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1 Medicinal Chemistry I 1435h Topic 1: Drug Structure & Pharmacological Activity Dr. Munjed Ibrahim

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1 1 Medicinal Chemistry I 1435h Topic 1: Drug Structure & Pharmacological Activity Dr. Munjed Ibrahim

2 2 Resources  Text Reading Reading Foye, Lemke & Williams, 6 th ed, Chapter 2 Foye, Lemke & Williams, 6 th ed, Chapter 2 Foye, Williams & Lemke, 5 th ed, Chapter 2 Foye, Williams & Lemke, 5 th ed, Chapter 2 Suggested additional reading Suggested additional reading An Introduction to Medicinal Chemistry, Patrick L. G., 3edAn Introduction to Medicinal Chemistry, Patrick L. G., 3ed Cairns Chs 1 & 2Cairns Chs 1 & 2 Delgado & Remers Ch 2, pp , Delgado & Remers Ch 2, pp , Foye, 4th ed Chs 3 & 4Foye, 4th ed Chs 3 & 4 Watson Ch 2Watson Ch 2

3 3 Objectives  Relationship of Functional Groups to Pharmacological Activity (SARs)  Physiochemical Properties of drug molecules  Acid - base properties of drug molecules  pH and pKa (Henderson-Hassalbach Equation)  ionisation and absorption  Water and lipid Solubility (hydrogen and ion bonds)  Predicting water solubility Empirical approachEmpirical approach Analytical ApproachAnalytical Approach  Partition coefficient absorption/distributionabsorption/distribution  Stereochemistry and pharmacological activity  Optical isomerism (enantiomers and distereomers)  Conformation isomers  Geometric isomers (cis and trans)  Isosterism and Bioisosterism  drug design

4 4 1.Enzyme inhibition  Enzyme inhibition may be reversible or non-reversible; competitive or non-competitive Sites of Drug Action 2. Drug-Receptor interaction  A receptor is the specific chemical constituents of the cell with which a drug interacts to produce its pharmacological effects  This is usually through specific drug receptor sites known to be located on the membrane 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 ENZYME ENZYME SUBSTRATESUBSTRATE

5 5 Mode of Drug Action  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. The primary effect is the desired therapeutic effect.  Secondary effects are all other effects beside the desired effect which may be either beneficial (good) or harmful (side effects, bad!!).  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

6 6 Mechanisms of Actions of Drugs 1. 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: Physostigmine and neostigmine compete with acetylcholine for cholinesterase Physostigmine and neostigmine compete with acetylcholine for cholinesterase 2. Through Receptors  A large number of drugs act through specific macromolecular components of the cell, which regulate critical functions like enzymatic activity, permeability, structural features, template function  The fundamental mechanisms of drug action can be distinguished into following categories ENZYME ENZYME SUBSTRATESUBSTRATE

7 7 Macromolecular target Drug Unbound drug Macromolecular target Drug Bound drug Bindingsite Drug Binding site Binding regions Binding groups Intermolecular bonds An Introduction to Medicinal Chemistry, Patrick, Third Edition Receptors and Drug Action Pharmacological response

8 8 Drug receptor Active site vdwinteraction ionicbond H-bond Phe Ser O H Asp CO 2 Drug-Receptor Interactions An Introduction to Medicinal Chemistry, Patrick, Third Edition Receptors/enzymes are proteins, so they are amino acids (Asp, Phe, Ser) Receptors/enzymes are proteins, so they are amino acids (Asp, Phe, Ser) amino acids contain: amino acids contain: carboxylic acids (ionic interaction) carboxylic acids (ionic interaction) amines (ionic interaction) amines (ionic interaction) hydroxyl (hydrogen bond) hydroxyl (hydrogen bond)

9 9 Mechanisms of Actions of Drugs 3. Chemical Properties The drugs react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc. The drugs react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc.  Aluminium hydroxide neutralizes acid in stomach  Toxic heavy metals can be eliminated by chelating agents like EDTA, BAL, penicillamine etc.

10 10  If acetylcholine interacts with its receptor, then molecules that are structurally similar to acetylcholine would also interact with the receptor  This is sort of a “lock & key” approach, wherein if you stop acetylcholine from binding to its receptor (by using another molecule that is similar in structure) then you will stop the effect of acetylcholine i.e. acetylcholine causes muscles to contract, if you stop it from binding to its receptor, muscles will therefore relax Antagonists are generally larger in size than the natural substrate Antagonists are generally larger in size than the natural substrateacetylcholine Functional Groups and Pharmacological Activity (Agonist, Antagonists) ENZYME ENZYME SUBSTRATESUBSTRATE

11 11  One feature that soon became apparent to the early scientists was that small changes in structure resulted in significant changes in biological activity: Crum-Brown & Fraser (1869) postulated that “muscle-relaxant activity” was related to quaternary ammonium groups (this was later proved wrong when acetylcholine was discovered)  Crum-Brown & Fraser (1869) postulated that “muscle-relaxant activity” was related to quaternary ammonium groups (this was later proved wrong when acetylcholine was discovered) Functional Groups and Pharmacological Activity

12 12  The discovery of acetylcholine (& its activity) prompted questions as to how a given functional group could have two different biological activities  In the early 20th century, scientists speculated that this could be achieved if “drug receptors” were present Functional Groups and Pharmacological Activity If acetylcholine interacts with its receptor, then molecules that are structurally similar to acetylcholine would also interact with the receptor  If acetylcholine interacts with its receptor, then molecules that are structurally similar to acetylcholine would also interact with the receptor

13 13 Physiochemical Properties  Acid-Base: Conjugate pair theory  Common acidic and basic functional groups W&L Table 2.1 and 2.2 respectively W&L Table 2.1 and 2.2 respectively Shows acids and their conjugate bases together with pK a Shows acids and their conjugate bases together with pK a  Be able to identify these from structures

14 14 Acidic groups (page 29) Acidic groups Table 2.1 (page 29)

15 15 Basic groups Table 2.2 (page 30)

16 16 Neutral groups Table 2.3 (page 30)

17 17  The human body is composed of ~75% water (55 L of water)  For an average drug (MW ~200; dose = 20 mg), this equates to a drug concentration of ~1.8 x M (i.e. a very dilute solution!)  For dilute solutions we use the Brönsted–Lowry theory to predict the behaviors of acids & bases è An Acid is any substance capable of yielding a proton (H + ) è A base is any substance capable of accepting a proton (H + )  Please refer to Table 2.1 (pg. 29, Foye), Table 2.2 (pg. 30, Foye), and Table 2.3 (pg. 30, Foye) Physiochemical Properties – Acids & Bases

18 18  Some drugs have both acidic and basic functional groups, and therefore can act as a base, an acid, or amphoteric (= both acidic & basic properties) Ciprofloxacin Physiochemical Properties – Acids & Bases  The location of the compound in the body will determine the overall charge of the compound

19 19  Henderson-Hasselbach Equation relates pH and pK a (acid strength)  This equation (the Henderson–Hassalbach eqn) allows us to calculate the percent ionisation of a given molecule at a given pH  since pKa is a constant for a given molecule, at a known pH (e.g. physiological) the concentration of the acidic and basic forms of a given drug will be able to be calculated  But why is this important??  percent ionisation (clue to absorption of drug and activity/interactions) Relative Acid Strength (pKa) (Henderson–Hassalbach)

20 20  Look at the sulphonamides (antibacterial)  Why is the following true? These compounds are only active in their ionised forms  These compounds are only active in their ionised forms  Despite only minor differences in half-life and lipo-solubility, there is a huge difference in activity  This is due to their respective pKa values:  For sulfadiazine, at pH 7.4 it is ~80% ionised  For sulfanilamide, at pH 7.4 it is only 0.03% ionised  The difference in pKa is due to the electron withdrawing nature of the sulfonamide nitrogen substituent, thereby stabilising the ionised form: Relative Acid Strength (pKa)

21 21 Ionisation of Drugs  For an acid drug: For a basic drug:  For a basic drug:

22 22 Example: %ionisation for aspirin pK a of aspirin (acetylsalicylic acid) is 3.5 pK a of aspirin (acetylsalicylic acid) is 3.5 Physiological pH = 7.4 Physiological pH = 7.4 For an acid drug

23 23 Rule of Thumb (acids) Weak acids Weak acids pH = pK a compound ~ 50% ionised pH = pK a compound ~ 50% ionised pH = pK a + 1compound ~ 90% ionised pH = pK a + 1compound ~ 90% ionised pH = pK a + 2compound ~ 99% ionised pH = pK a + 2compound ~ 99% ionised pH = pK a + 3compound ~ 99.9% ionised pH = pK a + 3compound ~ 99.9% ionised pH = pK a + 4compound ~ 99.99% ionised pH = pK a + 4compound ~ 99.99% ionised pK a of aspirin is 3.5pK a of aspirin is 3.5 Physiological pH = 7.4Physiological pH = 7.4 pH = pK a + 4 pH = pK a + 4 %ionisation= 99.99%

24 24 Rule of Thumb (bases) Weak bases Weak bases pH = pK a compound ~50%ionised pH = pK a compound ~50%ionised pH = pK a - 1 compound ~ 90% ionised pH = pK a - 1 compound ~ 90% ionised pH = pK a - 2 compound ~ 99% ionised pH = pK a - 2 compound ~ 99% ionised pH = pK a - 3 compound ~ 99.9% ionised pH = pK a - 3 compound ~ 99.9% ionised pH = pK a - 4 compound ~ 99.99% ionised pH = pK a - 4 compound ~ 99.99% ionised pK a of phenylpropanolamine is 9.4pK a of phenylpropanolamine is 9.4 Physiological pH = 7.4Physiological pH = 7.4 pH = pK a - 2 pH = pK a - 2 %ionisation= 99% ionised

25 25 Physical Properties (water and lipid solubility) Partition coefficient Partition coefficient lipophilic vs. hydrophilic character of drug lipophilic vs. hydrophilic character of drug determines water solubility of drug substances determines water solubility of drug substances affects drug distribution affects drug distribution confers target-drug binding interactions confers target-drug binding interactions

26 26 Water Solubility

27 27 Water Solubility  Given that we are ~75% water, the solubility of a drug in water directly affects the route of administration, distribution, and elimination (ADME).  The most important two key factors that influence this are:  Hydrogen bonding: more H-bonds =>  solubility  Ionisation: dissociable ions =>  solubility

28 28 Predicting Water Solubility  Empirical Approach  Analytical Approach

29 29  Lemke has developed an approach to predicting water solubility based upon the “solubilising potential” of various functional groups, versus the number of carbons Given that most drugs are polyfunctional, the second column is most relevant  Given that most drugs are polyfunctional, the second column is most relevant Predicting Water Solubility Empirical Approach

30 30 è We get a total “solubilising potential” of 9 carbons using this theory.  Since the molecule contains 22 carbons, it suggests that the molecule is insoluble in water (USP has water solubility listed as <1g per 10,000ml)  However, if we make the hydrochloride salt, then the compound becomes water soluble è Lemke estimates that a charge (either anionic or cationic) contributes a “solubilising potential” of between 20 and 30 carbons Predicting Water Solubility The Empirical Approach – a working example Anileridine (Narcotic analgesic)

31 31  The alternative approach for predicting water solubility utilises the “logP” of molecules  Essentially, logP is a measure of lipophilicity (hydrophobic) properties of a molecule  It is determined by measuring the “partition coefficient” between water and octanol for a given molecule (i.e. the solubility of the compound in octanol versus the solubility of the compound in water)  Octanol is used as a mimic of the characteristics of a lipid membrane (polar at one end, long hydrocarbon chain at the other)  LogP is calculated by adding the contributions from each functional group in the molecule  A hydrophobic substituent constant π has been assigned to most organic functional groups, such that LogP = ∑ π (fragments) Predicting Water Solubility Analytical Approach

32 32 Predicting Water Solubility Analytical Approach-a working example  Water solubility is defined (by the USP) as greater than 3.3%, or a logP <+ 0.5  Therefore, anileridine, with a logP greater than is considered insoluble  The “ionisation state” of a molecule not only influences water solubility, but also its ability to cross biological barriers or be absorbed  See Fig. 2.15, page 38, Foye’s. Fragment π value

33 33 Stereochemistry and Biological Activity

34 34  The physicochemical properties of a drug are not only influenced by which functional groups are present, but also by the spatial arrangement of groups.  The spatial arrangement of groups is especially important when dealing with biological systems, since receptors are susceptible to the shape of a molecule.  Stereoisomers contain the same number and kinds of atoms, the same arrangement of bonds, but a different spatial arrangement of atoms.  A carbon atom with four different substituents is an asymmetric molecules.  Stereochemistry is primary: –Optical isomerism (Enantiomers, Diastereomers) –Geometric isomerism –Conformational isomerism Stereochemistry and Biological Activity

35 35  Cahn, Ingold & Prelog (1956) devised a system of nomenclature for stereoisomer  Prioritise atoms around a chiral centre, based upon the atomic weight of the atom  Once you have assigned priority from 1 (= highest) to 4 (= lowest), then “look from the chiral centre towards the lowest priority and count from 1 to 3 è If you count clockwise it is “R” è If you count anticlockwise it is “S” Designation of stereoisomerism

36 36  Whilst enantiomers have identical physical properties, they can have very different biological properties (e.g. (+)-asparagine is sweet, whilst (–)-aspargine is tasteless). This was one of the earliest observation by in 1886). (–)-aspargine is tasteless). This was one of the earliest observation by in 1886).  Easson-Stedman hypothesis states that the more potent enantiomer must be involved in a minimum of three interactions with the receptor and that the less potent enantiomer only interacts with two sites  This difference is due to the asymmetry of receptor – ligand interactions Optical Isomers & Biological Activity

37 37 Selective Reactivity - Enantiomers  R-(-)-epinephrine vs. S-(+)-epinephrine –each enantiomer maps to the receptor site differently – (see Foye, Fig 2.19, page 41)

38 38 Diastereomers – Asymmetric Centres Diastereomers:  Stereoisomers with the same number and kinds of atoms, but in a different spatial arrangement (any stereoisomers compound that is not an enantiomer)  These compounds have different physical and chemical properties  These arise from compounds possessing two or more asymmetric centres  Consider isomethadol 2 asymmetric carbons2 asymmetric carbons 4 isomers (2 pairs of enantiomers)4 isomers (2 pairs of enantiomers) only the (3S,5S)-isomer has analgesic activity.only the (3S,5S)-isomer has analgesic activity.

39 39  Most drugs contain more than one chiral centre, so therefore diastereomers become important.  Two chiral centers: up to four stereoisomers, consists of two sets of enanatiomeric pairs. For each enantiomeric pair there is inversion of both chiral ecnters, while in the disteroemers there inversion in only one chiral center. Diasteroemers & Biological Activity

40 40 Enantiomeric Pair Differences Some examples Some examples Isomethadol (cf methadone) - analgesic Isomethadol (cf methadone) - analgesic Acetylisomethadol - transformation induced Acetylisomethadol - transformation induced Etomidate - nonbarbiturate hypnotic Etomidate - nonbarbiturate hypnotic Ibuprofen - NSAID/Analgesic Ibuprofen - NSAID/Analgesic Naproxen - NSAID/Analgesic Naproxen - NSAID/Analgesic Verapamil - Ca channel blocker Verapamil - Ca channel blocker Warfarin - anticoagulant Warfarin - anticoagulant

41 41 Geometric isomers & biological activity  Geometrical isomerism (= restricted rotation) Sometimes E- and Z- becomes difficult to determine when it is less obvious which substituents are the highest priority: Sometimes E- and Z- becomes difficult to determine when it is less obvious which substituents are the highest priority: è The key here is to assign the two groups on each side of the double bond, and then “simply” see if the two highest priority groups are on the same side or opposite sides Z- comes from German “Zusammen” (= together) E- comes from German “Entgegen” (= opposite)

42 42 Geometric isomers & biological activity  cis/trans isomers have different physical properties  distribution in biologic system varies generally leads to distinct biological activity generally leads to distinct biological activity But … difficult to correlate activity differences with stereochemistry alone But … difficult to correlate activity differences with stereochemistry alone eg different pK a s of isomers => different levels of ionisation and hence => differing penetration or absorption eg different pK a s of isomers => different levels of ionisation and hence => differing penetration or absorption

43 43 Cis-trans Spatial arrangement of pharmacophores eg Diethylstilbestrol (W&L p62) eg Diethylstilbestrol (W&L p62) trans isomer more active than cis trans isomer more active than cis cis-diethylstilbestrol trans-diethylstilbestrol

44 44 Conformational Isomers  Conformational isomerism - Eliel’s definition  “... the no identical spatial arrangement of atoms in a molecule, resulting from rotation about one or more single bonds.”  Involves both acyclic and cyclic drug molecules acyclic - flexible - Newman and sawhorse models acyclic - flexible - Newman and sawhorse models cyclic - rigid - chair/boat model of conformers cyclic - rigid - chair/boat model of conformers  cyclic molecules of more interest medicinally

45 45  Endogenous lead compounds often simple and flexible (e.g. adrenaline)  Fit several targets due to different active conformations (e.g. adrenergic receptor types and subtypes)  Rigidify molecule to limit conformations - conformational restraint  Increases activity (more chance of desired active conformation)  Increases selectivity (less chance of undesired active conformations)  Disadvantage:  Molecule more complex and may be more difficult to synthesise Conformational Isomers An Introduction to Medicinal Chemistry, Patrick, Third Edition

46 46 RECEPTOR 1 RECEPTOR 2 Conformational Isomers (Epinephrine) An Introduction to Medicinal Chemistry, Patrick, Third Edition

47 47 Target inetraction site Rotatable bonds An Introduction to Medicinal Chemistry, Patrick, Third Edition

48 48 Target interaction site Rotatable bonds An Introduction to Medicinal Chemistry, Patrick, Third Edition

49 49 Target interaction site Rotatable bonds An Introduction to Medicinal Chemistry, Patrick, Third Edition

50 50 Methods - Introduce rings  Bonds within ring systems are locked and cannot rotate freely Rigidification An Introduction to Medicinal Chemistry, Patrick, Third Edition

51 51 Isosterism and Bioisosterism

52 52  A poor “drug profile” includes issues such as bioavailability, unwanted side effects, inability to cross biological barriers, poor pharmacokinetics.  These undesirable features could be due to specific functional groups in the molecule.  Modify this molecule to reduce these undesirable features WITHOUT losing the desired biological activity with other groups having similar properties is known as ISOSTERIC or BIOISOSTERIC replacement.  In 1919 Langmuir first developed the concept of isosterism to describe the similarities in physical properties among atoms (same number of valence electrons O and S).  In 1925 Grimm developed his hydride displacement law (illustration of similar physical properties among closely related functional groups)  Thus, NH 2 is considered to be isosteric to OH, SH, CH 3 ) Isosterism and Bioisosterism

53 53 Grimm’s isosteres  Descending diagonally from left to right in the table H atoms are added to maintain the same number of valence electrons for each group of atoms within a column.  Each member of a vertical group is isoelectronic

54 54  Initially this concept related to the notion that different functional groups have the same number of valence electrons  NH 2 and OH are considered to be isosteric to each other  Both groups are able to participate in hydrogen bonding interactions  However, NH 2 is basic at physiological pH, which means that changing an OH to an NH 2 would give the molecule a positive charge at physiological pH (& therefore very different pharmacokinetics)  Some isosteric replacements do work well (e.g. replace benzene with pyridine), but it is difficult to generalise between different biological systems Isosterism

55 55  “isosteric replacement” replacement of functional groups, where the chemical group considered to be important for activity is replaced by a different chemical group which has the “same” properties  These “isosteres” are important when considering issues such as water solubility, acidity / basicity, lipophilicity, etc, since sometimes compounds with excellent biological activity have a poor “drug profile” Isosterism and Pharmacological Activity (example)

56 56  This process attempts to overcome the limitations of isosteric replacement by considering not just the similarity in chemical structure between functional groups, but to also look at the biological effects Friedman definition “bio-isosteres are functional groups or molecules that have chemical and physical similarities producing broadly similar biological properties” Friedman definition “bio-isosteres are functional groups or molecules that have chemical and physical similarities producing broadly similar biological properties” Burger definition: “bio-isosteres are compounds or groups that possess near equal molecular shape and volumes, and with exhibit similar physical properties such as hydrophobicity”. Burger definition: “bio-isosteres are compounds or groups that possess near equal molecular shape and volumes, and with exhibit similar physical properties such as hydrophobicity”.  The key point is that the same pharmacological target is influenced by bioisosteres as agonist or antagoinist.  There are two general types of “bio-isosteres” Classical and non-classicalClassical and non-classical Bio-isosterism

57 57  (Monovalent bio-isosteres) A common replacement is F instead of H (in the development of antineoplastic agent 5-fluorouracil from Uracil) A common replacement is F instead of H (in the development of antineoplastic agent 5-fluorouracil from Uracil)  van der Waal’s radii: F = 1.35Å; H = 1.2Å  (therefore very similar steric demand) è The only real difference is electronegativity  Tetravalent bio-isosteres of  -tocopherol:   -tocopherol (when X= C 14 H 29 ) was found to accumulate in heart tissue  All bio-isosteric analogues (when X= NMe 3, PMe 3 Or SMe 2 ) were found to produce similar biological activity X=C 14 H 29 Bio-isosterism… Classical

58 58 Examples of Bio-isosteres (Classical)

59 59  Replace a functional group with another group which retains the same biological activity  Not necessarily the same valency Example:antipsychotics Improved selectivity for D 3 receptor over D 2 receptor Pyrrole ring = bio-isostere for amide group Bioisosterism….Non-Classical An Introduction to Medicinal Chemistry, Patrick, Third Edition


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