fluids. 37 Increasing the pH of plasma (alkalization), for example by sodium bicarbonate administration, will increase extraction of weakly acidic drugs from the CNS into plasma while acidification of plasma (decreasing the pH), for example by administration of a carbonic anhydrase inhibitor, will cause weakly acidic drugs to become concentrated in the CNS, which may increase their neurotoxicity. 38 Factors Affecting physicochemical properties of the drug 1. Solubility of drugs. 2. Partition coefficient. 3. Drug ionization state. 4. Chemical and metabolic stability. 39 4. Chemical and Metabolic Stability Drugs bearing chemically labile functional groups, are either hydrolyzed in the stomach or metabolized rapidly by enzymes to active or inactive metabolites so, 1 The labile -lactam ring of penicillin is subjected to ring opening and inactivation. 40  2.The methyl group in the antidiabetic drug, tolbutamide, is easily oxidized to carboxylic acid and thus the drug can be quickly eliminated. Metabolic H3C SO2NHCONHC4H9 HOOC SO2NHCONHC4H9 oxidation (Tolbutamide) (Inactive metabolite) Replacing the methyl group by Cl in the antidiabetic drug, Cloropropamide, is hardly oxidized and thus the drug has a longer duration of action. 41  Catecholamine Metabolism so the NT is rapidly metabolized at the synapse by two special enzymes 3. Catechol O Methyl Transferase (COMT) and 4. Mono Amine Oxidase (MAO). 42  HO CH3O OH CH3 OH CH3 COMT HO CH CH2 NH CH HO CH CH2 NH CH CH3 CH3 Isoprenaline Inactive metabolite 3. The catechol moiety of -adrenergic agonist drug, isoprenaline, is rapidly metabolized and inactivated by COMT giving the methyl ether derivative, so the drug has a short duration of action. 4. Mona Amine Oxidase Amphetamine is a CNS stimulant drug, it undergoes oxidative deamination. CH3 CH3 MAO NH2 O 43  Forces of Attraction Drug-Receptor Interactions Interaction forces between drugs and receptors contribute to the binding strength and biological efficacy. The interaction of a drug with a functional group on the receptor, would be expected to take place by utilizing the same bonding forces involved as when simple molecules interact. Forces of the interactions are individually small, however summation is the key for drug-receptor interactions. 44 1. Irreversible Covalent Bond (-50 to-150 cal. /mole) It is the strongest bond, forming an irreversible complex. Cleavage of such bond does not occur under influence of body temperature or pH, but termination of such interaction is through enzymatic reaction, where the receptor molecule is usually destroyed to terminate the action of the drug. 45  Penicillin acylates transpeptidase enzyme of the bacteria, forming a covalent bond thus preventing cell wall formation. H H R CO N S Nu CH3 R CO N S CH3 N CH3 O + HN CH3 COOH O Nu COOH Transpeptidase (cell wall) Covalent bond 46 Nitrogen mustards (anticancer agents) alkylate nucleophilic targets on the double helix of DNA through covalent bonds. Cl Nu Nu Alkylation R N + 2 R N Cl Nu 47 2. Reversible Bonds Most drugs interact through weaker forms of interaction known as intermolecular bonds. The most important of which include: Electrostatic or (ionic) bonds Hydrogen bonds Vander Waals interactions Dipole–dipole interactions Hydrophobic interactions. 48 A. Electrostatic (Ionic) Bond It is the attraction between oppositely charged ions. At physiologic pH basic side chains of certain amino acids like arginine, lysine, are protonated and therefore provided a cationic environment. arginine lysine 49 Acidic groups like aspartic and glutamic acid are deprotonated to give negatively charged groups. glutamic acid Aspartic acid 50  Most drugs are weak acids or bases react with water to give ionized species that can react with an oppositely charged species on the receptor. Electrostatic (ionic) interactions between a drug and the binding site. 51 B. Hydrogen Bonding It is an interaction, where the positive end of one dipole is a H atom and the negative end of the other dipole is an electronegative atom.. H bond is easily broken, thus permitting dissociation of the drug-receptor complex Hydrogen bonding shown by a dashed line between a drug and a binding site (X, Y _ oxygen or nitrogen; HBD _ hydrogen bond donor, HBA _ hydrogen bond 52 acceptor). C. Vander Waals Force This type of bonding is weak, but its summation gives high attraction forces. This bonding is favorable between an aromatic ring or an aliphatic linear or slightly branched side chain on a drug molecule and a complementary part on a receptor. Vander Waals interactions between hydrophobic regions of a drug and a binding site. 53 D. Dipole-Dipole Bonds As a result of the greater electro-negativity of atoms such as oxygen, sulfur, nitrogen, and halogen relative to carbon, certain groups show an asymmetric distribution of electrons, thus producing dipoles. 54  The dipoles in a drug molecule can be attracted to complementary dipoles on the receptor to form a dipole-dipole Interaction or an ion-dipole Interaction. Dipole–dipole interactions between a drug and a binding site. 55 E. Hydrophobic Interaction It involves a non-polar-non-polar interaction between receptor and drug. The receptor and the aliphatic side chain of the drug molecule are surrounded by water molecules. Water molecules orient around the non-polar molecules leading to a higher energy and less favorable state known as quasi-crystalline structure or iceberg. 56 As the organic chains approach each other; water molecules are squeezed out to permit the non-polar chains to move closer. Thus the movement of the drug to its receptor will disturb water arrangement leading to energy gain, which stabilizes the close contact of non polar regions. Hydrophobic interactions. 57  STEREOCHEMICAL ASPECTS OF DRUGS Three steric factors may exert some effects on the pharmacologic activity, namely, optical isomerism, geometric isomerism and conformational isomerism. I. Optical Isomerism Members of this class are either enantiomers or diastereomers. 58 A. Enantiomers a. Enantiomers have a chiral atom. b. Enantiomers differ with regards to the spatial arrangement of the ligands. (S)-(+)-lactic acid (left) and (R)-(–)-lactic acid (right) are nonsuperposable mirror images of each other. c. Enantiomers differ in rotating polarized light. d. Enantiomers show no difference in most physical properties. e. Enantiomers may show differences in biological activity, which may be due to: 59 f. Sterospecific interaction with the receptor, where one enantiomer fits well on the receptor surface while the other fits badly or even does not fit the receptor. g. Enantioselectivity with respect to pharmacokinetics, since most of the natural (biological) environment consists of enantiomeric molecules as amino acids, nucleosides, carbohydrates and phospholipids…; processes as absorption, distribution and metabolism will be selective, and leading to different abilities for drug enantiomers to reach the receptor site. 60 Eason-Stedman Hypothesis i. Differences in biological activity between enantiomers is due to selective reactivity of one enantiomer with the receptor. ii. The interaction requires a minimum of a 3-point fit on the receptor. 61 According to this hypothesis, the drug must approach closely to the receptor and bonding by specific groups on the drug molecule. The drug receptor union leads to a biological response. 62 This hypothesis is illustrated by considering a receptor having 3 binding areas, an enantiomer will have a good fit on the receptor with a three-point attachment. While the second isomer will fit by only a two-point attachment, and thus expected to be less active. 63 The isomer with a three-point attachment is called the eutomer, while that with a two-point attachment is called the distomer. No generalization could be made concerning enantiomers, since they exhibit a wide variation in effects. 64  Examples: One of The Enantiomer Is Active And The Second May Be Toxic Thalidomide was a drug introduced in the 1960’s to alleviate morning sickness in pregnant women, but this resulted in severe birth defects. It was later discovered that the (S) isomer is the cause of these defects, consequently; the drug was withdrawn from the market. 65  One of The Enantiomers Is More Active The (-) enantiomer of epinephrine has the OH group in the direction of the binding site, and therefore has a much more potent pressor activity 66 The Two Isomers Exhibit Different Pharmacological Action: Levorphanol is a powerful narcotic analgesic with a high addiction liability, and is classified as a Schedule II narcotic, 67 while its enantiomer dextromethorphan has neither analgesic activity nor addiction liability, but it retains the antitussive action seen in levorphanol, and is widely used as anticough in OTC preparations. 68 B. Diastereomers Diastereomers have more than one chiral atom and different physical properties. Diastereomers may show different pharmacologic effects and sometimes only one isomer exhibits the desired effect. Some isomers may cause side effects or toxicity. An example is ephedrine which has 2 chiral carbons that form 4 isomers 69  Ph Ph Ph Ph H C OH HO C H HO C H H C OH H C NHCH3 CH3HN C H H C NHCH3 CH3HN C H CH3 CH3 CH3 CH3 D-(-) Ephedrine L-(+) Ephedrine D-(-) Pseudoephedrine L-(+) Pseudoephedrine The D-(-) ephedrine is used as an antiasthmatic and as a vasopressor drug. The L-(+) pseudoephedrine is used as a nasal decongestant. 70 II. Geometric Isomerism It occurs as a result of restricted rotation as in olefinic and cyclic structures. ▪ Geometric isomers may have different physical properties. 71 Difference in biological activity between such isomers is attributed to the difference in interatomic distances between the groups essential for the pharmacologic response at the receptor site. H H H3C H H3C CH3 H CH3 Cis or Z-Isomer T rans or E-Isomer 72 The E-isomer of the histamine H1-receptor antagonist, triprolidine, is more active than the Z-isomer, indicating that the distance between the pyridine and pyrrolidine rings is crucial for binding to the receptors. Geometric isomers of triprolidine 73 Trans Diethylstilbestrol is 14 times more active than the cis isomer, this is particularly due to the fact that the interatomic distance between the OH groups of the trans isomer closely approximates the distance between the OH groups in the natural hormone estradiol OH HO OH OH HO HO Estradiol (Natural Hormone) T rans-Diethylstilbestrol Cis-Diethylstilbestrol 14 T imes more active than Less active than the cis isomer the trans isomer 74 III. Conformational Isomerism It is the non-identical spatial arrangement of atoms in a molecule, resulting from the rotation around a single bond. Conformers are interconvertible, by free rotation around a single bond. Being reactive proteins; receptors undergo conformational changes on interaction with drug molecules. 75 76  Effect of conformational isomerism on biological activity C' Receptor C' Receptor C' Receptor C A' A' A' Drug A Drug A Drug A B B' B B' C B B' Agonist with essential Antagonist with essential groups Antagonist and optical isomer groups for binding and for binding but lacking the necessary that can bind but can not elicit eliciting a response groups for eliciting a response a response Group A and B are essential for binding and group C triggers the response The flexible drug molecule may have many conformations, but the receptor site binds to only one isomer that has the same correct spatial arrangement. 77 The antagonist molecule may bind to the receptor site, but it does not trigger the pharmacologic response because of the absence of some key functional groups on the molecule. The conformational flexibility of open chain molecules a acetylcholine and histamine, permits multiple biological effects by virtue of their ability to interact in different unique conformations with different biological receptors. 78  Conformational Isomers of Acetyl Choline Acetylcholine as an example, acts at the muscarinic and at the nicotinic receptors producing appropriate responses. Studies on rigid analogs of acetylcholine indicated that the “cisoid” conformation is required for the nicotinic receptors; whereas the “transoid” conformation is required for the muscarinic receptors. 79 Due to the flexibility of the ACh molecules, it can assume different conformational states to bind to its different receptors. In order to predict which conformational isomer of ACh will bind to which receptor, a series of restricted rotational analogs of ACh were made and studied. The study proposed that ACh probably assume the staggered conformation in order to bind to muscarinic receptors and the eclipsed conformation when bind to the nicotinic receptors. 9/25/2024 DR.Mona El Semary 80 DRUG METABOLISM (BIOTRANSFORMATION) Introduction The purpose of drug metabolism (biotransformation) is generally to make a compound more readily excreted. Products of drug metabolism are generally less lipid soluble and more polar, thus more likely to be partitioned into the bloodstream and presented to the kidneys for excretion and, being more polar, also more suitable for carrier-mediated excretion processes. 81 Sites of Drug Metabolism The liver is the main site of drug metabolism within the body. Here many drugs, particularly lipid-soluble weak organic acids and bases which are not readily excreted by glomerular filtration or tubular secretion, are metabolised by hepatic enzymes, often associated with cytochrome P-450, into compounds which are polar, less lipid-soluble and more readily excreted. 82 Drug metabolism also occurs to varying degrees in tissues such as the kidney and lung, in blood plasma, and in the lumen of the gut. 83 Consequences of the biochemical transformation of drugs: 1) Inactivation, during which an active drug is converted to inactive metabolite(s) 2) Activation, during which an inactive drug (or pro- drug) is converted to a pharmacologically active primary metabolite 3) Modification of activity after the conversion of an active drug to a metabolite that also has pharmacologic activity 84 4) Lethal synthesis (or intoxication), in which a drug is incorporated into a normal cellular metabolic pathway that ultimately leads to failure of the reaction sequence because of the presence of false substrate (cell death then occurs). 85  Reactions Involved in Drug Metabolism The reactions involved in drug metabolism or biotransformation can be grouped into Phase I 86 Phase I reactions: Oxidative reductive hydrolytic 87 Properties of phase I reactions: Result in the unmasking or introduction into the molecule of polar groups such as -OH, SH, -COOH or -NH2. Result in loss of pharmacological activity of a drug. Responsible also for conversion of inactive prodrug compounds to active compounds. 88 May be excreted in urine or subject to Phase II reactions. Oxidation is probably the most common reaction in drug metabolism and is catalyzed by a group of membrane-bound monooxygenases. 89 Phase I Reactions A. Oxidation Aromatic Hydroxylation Hydroxylation occurs most readily on rings that are electron-rich, i.e. those having electron-donating groups directly attached to the ring (OH, OCH3, NH2, alkyl groups) 90 Aromatic hydroxylation most often occurs at the position para-to the substituent. 91  Epoxidation Carbamazepine is an anticonvulsant drug, it undergoes epoxide formation. O O NH2 O NH2 Deamination or Desulfuration Amphetamine is a CNS stimulant drug, it undergoes oxidative deamination. CH3 CH3 MAO NH2 O 92 B. Reduction There are fewer specific reduction reactions than oxidation reactions. The nature of these reactions is also self-evident from their names. 1. Azo Reduction Sulfasalazine is a gastrointestinal antiinflammatory drug; it undergoes azo reduction where the azo group splits into 2 primary aromatic amines. COOH COOH OH OH N NH2 H N H N N N N + H2N S S O2 O2 93 2. Nitro Reduction Nitrazepam is an anxiolytic drug, it is metabolized to its amino metabolite. CH3 O CH3 N O N N O2N H2N N Nitrazepam 7-Amino metabolite 94 C. Hydrolysis By which, water splits the toxicant into 2 fragments of smaller molecules. Esters, amines, hydrazines and carbamates are biotransformed by hydrolysis. Procaine, a local anesthetic ester Esterase Enzyme Fast Procainamide, an antiarrhythmic amide are derivatives of p- aminobezoic acid, Amidase Enzyme Slow they undergo hydrolysis, yielding the parent acid. O C2H5 O N O C2H5 OH Fast Procaine H2N H2N O C2H5 p-Aminobenzoic Acid N Slow N C2H5 H H2N Procainamide 95 Another famous example is acetyl salicylic acid (Asiprin) 96 Phase II Reactions They are mainly conjugation reactions that involve coupling of a drug or its metabolite with an endogenous substrate as glucuronic acid, sulfuric acid or an amino acid. Conjugated products are large molecules and are generally more polar, thus can be readily excreted from the body via urine or bile. Due to its high polarity; conjugated product has poor ability to cross cell membranes. 97 1. Glucuronide Conjugation Glucuronide conjugation is the major phase II pathway in mammals. It occurs frequently with a compound containing an OH as phenols and alcohols, an NH as amines or amides or an SH as thiols, to form O-, N- or S- glucuronides. The reaction occurs in liver microsomes via uridinediphosphate glucuronate (UDP). COOH O ROH + HO Drug or Metabolite OH OH O O OH O COOH - - O P O O P O O NH NH + O O HO - - O P O CH2 O N O O P O CH2 O N O RO OH O H H O OH H H H H H H Glucuronate Conjugate OH OH OH OH 98 Uridinediphosphate (UDP) Uridinediphosphate Glucuronate (Recycled) 2. Sulfate Conjugation It is an important reaction for the biotransformation of phenolic drugs, steroid hormones, catecholamine neurotransmitters, thyroxin, bile acids and others. The reaction is mediated by sulfotransferases present in liver and other tissues. OH H OH H N CH3 N CH3 HO HO CH3 CH3 CH3 CH3 O HO - O S O Salbutamol O O-Sulfate Conjugate 99 One compound can undergo many types of conjugation in a time,for example paracetamol 100 3.Acetylation The reaction is mediated by acetyl transferase and involves the transfer of acetyl group from acetyl-CoA to primary aliphatic or aromatic amines, amino acids, hydrazines or sulfonamides. Acetylation reaction makes the metabolite less hydrophilic and may have a longer half-life than the parent compound. O O R NH2 + H3C C SCoA RHN C CH3 101 4.Conjugation With Amino Acids Carboxylic acids can be conjugated to amino acids via their CoA thiolesters. The amino acids involved in the conjugation are glycine, glutamine, ornithine, serine.. The conjugates are water soluble and mainly excreted through urine or bile. O O O C OH OH + H2N N OH H O Benzo ic Acid Glycine Hippuric Acid 102 5.Glutathione conjugation It is a major detoxification pathway for polycyclic phenols, carcinogens and halides. Glutathione is glycine + cysteine + glutamine. Cysteine provides an SH nucleophile to attach to electrophilic centers. H Cysteine O N COOH Glycine S H N O NH2 OH O Benzene Epoxide Glutamine COOH 103 3. Role of Metabolism In Drug design Understanding drug metabolism and the chemical aspects of metabolic transformations lead to the introduction of the concept of prodrugs, active metabolites, soft and hard drugs. 104 1. Prodrugs Not all administered drugs are pharmacologically active; some might be metabolically converted to active form. these drugs are known as prodrugs. Biotransformation or activation of a prodrug may occur prior, during, or after absorption or at specific target sites within the body. 105  Objectives of Prodrugs Design Prodrugs aim at overcoming a number of barriers that limit drug's usefulness. These barriers fall into three categories. a. Pharmaceutical barriers Prodrugs are designed so as : To improve solubility. To improve stability. To improve taste. To solve chemical formulation problems. 106  b. Pharmacokinetic barriers Prodrugs are designed so as: To improve absorption and distribution. To slow and prolong drug action. To improve site-selective delivery. To decrease the first pass effect. C. Pharmacodynamic barriers Prodrugs are designed so as to decrease toxicity and side effects. 107 1. Bacampicillin is an ester H H H and a prodrug of CH CO N S CH3 Ampicillin, that improves NH2 N CH3 CH3 O oral absorption COO CH O COOEt 2. Dipiverin is the dipivaloyl ester of Epinephrine, OH H It is an adrenergic antiglaucoma N O CH3 prodrug, it allows greater O corneal permeability and is O O hydrolyzed by corneal and aqueous humor esterases to release Epinephrine. 108  III. Chloramphenicol Chloramphenicol Succinate is an ester Chloramphenicol palmitate is an prodrug of Chloramphenicol. ester prodrug of It is very water-soluble designed management and treatment of Chloramphenicol. superficial eye infections such as It is insoluble designed to bacterial conjunctivitis, and otitis overcome formulation problems. externa. It has also been used for the Bitterness in pediatric treatment of typhoid and cholera. preparations. 109  2.Bioprecursors These prodrugs are bioactivated by oxidation, reduction or hydrolytic reaction without releasing the existing carrier group i. Phenacetin is an analgesic antipyretic, and is subjected to oxidative O-dealkylation to yield the active drug Acetaminophen. O O H H N CH3 N CH3 O CH3 OH 110 ii. Sulindac is a nonsteroidal antiinflammatory, it is inactive in vitro, but highly active in vivo where It is reduced to the sulfide which is active both in vitro and in vivo CH3 CH3 HO HO O CH3 O CH3 S S O F F 111 II. Active Metabolites The discovery of the pharmacological activity of some metabolites led to their synthesis and clinical use thus decreasing the load on liver. i.Acetaminophen from Phenacetin ii.Oxyphenbutazone from Phenylbutazone iii.Fexofenadine from Terfenadine 112 III. Hard Drugs And Soft Drugs Hard drugs are non-metabolizable drugs. Soft drugs are pharmacologically active drugs that undergo predictable and controllable metabolism to nontoxic and inactive metabolites. 113 Basic Principles of Hard Drug Design ▪ To minimize drug metabolism. ▪ To minimize individual variability. ▪ To reduce the possibility of toxic metabolites production. 114 Basic Principles of Soft Drug Design To avoid, as much as possible, oxidative metabolism that causes undesirable effects. To use hydrolytic enzymes to achieve predictable and controllable drug metabolism. 115