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

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

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


H R 0 H 

^ ^ ^ H-bonds 

O R H O 

Antiparallel Chains 

Residues 

/ above 

,X

The tertiary structure of proteins 19 

CD2 

H24 

Fig.


I I I 10 

\\

The tertiary structure of proteins 21 

3.3.1 Covalent bonds 

Covalent bonds


Fig. 3.10 Hydrogen bond. 

3.3.4 Van der Waals bonds 

Bond strength


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.


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


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

R 

The catalytic role of enzymes 

Thymidylate 

Synthetase 

41 

o 

HN X 

R

42 Drug action

I 

NH 2 

CHO 

(OH 

Condensation R< The catalytic role


met in the body and would have shown little or no selectivity. (The uses of alkylating 

agents

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


Fig. 5.5 Binding of a messenger to a receptor. 

reaction takes place, what


Induced Fit 

and 

Opening

How does the message get received? 53 

Receptor 

Enzyme 

Active site 

(open) 


Enzyme 

CD 

MESSENGER 

LJ 


im 

Enzyme 

X 

MESSENGER 


Enzyme 

Fig.


MESSENGER 

MESSENGER 


——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


RECEPTOR 

PROTEIN 

CYTOPLASM 

Fig. 5.12 Receptor protein positioned


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


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


D Neurotransmitter 


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


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


Fig. 6.9 Proflavine. 

best agents

Drugs acting on DNA 75 

CH3—N: 

MECHLORETHAMINE

Ribonucleic acid


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


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


7.5.1 Variation

Synthetic analogues


covered

Synthetic analogues


avoiding patent restrictions

Synthetic analogues


,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


Frequently,

Lead compounds


O 

IIS—NH 

— C—NH-CH2CH 2CH 2CH 3 

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


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


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,


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


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


Me 

AZATHIOPRINE 

6-MERCAPTOPURINE 

Fig. 8.15 Azathioprine acts


Fig. 8.18 

SALICYLIC ACID 

ASPIRIN 

R = H


Many peptides


——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,


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)



words, compounds having



fact true constants and are accurate only for the structures from which they were 

derived. They



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


O—P—OEt 

Fig. 9.11 Diethyl phenyl phosphate. —# Q Et 

membrane

Quantifying steric properties 

Hansch equation 141


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


+ CT 1.0 

NO 2 

• 

CN 

SOjNHj CH3SO2 

3 

* - 50 

. 

CH 3CO 

CONH 2 

.25 

COjH 

-2.0 -1.6 -1.2 -- 8 '- 4 

CH 3CONH 

C? Br 

CF 3 

•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


CH 3 

.—————————————————— Pr« ———————————— 

E 

H, CH 2OCH 3

The Topliss scheme 147 

with a negative a factor (i.e. 4-OMe). If activity improves, further changes are suggested 

to test


A AA N —N\k 

CH 2CH 2CO 2H 

Order of 

Synthesis 

R 

1 

2 

3 

4 

5678 

H 

4-C1 

4-MeO 

3-C1 

3-CF 3 

3-Br 

3-1 

3,5-Cl 2 

Biological 

Activity 

_ 

L 

LMLM 

L 

M 

High 

Potency 

* 

* 

* 

M= More Activity 

L= Less Activity

Planning


activity. For example, a hydrophobia substituent may be favoured in one part of the 

skeleton, while

Case study


group

156 Antibacterial agents 

prontosil

158 Antibacterial agents

Antibacterial agents which

others. 

Antibacterial agents which act against cell metabolism (antimetabolites) 161


MeO 

OMe 

Fig. 10.11 Sulfamethoxine.

Antibacterial agents which act against cell metabolism (antimetabolites) 163 

I 

S—NHR" 

O 

Reversible Inhibition


Fig. 10.15 Sulfonamide prevents PABA from binding



drug would have

Antibacterial agents which inhibit cell wall synthesis 167 

but was actually placed above the surface of the disinfectant. It says much for 

Fleming's observational powers that


-CH2- 

R——C- 

Acyl side chain 

-^- 

Benzyl Penicillin 

PEN G 

-O —CH 2 - 

Phenoxymethylpenicillin 

PEN V

Antibacterial agents which inhibit cell wall synthesis


• Ineffective when taken orally. Penicillin G can only be administered by injection. It 

is ineffective orally since it breaks down in the acid conditions of the stomach.

is tolerated 

Antibacterial agents which inhibit cell wall synthesis 171


H 

^S 

Fig. 10.27 Reduction


The problem of fi-lactamases became critical in 1960 when the widespread use of 

penicillin



Permeability barrier. 

It is difficult for penicillins to invade a Gram-negative bacterial cell due to the make 

up of the cell wall. Gram-negative bacteria have a coating on the outside of their eel 

wall which consists



H0 2C—C—CH 2CH 2CH 2—C—NH| 

Penicillin

groups 


180 

R


probenicid slows down the rate at which penicillin is excreted by competing with it in 

the excretion mechanism. As a result, penicillin levels in the bloodstream are enhanced 

and the antibacterial activity increases—a useful tactic if faced with a particularly 

resistant bacterium. 

10.5.2 Cephalosporins 

Discovery and structure of cephalosporin C 

The second major group of (3-lactam antibiotics to be discovered were the cephalosporins.


Analogues of cephalosporin C by variation of the 7-acylamino side-chain 

Access to analogues with varied side-chains at the 7-position initially posed a problem. 

Unlike penicillins,


Fig. 10.45 Cephalothin. 

CO 2 H 

reacted with an alcohol to give an imino ether. This product is now more susceptible


r\ IU H H


= CH 3 

C0 2Me 

C0 2 Me 

- ttX I 

3 

C0 2 Me 

Fig. 10.48 Synthesis of 3-methylated cephalosporins. 

synthesis, which was first demonstrated by Eli Lilly, involves a ring expansion, where 

the five-membered thiazolidine ring in penicillin is converted to the six-membered 

dihydrothiazine ring



Second- and third-generation cephalosporins—oximinocephalosporins 

Research



Fig. 10.54 Clavulanic acid as an irreversible mechanism based inhibitor. 

Plays a role 

in 6-lactamase •< 

resistance 

Acylamino side Opposite 

chain ^fcsent stereochemistry 

OH i to penicillins 

H N 

/ Carbon 

/ H / 

i^^--\ 

H 3 C^'***', ' 

// 

) ——— S " 

N-*^/^ 

C0 2© 

Carbapenam nucleus 

Fig. 10.55 Thienamycin. 

Double bond leading


Olivanic acids 

The olivanic acids (e.g. MM13902) (Fig. 10.56) were isolated from strains of Streptomyces 

olivaceus

192 Antibacterial agents



[Normal Mechanism) 

Peptide 

Chain 

^ — c* D-Ala—D-Ala —COzH 

OH 

/Transpeptidase Enzyme 

Peptide 

Chain 

C 

^— D-Ala 

I 

X X 

Peptide 

Peptide 

Peplide Chain 

Chain ^> 

X-D-Ala——Gly 

[Mechanism Inhibited



L-Valine Me 

L-Lactate 

D-Valine 

Me 

NH / 

D ' Hyi 

D-Valine 

D-Hyi = 

D-Hydroxyisovaleric acid 

D-Hyi 

Fig. 10.64 Valinomycin. 

groups



L-LEU — L-DAB 

/ \ 

D-PHE 

L-DAB 

L-DAB 

L-DAB 

L-DAB 

L-THR 

POLYMYXIN B 

L-DAB 

C=0 

I 

(CH 2) 4 

CH-CH 3 

Fig. 10.69 Polypeptide antibiotic. CH 2 CH 3 

such as nucleosides from the cell. The drug is injected intramuscularly and is useful 

against Pseudomonas strains which are resistant to other antibacterial agents. 

10.7 Antibacterial agents which impair protein synthesis 

Examples of such agents are the rifamycins which act against RNA, and the aminoglycosides, 

tetracyclines, and chloramphenicol which all act against the ribosomes. 

Selective toxicity

Antibacterial agents which impair protein synthesis


which was discovered in 1948. It is a broad-spectrum antibiotic, active against both 

Gram-positive and Gram-negative bacteria. Unfortunately, it does have side-effects

Agents which


o 

,CO2H 

HN > J Cl-LCKt, HNL 

NALIDIXIC ACID ENOXACILIN CIPROFLOXACIN 

Fig. 10.74 Quinolones and fluoroquinolones. 

compounds. It is active against Gram-negative bacteria and is useful in the short-term 

therapy

Drug resistance 203 

10.9 Drug resistance 

With such


transferred by means of bacterial viruses (bacteriophages) leaving the resistant cell 

and infecting a non-resistant cell. If the plasmid brought to the infected cell contains 

the gene required for drug resistance, then the recipient cell will be able to use that 

information and gain resistance. For example, the genetic information required to 

synthesize (3-lactamases can be passed on in this way, rendering bacteria resistant to 

penicillins.

11- The peripheral nervous 

system—cholinergics, 

anticholinergics, and 

anticholinesterases 

In Chapter 10, we discussed the medicinal chemistry of antibacterial agents and noted

206 The peripheral nervous system 

your home computer software, or perhaps trying to trace where a missing letter went, 

or finding the reason for the country's balance of payments deficit. 

However,

Motor nerves


Skeletal 

" Muscle 

SOMATIC 

AUTONOMIC 

Smooth Muscle 

Cardiac Muscle 

Fig. 11.2 Motor nerves of the peripheral nervous system. N, Nicotinic receptor; 

M, muscarinic receptor. 

parasympathetic nerves. However, they synapse with different receptors on the 

target organs

Actions


Note that the sympathetic and parasympathetic nervous systems oppose each other in 

their actions and could be looked upon as a brake and an accelerator. The analogy is

The cholinergic system 211 

I 

j 

V 

Acetyl 

| Choline


11.6 Agonists at the cholinergic receptor 

One point might have occurred to the reader. If there is a lack of acetylcholine acting 

at

Agonists

Agonists at the cholinergic receptor 215 

RECEPTOR SITE 

(MUSCARINIC) 

Fig. 11.11

Agonists at the cholinergic receptor 217 

but since they are ring structures, the left-hand portion of the acetylcholine molecule 

is

Water 

Design of acetylcholine analogues 219

220 The peripheral nervous system

Design

Antagonists


Hyoscine (1879-84) 

Hyoscine

Structural analogues based 

Antagonists of the muscarinic cholinergic receptor 225

A large variety 

Antagonists of the muscarinic cholinergic receptor 227


In practice, the procedure is not always as simple as this, since the highly react 

electrophilic centre might react with another nucleophilic group before it reaches 

receptor binding site.



pleasing that theory



; ^.---- Acetyl choline 

skeleton 

Atracurium 

Acetyl choline ----- '^X^-^/' 

skeleton 

Fig. 11.39 Pancuronium and vecuronium. 

R = H VECURONIUM 

R = Me PANCURONIUM 

The design of atracurium (Fig. 11.40) was based on the structures of tubocurarine and 

suxamethonium. It is superior to both since it lacks cardiac side-effects and is rapidly 

broken down in blood. This rapid breakdown allows the drug to be administered as an 

intravenous drip. 

MeO, 

OMe 

MeO' 

Me 

CH: 

,CH2-C—O—(CH2)5—O—C—CH2 

'OMe 

OMe 

'OMe 

Fig. 11.40 

MeO' 

Atracurium. 

OMe

drug design 

Other cholinergic antagonists 233

Anticholinesterases

Anticholinesterases


ro 

^ii 0 

CH3 —C —O —CH2CH2NMe3 '0- fn 

x I " *> u 0 

» 

i •*' ^r NH StageB ^v^&v ^ CH3 - "" C^\ ^/^NH Stage 

O N I ———— O

Anticholinesterase drugs 239 

- PyrrolidineN 

Fig. 11.48 Physostigmine. 

Me 

discovered in 1864 as a product of the poisonous calabar beans from West Africa. The 

structure was established in 1925 (Fig. 11.48). 

Structure-activity relationships :

Anticholinesterase drugs


Me 

O

Anticholinesterase drugs


Fortunately, there

Pralidoxime—an organophosphate antidote

N—CH 3 

MeO. 

R'O* 

R

248 The opium analgesics 

Chinese decision—one

Morphine 249 

12.2 Morphine 

12.2.1 Structure and properties 

MeN 

N—CH3 

N——CH3 

Fig. 12.2 Structure

Morphine

Morphine 253 

To conclude, the 6-hydroxyl group is not required for analgesic activity and its 

removal can be beneficial to analgesic activity. 

The double bond at 7-8 

Several analogues including dihydromorphine (Fig. 12.6) have shown that

Development of morphine analogues 255 

morphine. Let us consider a diagrammatic representation of morphine as a T-shaped 

block with

Development


R= ——CH 2 -CH=CH 2 

^ Allyl_______ 

Antagonists 

NALORPHINE 

NALOXONE 

Fig. 12.16


But how can this be? How can a compound be an antagonist of morphine but also 

act


(A) BINDING

Development


morphine. Notice that the two methyl groups in metazocine are cis with respect to 

each other and represent the 'stumps' of the C ring. 

If

Development


o 

N——C—CH=CH-Ph 

Et °2 C \__/ V.^V^ ^£--—N——C—CH=CH-Ph 

H 

\ 

Fig. 12.23 Effect 

3Qx more potent than pethidine 

Zero Activity


Chiral Centre 

R


morphine


RMgBr 

NMe 

Grignard 

NMe 

MeO 

MeO 

Fig. 12.28 Drug extension. 

MeN 

' 

[Complcxedl 

MeN 

Fig. 12.29 Grignard reaction leads

Receptor theory


analgesic has to cross the blood-brain barrier as the free base, but once across has to 

be ionized in order to interact with the receptor.

Receptor theory


acts as a partial agonist at the JJL receptor to produce its analgesic effect. This might 

suggest that buprenorphine should suffer the same side-effects as morphine. The fact 

that

Agonists

Enkephalins

e 

Receptor mechanisms 277


narcotic analgesics. There is still a search to see if there are possibly two slightly 

different mu receptors, one which is solely due to analgesia and one responsible for 

the side-effects. 

12.7.2

membrane to a second membrane-bound protein. 

This protein then acts 

The future 279


O 

II 

N —C-CH 2 

N-CH2-^ 

Ethylketocyclazocine 

(Kappa=mu > delta) 

U 50488 

(kappa

284 Cimetidine—a rational approach to drug design 

13.3 Histamine 

Histamine

Searching

Searching

Searching for a lead—AT-guanylhistamine 289 

as long as A/^-guanylhistamine is bound to the receptor, it prevents histamine from 

binding


reach

Developing the lead—a chelation bonding theory 291 

HN 

cH 2 -cH 2 -x—c' 

N—I 

H 

H 

Strong 

Interaction 

Weak 

Interaction 

>- 

RECEPTOR 

X=NH, S 

RECEPTOR 

X=Me,

From partial agonist

Development of metiamide 295 

meaning that the ring is a weak base and mostly un-ionized. The pK a value for 

imidazole itself

Development of metiamide 297 

the same pK a as for imidazole itself, which shows that the electronic effects of the 

methyl group and the side-chain are cancelling each other out as far as pK a is 

concerned.) A pK a of 6.80 means that 20 per cent of metiamide is ionized in the 

imidazole ring. However, this is still significantly lower than the corresponding 40 per 

cent

Development

Cimetidine

Further studies—cimetidine analogues

304 Cimetidine — a rational approach to drug design 

they are likely to be highly solvated (i.e. surrounded by a 'water coat'). Before 

hydrogen bonding can take place to the receptor , this 'water coat' has to be removed. 

The more solvated the group, the more difficult that will be.

Further studies—cimetidine analogues


Me 

N P* 

/ \ 

Fig. 13.50 Cimetidine analogue with a 

nitroketeneaminal group. 

HN^\ 

I V-CH 2-S—CH 2-CH 2-NH-C V 

l^_ 

# H

Further studies—cimetidine analogues 

NC, 

OjjN 

"S, 

=-6 

=16.7 

I * ^H 

k 

4> =27 

H =14.2 

NMe 

H 

=33 

=15.1 

Fig. 13.53 Dipole moments


dipole moment

Famotidine and nizatidine 309 

• Replacing the sulfur atom with a methylene unit leads to a drop in activity. 

• Placing the sulfur next to the ring lowers activity. 

• Replacing the furan ring with more hydrophobic rings such as phenyl or thiophene 

reduces activity.


effects.

Appendix

Appendix

(vesicles) containing 

The action of nerves 315

a 

The action of nerves 317

The action of nerves 319 

x 

Briv "-

Appendix

Secondary messengers

322 Secondary messengers 

number

Secondary messengers 323 

the process shown 

o=co=

Secondary messengers

Appendix 4 • Bacteria and 

bacterial nomenclature 

Bacterial nomenclature 

COCCI 

(Spherical) 

BACILLI 

(Cylindrical) 

STREPTOCOCCI 

(Chains) 

Fig. A4.1 Bacterial nomenclature. 

STAPHYLOCOCCI 

(Clusters) 

Some clinically important bacteria 

Organism 

Staphylococcus aureus 

Gram 

Positive 

Infections 

Skin 

Streptococcus 

Escherichia coli 

Positive 

Negative 

Proteus species 

Salmonella species 

Shigella species 

Enterobacter species 

Pseudomonas aeruginosa 

Negative 

Negative 

Negative 

Negative 

Negative

Haemophilus influenzae 

Bacteroides fragilis 

Negative 

Negative 

Bacteria and bacterial nomenclature 327 

patients, i.e. cancer patients, commonly causes 

chest infections

Glossary 

ADDICTION 

Addiction can be defined as a habitual form of behaviour. It need not be harmful.

Glossary

Further reading 

Albert,

Index 

acetylcholine 47-8, 207, 209-26, 

229-40, 243, 282, 315,

drug 

addiction 1, 3, 5, 127, 248, 

262-3, 271-2, 

Index 333

334 Index 

intestinal infections

penillic acids 172 

pentagastrin 

Index 335

336 Index 

structure-activity analysis (SAR) 

82, 84-9, 248 

acetylcholine 214-15 

aryl tetrazolylalkanoic acids 

147-8 

benzenesulfonamides

An Introduction to Medicinal Chemistry

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