An Introduction to. Medicinal Chemistry

An Introduction to Medicinal Chemistry GRAHAM

Oxford University Press, Walton Street, Oxford OX2 6DP Oxford

Preface This text is aimed at undergraduates who have a basic grounding in chemistry and are interested in a future career in the pharmaceutical industry. It attempts to convey something

Acknowledgements Figure

Contents Classification of drugs xiii 1. Drugs

viii Contents

Contents

x Contents 10.5 Antibacterial agents which inhibit cell wall synthesis 166 10.5.1 Penicillins 166 10.5.2 Cephalosporins

Contents xi 11.16.2 Structure

xii Contents 13.12.1 Conformational isomers 302 13.12.2 Desolvation 303 13.13 Variation

Classification of drugs

xiv Classification

1 Drugs and the medicinal chemist In medicinal chemistry, the chemist attempts to design and synthesize a medicine or a pharmaceutical agent which will benefit humanity. Such

Drugs

Whilst penicillin Drugs and the medicinal chemist 3

4 Drugs and the medicinal chemist The drug is called diamorphine and it is the drug of choice when treating patients dying

Drugs

Drugs

10 The why and the wherefore Cytoplasm Nucleus Nuclear membrane Cell membrane Fig. 2.1 A typical cell. Taken from J. Mann, Murder, magic, and medicine, Oxford University Press (1992), with permission. Polar Head Group Polar Head Group Hydrophobia Tails Hydrophobia Tails Fig.

Where

12

Where do drugs work? 13 Amphotericin is a fascinating molecule in that one half of the structure is made up of double bonds and is hydrophobic, while the other half contains a series of hydroxyl groups

14

3 Protein structure In order to understand how drugs interact with proteins, it is necessary to understand their structure. Proteins have four levels of structure primary, secondary, tertiary, and quaternary. 3.1 The primary structure of proteins

16 Protein structure [ H O

18 Protein structure H R 0 H ^ ^ ^ H-bonds O R H O Antiparallel Chains Residues / above,x

The tertiary structure of proteins 19 CD2 H24 Fig.

20 Protein structure I I I 10 \\

The tertiary structure of proteins 21 3.3.1 Covalent bonds Covalent bonds

22 Protein structure Fig. 3.10 Hydrogen bond. 3.3.4 Van der Waals bonds Bond strength

24 Protein structure H-Bond Peptidef Chain r Peptide Chain Fig. 3.14 Bonding interactions with water. Therefore,

The quaternary structure of proteins 25 number of ionic and hydrogen bonds contributing to the tertiary structure is reduced.

26 Protein structure again that tertiary structure

28 Drug action at enzymes Energy Transition State New Transition State Product WITHOUT CATALYST WITH CATALYST Product Fig. 4.2 Activation energy. Energy difference

Substrate binding

32 Drug action at enzymes Fig.

Substrate binding at an active site 33 unable to accept any more substrate. Therefore, the bonding interactions between substrate and enzyme have to be properly balanced such that they are strong enough to keep

34 Drug action

Substrate binding

The catalytic role of enzymes 37 Fig. 4.16 6-Mercaptopurine. an example of an allosteric inhibitor. It inhibits the first enzyme involved in the synthesis of purines and therefore blocks purine synthesis. This in turn blocks DNA synthesis. 4.5 The catalytic role of enzymes We

The catalytic role of enzymes 41 R Thymidylate Synthetase HN X o R

42 Drug action

The catalytic role I NH 2 CHO (OH Condensation R<

44 Drug action at enzymes met in the body and would have shown little or no selectivity. (The uses of alkylating agents

5

Nerve Neurotransmitters

48 Drug action at receptors CH 2 + xnme3 NHR Acetylcholine R=H Noradrenaline R=Me Adrenaline NH Dopamine Serotonin H 2NL CH 2 k CH 2 5-Hydroxytryptamine Fig. Gamma-aminobutanoic acid

Receptors

50 Drug action at receptors Fig. 5.5 Binding of a messenger to a receptor. reaction takes place, what

52 Drug action at receptors Induced Fit and Opening

How does the message get received? 53 Receptor Enzyme Active site (open) Receptor Enzyme CD MESSENGER LJ Receptor im Enzyme X MESSENGER Receptor Enzyme Fig.

54 Drug action at receptors MESSENGER MESSENGER Receptor v^/ Enzyme No Reaction Fig. 5.10 Membrane-bound enzyme deactivation. change in shape conceals the active site, shutting down that particular reaction (Fig. 5.10). Neurotransmitters switch

process whereby How does a receptor change shape? 55

56 Drug action at receptors RECEPTOR PROTEIN CYTOPLASM Fig. 5.12 Receptor protein positioned

58 Drug action at receptors neurotransmitter. The binding forces must be strong enough to bind the neurotransmitter effectively such that the receptor changes shape. However, the binding forces cannot be too strong, or else the neurotransmitter would not be able to leave and the receptor would not be able to return to its original shape. Therefore, it is reasonable to assume that

60 Drug action at receptors left-handed ammo acids) are also present as single enantiomers and therefore catalyse enantiospecific reactions reactions which give only

A thorough understanding The design of antagonists 61

62 Drug action

Partial agonists 63 RECEPTOR RECEPTOR Fig. 5.22 Antagonism

64 Drug action

Tolerance and dependence 65 5.9 Desensitization Some drugs bind relatively strongly

66 Drug action at receptors D Neurotransmitter Receptor Synthesis \ u \ I// u. D Increase Antagonist D Fig. 5.26 Process of increasing cell sensitivity. for what little neurotransmitter

Tolerance and dependence 67 level. During this period, the patient may be tempted to take the drug again in order to 'return

Structure of DNA 69 NH 2 NHo NHo Adenine Guanine. ^Cytosine H Thymi Purines Fig. Pyrimidines

70 Nucleic acids 6.1.2

Structure

72 Nucleic acids able to coil into a 3D shape and this is known as super-coiling. During replication, the double strand of DNA must unravel, but due to the tertiary supercoiling this leads to a high level

Drugs acting

74 Nucleic acids Fig. 6.9 Proflavine. best agents

Drugs acting on DNA 75 CH3 N: MECHLORETHAMINE

Ribonucleic acid

78 Nucleic acids end AMINO «A/* Base Pairing ml Methylmosine I Ino.ic UH 2 Dihydraundine

Ribonucleic acid 79 GROWING PROTEIN Growing Protein Fig. 6.19 Protein synthesis. Messenger

Summary 81

the never-ending quest Structure determination 83

84 Drug development

Structure-activity relationships

86 Drug development Potential Ionic Binding Sites O Potential

Structure-activity relationships

88 Drug development bonding or not, it could be replaced with an isosteric group such as methyl (see later). This would be more conclusive, but synthesis is more difficult. Another possibility

Synthetic analogues

90 Drug development 7.5.1 Variation

Synthetic analogues

92 Drug development covered

Synthetic analogues

94 Drug development avoiding patent restrictions

Synthetic analogues

96 Drug development,oh OH GLIPINE A Fig. 7.20 Glipine analogues. B Me- COCAINE H Et 2NCH 2CH 2 O C O PROCAINE Fig. 7.21 Cocaine

Receptor theories 97 NH 2 Me BOND ROTATION RECEPTOR 1 RECEPTOR

Receptor theories

102 Drug development Frequently,

Lead compounds

104 Drug development O IIS NH C NH-CH2CH2CH2CH3 O O Fig. 7.29 Cimetidine. Fig. 7.30 Tolbutamide. described above. Clearly, this is a more demanding objective, but the cimetidine story proves that

A case study oxamniquine

Et 2NCH 2CH 2 CH 2NEt 2

A case study oxamniquine

108 Drug development Zero Activity Fig. 7.39 Addition of a methyl group. _ Net [ CH 2- CH 2-NH 2R

A case study oxamniquine 109 CH 3 Cl Fig. 7.42 Structure V. CH 2 OH Fig. 7.43 Oxamniquine. Adding

110 Drug development found

112 Pharmacodynamics stream. Thirdly,

Drug distribution and 'survival' 113 OXIDATIONS (catalysed by cytochrome P-450) Oxidation

Drug dose levels 115 can easily negotiate the fatty cell membranes get mopped up by fat tissue or are too weak to bind to their receptor sites. Consequently,

116 Pharmacodynamics Drugs

Drug design for pharmacokinetic problems 117 NH C CH 2CH2NEt 2 LIDOCAINE A further example of these tactics is provided in the penicillin field with methicillin (Chapter 10). 8.3.3 Metabolic blockers Some drugs

118 Pharmacodynamics Other common metabolic reactions include aliphatic and aromatic C-hydroxylations (Fig. 8.7), N- and S-oxidations, O- and S-dealkylations, and deamination. Susceptible groups

Drug design

120 Pharmacodynamics

Drug design for pharmacokinetic problems 121 Blood Suppy Brain Cells H2N^ COOH COOH L-Dopa ^N Enzyme Dopamine Fig. 8.14 Transport

122 Pharmacodynamics Me AZATHIOPRINE 6-MERCAPTOPURINE Fig. 8.15 Azathioprine acts

Drug design for pharmacokinetic problems 123 Fig. 8.18 SALICYLIC ACID ASPIRIN R = H

124 Pharmacodynamics Many peptides

Drug design for pharmacokinetic problems 125 C O CH 2CH 2NEt 2 O ADRENALINE PROCAINE Fig. 8.22 used successfully in this respect and effectively inhibits dopa decarboxylase. Furthermore, since it is a highly polar compound containing two phenolic groups, a hydrazine moiety,

126 Pharmacodynamics 8.3.9 Self-destruct drugs Occasionally, the problems faced are completely the opposite of those mentioned above.

grown Neurotransmitters as drugs? 127

Graphs and equations 129 What are these physicochemical features which we have mentioned? Essentially, they refer

130 Quantitative structure-activity relationships (QSAR) Log(l/C) Fig.

Physicochemical properties

132 Quantitative structure-activity relationships (QSAR)

Physicochemical properties

134 Quantitative structure-activity relationships (QSAR) words, compounds having

Physicochemical properties

136 Quantitative structure-activity relationships (QSAR) fact true constants and are accurate only for the structures from which they were derived. They

Physicochemical properties

138 Quantitative structure-activity relationships (QSAR) Benzole acids containing electron donating substituents will have smaller K x values than benzoic acid itself and hence the value of a

Meta Hydroxyl Group Physicochemical properties 139

140 Quantitative structure-activity relationships (QSAR) O P OEt Fig. 9.11 Diethyl phenyl phosphate. # Q Et membrane

Quantifying steric properties Hansch equation 141

142 Quantitative structure-activity relationships (QSAR) activity is related to only one such property, a simple equation can be drawn up. However, the biological activity of most drugs is related to a combination of physicochemical properties. In such cases, simple equations involving only one parameter are relevant only if the other parameters are kept constant. In reality, this is not easy to achieve and equations which relate biological activity to more than one parameter are more common. These equations are known as Hansch equations and they usually relate biological activity

log [I] The Craig plot 143

144 Quantitative structure-activity relationships (QSAR) + CT 1.0 NO 2 SOjNHj CH3SO2 3. CONH 2 CN * CH 3CO -2.0-1.6-1.2 -- 8 '- 4 CH 3CONH COjH - 50.25 CF 3 C? Br OCF 3.4.8 1.2 1.6 2.0 + + T 7C OH OCH 3..-.50 t-butyl NMej -.75 - CT..-1.0 Fig. 9.16 Craig plot. 9.16

The Topliss scheme 145 and electron withdrawing properties (positive IT and positive a), whereas an OH substituent

146 Quantitative structure-activity relationships (QSAR) H, CH 2OCH 3 CH 3. Pr«E

The Topliss scheme 147 with a negative a factor (i.e. 4-OMe). If activity improves, further changes are suggested to test

148 Quantitative structure-activity relationships (QSAR) Order of Synthesis R Biological Activity High Potency A AA N N\k CH2CH2CO2H 1 2 3 4 56 7 8 H 4-C1 4-MeO 3-C1 3-CF 3 3-Br 3-1 3,5-Cl 2 _ L LM L M L M * * * M= More Activity L= Less Activity

Planning

150 Quantitative structure-activity relationships (QSAR) activity. For example, a hydrophobia substituent may be favoured in one part of the skeleton, while

Case study

152 Quantitative structure-activity relationships (QSAR) group