Introduction To Pharmaceutical Chemistry PDF

INTRODUCTION TO PHARMACEUTICAL CHEMISTRY 1 PHARMACEUTICAL (MEDICINAL) CHEMISTRY: DEALS WITH THE STUDY OF DRUGS FROM A CHEMICAL POINT OF VIEW, INCLUDING THEIR DESIGN, SYNTHESIS AND STRUCTURAL ANALYSIS. Medicinal Chemistry is difficult to define because it is an interdisciplinary...

INTRODUCTION TO PHARMACEUTICAL CHEMISTRY 1 PHARMACEUTICAL (MEDICINAL) CHEMISTRY: DEALS WITH THE STUDY OF DRUGS FROM A CHEMICAL POINT OF VIEW, INCLUDING THEIR DESIGN, SYNTHESIS AND STRUCTURAL ANALYSIS. Medicinal Chemistry is difficult to define because it is an interdisciplinary science and touches upon various branches chemistry and biology.  It involves on one hand the isolation, characterization and synthesis of compounds that can be used in medicine for the treatment and cure of disease, and on the other hand establish a link between chemical structure and biological activity. Medicinal Chemistry has also contributed indirectly to the development of organic chemistry in terms of designing routes of synthesis, and to pharmacology in terms of spectrum of action of new compounds. Research programs in medicinal chemistry have created products like hormones, vitamins, and biochemical drugs (a molecule derived from biological sources rather than synthesized through traditional chemical processes and delivered to the body to produce a biological effect). 2  Medicinal chemistry is best to be defined as an interdisciplinary research area incorporating different branches of chemistry and biology (synthetic chemistry, organic chemistry, biochemistry, pharmacology and molecular biology) in the research for better and new drugs (Drug Discovery). In other words, medicinal chemistry is the science, which deals with the discovery and design of new and better therapeutic chemicals and development of these chemicals into new medicines and drugs. This cover a wide range of chemistry: ✓ Synthesis and characterization of compounds (novel and natural products). ✓ The mechanistic aspects of how drugs work (mode of action). ✓ The interface between chemistry and biology and pharmacology (e.g. metabolism, pharmacokinetics and determination of beneficial biological effect). Generally Medicinal Chemists can: ✓ Make new compounds ✓ Determine their effect on biological processes. ✓ Alter the structure of the compound for optimum effect and minimum side effects. 3 ✓ Study uptake, distribution, metabolism and excretion of drugs. SAR The modifications of the structure by medicinal chemists are by performing structure activity relationship (SAR). SAR will overcome the problems associated of certain drug such as; physicochemical properties (solubility, acidity/basicity, reactivity, binding affinity.) pharmacokinetics (absorption, distribution, metabolism, excretion), pharmacodynamics (onset of action “the length of time it takes for a medicine to start to work”, duration of action), pharmaceutics (formulation, stability) and pharmacological (effect, side effects, mode of action) To have optimum drugs suitable for clinical uses. 5  Drug Classification Pure organic compounds are the chief source of agents for the cure, mitigation or the prevention of disease. These remedial agents could be classified according to their origin: Natural compounds: materials obtained from both plant and animal, e.g. vitamins, hormones, amino acids, antibiotics, alkaloids…. etc.). Synthesis compounds: either pure synthesis or synthesis naturally occurring compounds (e.g. morphine, atropine, steroids and cocaine) to reduce their cost. Semi-synthesis compounds: Some compounds either can not be purely synthesized or can not be isolated from natural sources in low cost. Therefore, the natural intermediate of such drugs could be used for the synthesis of a desired product (e.g. semi synthetic penicillins).6  Drug Classification Drugs can be classified according to their medicinal uses into two main classes: I. Pharmacodynamic agents: Drugs that act on the various physiological functions of the body (e.g. general anaesthetic, hypnotic and sedatives, analgesic etc.). II. Chemotherapeutic agents: Those drugs which are used to fight pathogenic (e.g. sulphonamides, antibiotics, antimalarial agents, antiviral, anticancer etc.). 6 Drugs can treat different types of diseases: 1 Infectious diseases: Born (transmitted) from person to person by outside agents, bacteria (pneumonia, salmonella), viruses (common cold, AIDS), fungi (thrush, athletes foot), parasites (malaria) 2 Non-infectious diseases: disorders of the human body caused by genetic malfunction, environmental factors, stress, old age etc. (e.g. diabetes, heart disease, cancer. Haemophilia, asthma, mental illness, stomach ulcers, arthritis). 3 Non-diseases: alleviation of pain (analgesic), prevention of pregnancy (contraception) , anesthesia. 8  Physico-chemical properties in relation to biological action Drugs normally interact with targets (which they are proteins, enzymes, cell lipids, or pieces of DNA or RNA). The ability of a chemical compound to elicit a pharmacologic /therapeutic effect is related to the influence of its various physical and chemical (physicochemical) properties The most pharmacologically influential physicochemical properties of organic medicinal agents (OMAs) are: 1. Solubility 2. Acidity and basicity 3. Reactivity 9 1- SOLUBILITY OF ORGANIC MEDICINAL AGENTS Importance of solubility: (1)Formulation of the drug in an appropriate dosage form and (2)Bio-disposition: Disposition of OMAs in the living system after administration (absorption, distribution, metabolism, and excretion). The solubility expression: in terms of its affinity/philicity or repulsion/phobicity for either an aqueous (hydro) or lipid (lipo) solvent. hydrophilic....................water loving lipophobic.....................lipid hating lipophilic.......................lipid loving 9 hydrophobic..................water hating Majority of OMAs possess balanced solubility (have some degree of solubility in both aqueous and lipid media). Because there is a need for OMAs to move through both aqueous (plasma, extracellular fluid, cytoplasm, etc.) and lipid media (biologic membranes) in the biological system. 11 Solubility of OMAs should be viewed as being on a continuum between high lipophilicity on one end of the spectrum and high hydrophilicity on the other. M o r e lipophilic M o r e hydrophilic OMAs OMA s Equally soluble OMA s L ip o p h ilic H y d ro p h ilic In order for a chemical compound to dissolve in a particular solvent/medium the compound must establish attractive forces between itself and molecules of the solvent. 12 It is possible to estimate the solubility properties of an OMA (hydrophilic vs. lipophilic) by examining the structure of the OMA and noting whether its structural features promote affinity for aqueous or lipid media. 13 The most important intermolecular attractive forces (bonds) that are involved in the solubilization process are: 1. Van der Waals Attraction weakest intermolecular force electrostatic occurs between nonpolar groups (e.g. hydrocarbons) highly distance and temperature dependent 2. Dipole-Dipole Bonding stronger occurs electrostatically between electron deficient and electron excessive /rich atoms (dipoles) hydrogen bonding is a specific example of this bonding and serves as a prime contributor to hydrophilicity − + − + O H N: H O C + O H H O H − 14 3.Ionic Bonding electrostatic attraction between cations and anions common in inorganic compounds and salts of organic molecules O strong + - C Na+ N H Cl O- 4.Ion-Dipole Bonding electrostatic between a cation/anion and a dipole relatively strong low temperature and distance dependence important attraction between OMAs and H2O H − O O H N + H C - + O H O H 14 Solubility Prediction The relative solubility of an OMA is a function of the presence of both lipophilic and hydrophilic features within its structure, which serve to determine the extent of interaction of the OMA with lipid and/or aqueous phases. The relative solubility of an OMA can be determined in the laboratory, i.e. the partition coefficient [P; the ratio of the solubility (concentration) of the compound in an organic solvent to the solubility of the same compound in an aqueous environment (i.e., P=[Drug]lipid/ [Drug]aqueous). P is often expressed as a log value. 15 A mathematical procedures also have been developed to estimate the relative solubility of an organic molecule based upon differential contributions of various structural features to overall solubility. For example, the relative solubility of an OMA is the sum of the contributions of each group and substituent to overall solubility. Example: Examination of the structure of chloramphenicol (indicates the presence of both lipophilic (nonpolar) and hydrophilic (polar) groups and substituents. 16  Solubility Prediction L ip o p h ilic Hydrophilic Hydrophilic L ip o p h ilic O H O O 2 N C H C H N H C CHCl 2 C H 2 O H Chloramphenicol Hydrophilic The presence of oxygen and nitrogen containing functional groups usually enhances water solubility. While lipid solubility is enhanced by nonionizable hydrocarbon chains and ring systems. 18 1.Laboratory Estimation of Relative Solubility The relative solubility of an organic compound is measured by determining the extent of its distribution into an aqueous solvent (usually pH 7.4 buffer) and a lipid solvent (usually n-octanol).These experiments generate a value, P, the partition coefficient for that particular compound. Conc. of compunds in C 8 H 1 6 O H Partition coefficient = Conc. of compunds in H 2 O 19 2- Mathematical Estimation of Relative Solubility Solubility contributions (groups and substituents) are expressed as hydrophilic or lipophilic fragment constants. Log Pcalc =  Where; Log Pcalc = log of partition cofficient and = sum of hydrophilic- lipophilic constants. Hydrophilic-Lipophilic constants.  Value Fragment C (aliphatic) +0.5 C6H5- +2.0 Cl +0.5 O2NO +0.2 Intramolecular hydrogen bonding (IMHB) +0.65 S +0.0 O=C-O -0.7 O=C-N -0.7 O(hydroxyl, phenyl, ether) -1.0 N (amine) -1.0 O2N (aliphatic) -0.85 20 O2N (aromatic) -0.28  Calculation steps of Log P for OMA (i) The molecule is dissected into its various groups, functionalities and substitutents (ii) Appropriate hydrophilic/lipophilic fragment constants are assigned and summed (iii) Compounds with log Pcalc values greater than +0.5 are considered water insoluble (lipophilic) and those with log Pcalc values less than +0.5 are considered water soluble (hydrophilic). Calculated log P Values for salicylic acid and p-Hydroxybenzoic acid: Salicylic acid p-Hydroxybenzoic acid Fragment  Value Fragment  Value Phenyl +2.0 Phenyl +2.0 OH -1.0 OH -1.0 COOH -0.7 COOH -0.7 Salicylic IMHB +0.65 - - acid p-Hydroxybenzoic acid Sum +0.95 +0.3 21 Prediction Water insoluble Prediction Water soluble Log Pcalc for chloramphenicol (see above) would be +2.02, a lipophilic compound (water insoluble) aromatic-NO 2 = -0.28; two OH functions = -2.0; O=C-N function = -0.7; phenyl = +2.0; four C's = +2.0 and 2 Cl's = +1.0 22 Extra examples para amino benzene sulfonamide Penicillin V  Quantitative Structure Activity Relationship (QSAR) QSAR is a computational technique used in chemistry and pharmacology to predict the biological activity or other properties of molecules based on their chemical structure. used to predict the biological activity, toxicity, or physicochemical properties of compounds based on their molecular structure alone. As shown we can estimate the relative solubility of drugs on the basis of the structure features. However, there is a relationship between the quantity of the drug that binds to the active site and its structure and thus, the biological activity. This relationshipis called quantitativestructure activity relationship (QSAR). 22  QSAR can be used: To predict the design of new compounds and To reduce the types of chemical process involved in the biological activity (reduce the experimental steps needed to study the relationship between chemical structures and biological activity). Because, the biological activity of substances is related to oil water distribution coefficient (distribution of the compound between the aqueous and the lipid phases of the tissue), which is an important parameter for solubility and thus the quantity of the drugs that binds to the active site.  2- Acidity and Basicity Acidic and/or basic properties of OMAs are important in both: 1 Pharmaceutical phase (dosage formulation) and 2 Pharmacological phases (disposition, structure at target site, etc.). Disposition (Pharmacokinetics) = ADME The three aspects of acid-base chemistry: (1) Definitions (2) Recognition of acidic or basic organic functional groups and (3) An estimation of the relative acid/base strength of these groups. Definitions: Acid: An organic compound containing a functional group that can donate a proton (H+) Base: An organic compound that contains a functional group that can accept a H+23  2- Recognition of acidic or basic organic functional groups Common acidic organic functional groups Carboxylic acid (-COOH), Phenol (Ar-OH), Sulfonamide (R-SO2NH2), Imide (R- CO-NH-CO-R). 28 Common basic organic functional groups Aliphatic 1º (R-NH2), 2º (R2NH) and 3º (R3N)-amines Heterocyclic amines, Aromatic amines (Ar-NH2) 29 Estimation of the Relative Acid/Base Strength The ionization constant (ka) indicates the relative strength of the acid or base. An acid with a ka of 1x10-3 is stronger acid (more ionized) than one with a ka of 1x10-5 A base with a ka of 1x10-7 is weaker (less ionized) than one with a ka of 1x10-9 The negative log of the ionization constant (pka) also indicates the relative strength of the acid or base. An acid with a pka of 5 (ka=1x10-5) is weaker (less ionized) than one with pka of 3 Whereas a base with a pka of 9 is stronger (more ionized) than one with a pka of 7 E.g. Ionization of weak acid (e.g. acetic acid, pka =4.76) is as follows: - + CH3COOH CH3COO + H NH3 + H3O+ NH4+ + H2O 30  I-Acids Ionization of Acidic and Basic Functional Groups Carboxylic acids Sulfonamides O O + R SO2NH - + H3O+ R C + H3O ArSO 2 NHR + H2O R C + H2O O- O H O O O O- R H R - + H2O + H3O+ N H + H2O N + H3O+ R R O O Phenols Imides II-Bases R NH2 NH3+ R + R N + H3O+ R N H+ H2O + H3O+ + H2O R R Aliphatic amines Aromatic amines + H3O+ + H2O + N N 29 Heteroaromatic amines H  Acidic and Basic Functional Group - Salt Formation Salt: is the combination of an acid and a base The salt form of the drug is more soluble than its parent molecule Drug salts can be divided into two classes: 1) Inorganic salts: are made by combining drug molecules with inorganic acids and bases, such HCl, H2SO4, KOH and NaOH. Inorganic salts are generally used to increase the aqueous solubility of a compound 2) Organic salts: are made by combining two drug molecules, one acidic and one basic. Or when a drug is combined with organic acids or bases. The salt formed by this combination has increased lipid solubility and generally is used to make depot injections (e.g. procaine penicillin). Sodium salt formation from carboxylic acid: RCOOH + NaOH RCOO-Na+ + H2O R3N + HCl R3NH+Cl- 30 Hydrochloric salt formation from an aliphatic amine  For depot injections, enhanced lipid solubility allows the drug to be stored in body fat and released slowly over time, providing a sustained therapeutic effect. Procaine penicillin is a depot formulation where procaine (a basic compound) and penicillin (an acidic drug) form an organic salt. This results in a slow-release formulation, reducing the frequency of injections. Penicillin G: A natural beta-lactam antibiotic Procaine: A local anesthetic that helps reduce the pain of the injection and prolongs the release of penicillin from the injection site. Drug activity can be classified as (a)Structurally non-specific or (b) Structurally specific 1-Structurally non-specific activity is dependent on physical properties like solubility, partition coefficients and vapour pressure and not on the presence or absence of some chemical group (without drug target) Structurally non-specific drugs don't bind to a particular receptor, enzyme, or biological target. Instead, they distribute themselves across membranes and accumulate in tissues (especially lipid-rich areas), where they exert their effects more generally. Substances such as alkanes, alkenes, alkynes, alcohols, amides, ethers, ketones and chlorinated hydrocarbons exhibit narcotic activity and potency of each substance is related to its partition coefficient as this property influence how readily they accumulate in lipid-rich 31 areas.  Potency: is a measure of the amount of drug required to produce a specific therapeutic effect. A highly potent drug will produce the desired effect at a lower dose compared to a less potent drug. Structurally non-specific action results from accumulation of a drug in some vital part of a cell with lipid characteristics. The structurally non-specific drugs include general anaesthetics, hypnotics, a few bactericidal compounds and insecticides 2-Structurally specific activity is dependent upon factors such as the presence or absence of certain functional groups, intramolecular distance (3D structure), and shape of the molecules. Activity is not easily co-related with any physical property and small changes in structure often lead to changes in activity. Structurally specific activity is dependent upon the interaction of the drug with a cellular receptor. 32  Drug-receptor Interaction Receptor is the site in the biological system where the drug exerts its characteristic effects or where the drug acts. Receptors have an important regulatory function in the target organ or tissue. Most drugs act by combining with receptor in the biological system (structurally specific drugs). 1 Cholinergic drugs interacts with acetylcholine receptors (cholinergic receptor). 2- non steroidal anti inflammatory (NSAID) drugs inhibit cyclooxygenase enzyme that will inhibit the formation of prostaglandins which will lead to inflammation symptoms. Structurally non-specific drugs do not act upon receptors. The ability of a drug to get bound to a receptor is termed as the affinity of the drug for the receptor. 33  Drug-receptor Interaction The receptors are also dynamic in nature and have a special chemical affinity and structural requirements for the drug. The drug elicits a pharmacological response after its interaction with the receptor. A given drug may act on more than one receptor differing both in function and in binding characteristics (non-selective drugs). There are also many factors effect changes in receptor concentration and/or affinity. The higher the concentration of receptors, the more binding sites are available for a drug or ligand, which can result in a stronger pharmacological effect. Conversely, if receptor concentration is low, fewer drug molecules can bind, leading to a weaker response. receptor concentration can vary from one person to another. 34  A drug, which initiates a pharmacological action after combining with the receptor, is termed agonist. Drugs which binds to the receptors but are not capable of eliciting a pharmacological response produce receptor blockage, these compounds are termed antagonists.  Structural features of drugs and their pharmacological activity Stereochemistry: Space arrangement of the atoms or three- dimensional structure of the molecule. Stereochemistry plays a major role in the pharmacological properties because: (1)Any change in stereospecificity of the drug will affect its pharmacological activity (2) The isomeric pairs have different physical properties (partition coefficient, pka, etc.) and thus differ in pharmacological activity. The following steric factors influence pharmacological activity: Optical and geometric isomerism Conformational isomerism Isosterism and bioisosterism 35 I-Optical and geometric isomerism and pharmacological activity Optical isomers are compounds that contain at least one chiral carbon atom or are compounds that differ only in their ability to rotate the pollarized light. The (+) or dextrorotatory: isomer rotates light to the right (clockwise). The (-) or levorotatory: isomer rotates light to the left (counterclockwise). 42  2-Hydroxybutane enantiomers (mirror images can not superimpose) Enantiomers (optical isomers) can have large differences in potency, receptor fit, biological activity, transport and metabolism. For example, levor-phanol has narcotic, analgesic, and antitussive properties, whereas its mirror image, dextror-phanol, has only antitussive activity. Dextrorphanol Levorphanol 43 Geometric isomerism (cis-trans isomerisms). Occur as a result of restricted rotation about a chemical bond, owing to double bonds or rigid ring system in the molecule. They are not mirror images and have different physicochemical properties and pharmacological activity. Because different distances separate the functional groups of these isomers. They generally do not fit to the same receptor equally well. For example, cis-diethylstilbestrol has only 7% of the oestrogenic activity of trans- diethylstilbestrol Trans-diethylstilbestrol is the more active form with a higher binding affinity for estrogen receptors, allowing it to exhibit significant estrogenic effects. 38  II- Conformational isomersim and pharmacological activity Conformational isomersim is the non-identical space arrangement of atoms in a molecule, resulting from rotation about one or more single bonds. Almost every drug can exist in more than one conformation and thus the drug might bind to more than one receptor but a specific receptor site may bind only to one of many conformations of a drug molecule. For example, the trans conformation of acetylcholine binds to the muscarinic receptor, where as the gauche conformation binds to the nicotinic receptor. 39 III- Isosterism, Bioisosterism and pharmacological activity Isosterism: Isosteres are atoms, molecules, or ions of similar size containing the same number of atoms and valence electrons. (CO2 and N2O) (N-3 and NCO). Bioisosterism is the procedure of the synthesis of structural analogues of a lead compound by substitution of an atom or a group of atoms in the parent compound for another with similar electronic and steric characteristics. Bioisosetres are functional groups which have similar spatial and electronic character, but they retain the activity of the parent. Bioisosterism is important in medicinal chemistry because: 1 Maintain similar biological properties. 2 Resolved biological problems effectively (potency, side effects, separate40 biologic activities and duration of action)  III- Isosterism and pharmacological activity Friedman defined bio-isosterism as- the phenomenon by which compounds usually fit the broadest definition of isosteres and possess the same type of biological activity. E.g. (Antihistamine; A; B and C) CH2CH3 CH3 CHO CH2CH2 N CHO CH2CH2 N CHO CH2CH2 N CH2CH3 CH3 A B C Compound A has twice the activity of C, and many times greater than B In the above three structure analogues it has been found that A has twice the activity of C, and many times greater than B (open-chain diethylamino analogue).. 41 Classical and non-classical bioisosteres Classical bioisosteres are functional groups or molecules that are known to be interchangeable due to their similar size, shape, and electronic properties. The substitution of one classical bioisostere for another typically maintains similar biological activity. Non-classical bioisosteres are less straightforward in their similarity compared to classical bioisosteres. They may not have similar size or electronic properties but still provide similar biological activity through different mechanisms or by interacting with the same biological targets in a similar way. Classical and non-classical bioisosteres ⚫ for the classical ones, where size equivalence is the key, the replacement should have roughly the same size. ⚫ The key replacements (for example, the C, O, and N replacements are seen for three of the classical isosteres: CH3-,- OH,- NH2 for univalent; ⚫ -CH2-, -O-, and -NH- for divalent; ⚫ and -COCH2-R (ketone), -COOR (ester), and- CONHR (amide) for the carbonyl containing compounds. ⚫ For example we could change the ester alcohol oxygen (not the carbonyl oxygen) with a CH2 (ketone), NH (amide), or S (thioester). 42  All the examples you provided fall under the category of classical isosteric replacements because they involve substituting atoms or groups with similar sizes and properties, allowing the compound to retain its overall biological activity while possibly enhancing its pharmacokinetic and pharmacodynamic profiles. This approach is commonly employed in drug design to optimize the efficacy and safety of therapeutic agents. Non classical Change in Backbone Structure: Changing a linear alkane structure to a cyclic structure while maintaining similar pharmacological effects could be considered a non-classical isosteric modification. Ring Variations: For instance, replacing a six-membered aromatic ring with a five-membered ring (like a furan) that still exhibits the desired biological activity.