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22 Pharmaceutical Chemistry
measurements and biological assays. QSARs currently are being applied in many
disciplines, with many pertaining to drug design and environmental risk assessment.
1.6 ROLE OF NATURAL PRODUCTS IN TARGET IDENTIFICATION
Various biologically active natural products play a key role in the identification and
characterization of receptors and such receptors are often named after these compounds.
Morphine is a classical example of a natural product used for receptor characterization.
Radiolabelled morphine was shown to bind with high affinity to receptors in the nervous
system and these receptors were, and still are, named opiate receptors. Some three decades
ago, the physiological relevance of these receptors was documented by the findings that
endogenous peptides, notably enkephalins and endorphins, served as receptor ligands
(agonists). Analogues of morphine have been useful tools for the demonstration of
heterogeneity of opiate receptor.
The key toxic and convulsive alkaloid, strychnine, has been extensively studied
pharmacologically. Using electrophysiological techniques and triturated strychnine for
binding studies, strychnine was shown to be an antagonist for the neuroreceptor mediating
the inhibitory effect of glycine, primarily in the spinal cord. This receptor is currently
named the strychnine-sensitive glycine receptor or the glycine
receptor (Fig. 1.12).
A
HO
O
OH
Ryanodine
HO
OH
OH
OH
O
O
O
Muscarine
NH
N
O
Thapsigargin
N
Nicotine
O
O
O
N
Fig. 1.12: Strychnine-sensitive glycine receptors
O
O
O
O
OH
O
OH
O
O
Strychnine
N
N
O
Acetylcholine is a key transmitter in the central and the peripheral nervous system.
Acetylcholine operates through multiple receptors, and the original distribution of receptor
heterogeneity was achieved using the naturally occurring compounds, nicotine and
muscarine. Whereas the ionotropic class of acetylcholine receptors binds nicotine with
high affinity and selectivity, muscarine potently activates the metabotropic class of these
receptors. Using molecular biological techniques including SAR, a number of subtypes of
both nicotinic and muscarinic acetylcholine receptors have been identified and characterized.
Drug Discovery, Design and Development 23
The ryanodine receptor is named after the insecticidal naturally occurring compound,
ryanodine. Extensive studies have disclosed that ryanodine interacts with high affinity
and in a Ca-dependent manner with its receptor, which functions as a Ca-release channel.
There are three genetically distinct isoforms of the ryanodine receptor, which play a role
in the skeletal muscle disorder, and central core disease.
The sesquiterpene lactone, thapsigargin, which is structurally unrelated to ryanodine,
also interacts with an intracellular Ca-mechanism. Thapsigargin has become the key
pharmacological tool for the characterization of the sarco(endo)plasmic reticulum Ca
2+
ATPase (SERCA). Thapsigargin effectively inhibits this ATPase, causing a rise in the
cytosolic Ca-level, which eventually leads to cell death. Although, the SERCA pump is
essential for all cell types, attempts to target thapsigargin towards prostate cancer cells
have been made based on a prodrug approach.
1.6.1 Natural Products as Lead Structures
Although a number of biologically active natural products have been indispensable as
tools for identification and characterization of pharmacological and potential therapeutic
targets, these compounds normally do not satisfy the multiple demands on drugs for
therapeutic use. Thus, although morphine is used therapeutically, it is not an ideal drug,
and has to some extent been replaced by a number of analogues showing slightly lower
side effects and higher degrees of selectivity for subtypes of opiate receptors. Prominent
examples are the Ǎ-selective opiate agonist, fentanyl, and U50488, which selectively
activates the Nj-subtype of opiate receptors (Fig. 1.13).
H2N
Fentanyl
O
Muscimol
N
N
N N
OH
N
O
U50488
O
OH
OH
HO
N
N
Varenicline
Cl
Cl
Fig. 1.13: Nj-Subtype of opiate receptors
CP55940
NH
O
N
Cytisine
HN
THIP (Gaboxadol)
N
H
OH
O
Tetrahydrocannabinol (THC)
O
N
Pro
OH
O
OH
N
Captopril
Gln
Pro
O
Ile
OH
Try
O
HS
Arg
Pro
Teprotide
N
O
O
N
H
24 Pharmaceutical Chemistry
The main psychoactive constituent of Cannabis sativa, the highly lipophilic
tetrahydrocannabinol (THC) has been a useful tool for the identification of the two
cannabinoid receptors, CB
and CB2, operated by endocannabinoids. Since different
1
preparations of C. Sativa have psychoactive effects, health authorities have been reluctant
to accept THC and analogues as therapeutic agents for the treatment of pain and other
disease related conditions. This may change with time, as medicinal chemists have
synthesized a number of cannabinoid receptor ligands, including the receptor agonist
CP55940, which is markedly less lipophilic than THC.
The nicotine acetylcholine receptors (nAChRs) have become a key target for therapeutic
approaches to treat pain, cognition disorders, depression, schizophrenia, and nicotine
dependence. For several reasons, nicotine has limited utility as a therapeutic agent, and a
wide variety of nAChR agonists have been synthesized and characterized. (-)Cytisine is a
naturally occurring toxin acting as a powerful nAChR agonist. Using (-)Cytisine as a lead
structure, varenicline was developed as a partial nAChR agonist showing an optimally
balanced agonist/antagonist profile for smoking cessation.
Muscimol is a naturally occurring toxin, which has been extensively used as a lead for
the design of specific J-aminobutyric acid (GABA) receptor agonists and GABA uptake
inhibitors. Muscimol, a 3-isoxazolol bioisostere of GABA, is a constituent of the mushroom
Amanita muscaria. It is toxic, metabolically unstable, and interacts with different GABA
synaptic machanisms and with a broad range of GABA
receptor subtypes. The cyclic
A
analogue of muscimol, THIP (Gaboxadol) is highly selective for the therapeutically
interesting extrasynaptic GABA
receptors. Gaboxadol is a clinically active nonopioid
A
analgesic and nonbenzodiazepine hypnotic, which is in clinical trials at present.
The angiotensin-converting enzymes (ACE), is a Zn carboxypeptidase centrally involved
in the regulation of blood pressure and is an important target for therapeutic intervention.
Peptide toxins from the Brazilian pit viper, Bothrops jararaca and the synthetic peptide
analogue, teprotide, are inhibitors of ACE, but are not suitable for therapeutic use.
Systematic molecular dissections of teprotide lead to the nonpeptide ACE inhibitor,
N-succinylproline, which has converted into the structurally related and much more
potent analogue. Captopril, is now marketed as an effective antihypertensive drug.
1.7 BIOISOSTERISM
In the broadest sense of the term, bioisosteres are defined as functional groups or molecules
that produce a similar biological effect. The tactics of bioisosterism, also named molecular
mimicry, has been extensively used by medicinal chemists in the optimization of drug
molecules pharmacodynamically or pharmacokinetically.
Bioisosteres have been classified as either classical or nonclassical. In classical
bioisosterism, similarities in certain physiochemical properties have enabled investigators
to successfully exploit several monovalent isosteres. These can be divided into following
groups:
Drug Discovery, Design and Development 25
Fluorine versus hydrogen replacement
Amino-hydroxy interchanges
Thiol-hydroxyl interchanges
Fluorine, hydroxyl, amino, and methyl group interchanges (Grimm’s hydride
displacement law, referring to the different number of H-atoms in the isosteric
groups to compensate for valence differences).
The nonclassical bioisosteres include all those replacements that are not defined by the
classical definition of bioisosteres. These isosteres are capable of maintaining similar
biological activity by mimicking the spatial arrangement, electronic properties, or some
other physicochemical properties of the molecule or functional group that are of critical
importance. The concept of nonclassical bioisosterism, in particular, is often considered to
be qualitative and intuitive, but there are numerous examples of effective use of this
concept in drug design.
The conversion of the muscarinic acetylcholine receptor agonist is coline containing a
hydrolysable ester group, into different hydrolysis-resistant heterocyclic bioisosteres (Fig.
1.14).
Me
N
O
A6
O
N
Me
Arecoline
OMe
N
O
OMe
N
Me
A1 A2 A3 A4, Z = O
N
Me
Fig. 1.14: Arecoline and analogues
O
N
N
OMe
N
Me
N
N
N
Me
N
N
Me
A5
N
, Z = S
Me
N
Z
N
Me
The annulated (A1) and nonannulated (A2 and A3) bicyclic bioisosteres are potent
muscarinic agonists. Similarly, compounds A4 and A5 interact potently with muscarinic
receptors as agonists, whereas A6 in which the 1,2,4-oxadiazole ester bioisosteric group of
A4 is replaced by an oxazole group, shows reduced muscarinic agonist effects. Thus, the
electronic effects associated with these heterocyclic rings appear to be essential for
muscarinic activity.
It must be emphasized that a bioisosteric replacement strategy, which has been successful
for a particular group of pharmacologically active compounds, cannot necessarily be
effectively used in other groups of compounds active at other pharmacological targets.
1.8 ROLE OF STEREOCHEMISTRY IN DRUG DISCOVERY
Receptors, enzymes and other pharmacological targets are composed of proteins, which
are highly chiral. Thus, it is not surprising that chirality in the drug structures normally
plays an important role in pharmacological responses. In a racemic drug candidate, the
26 Pharmaceutical Chemistry
desired pharmacological effects typically reside in one enantiomer, whereas the other
stereoisomer(s) are pharmacologically inactive or possess different pharmacological
effects. Thus, chiral drugs should preferentially be resolved into stereochemically pure
isomers prior to pharmacological examination.
Figure 1.15 includes four stereoisomers of A6, which actually are two pairs of enantiomers
of two diastereomeric compounds. These 1-piperazino-3-phenylindans were synthesized,
resolved, structurally analysed, and pharmacologically characterized as part of a
comprehensive drug research programme in the field of central biogenic amine
neurotransmission. Whereas one of these stereoisomers turned out to be inactive, two of
them were inhibitors of dopamine (DOPA) and noradrenaline (NE) uptake, and one isomer
showed antagonist effects at DOPA, NE, and serotonin (5-HT) receptors. It is evident that
pharmacological characterization of a synthetic mixture of these compounds would be
meaningless.
The 3-isoxazolol amino acid, (RS)-2-Amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)
propionic acid (APPA), is an analogue of the standard agonist, D-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid receptor (AMPA or quisqualate receptor), for the AMPA
subgroup of excitatory glutamate receptors. APPA was tested pharmacologically as the
racemate, which showed the characteristic of a partial agonist at AMPA receptors.
Subsequent pharmacological characterization of the pure enantiomers quite surprisingly
disclosed that (S)-APPA is a full AMPA receptor agonist, whereas (R)-APPA has no AMPA
antagonist activity. This observation prompted intensive pharmacological studies, and as
a result it was demonstrated that administration of a fixed ratio of an agonist and a
competitive antagonist always provides a partial agonist response at an efficacy level
dependent on the administered ratio of compounds and their relative potencies as agonist
and antagonist. This phenomenon was named “functional partial agonism”. An interesting
aspect of this pharmacological concept is that administration of an antagonist drug
inherently establishes functional partial agonism together with the endogenous agonist at
the target receptor.
()R
N
()S
R
N
X
Y
()R
N
()R
R
N
X
N
()S
()S
Y
R
N
X
DA-/NE-/5-HT-antagonist DA-/NE-uptake inhibitors Inactive
N
()R
()S
Y
Fig. 1.15: A6 (1-Piperazino-3-phenylindans): Four stereoisomers and their activity
X
Y
R
N
Drug Discovery, Design and Development 27
QUESTIONS
1. What are the historical perspectives of drug discovery?
2. What do you mean by drug discovery and development programme?
3. What do you mean by ADME?
4. What are the various tools for working with drug-like properties?
5. How different aspects of understanding lead to a high quality drug?
6. What is interdisciplinary medicinal chemistry, in drug discovery and development
programmes?
7. How drugs are classified by generations?
8. What are the drug discovery stages and explain the goals and major activities of
each stage?
9. How can someone focus on emphasizing properties in discovery?
10. What is SAR?
11. What is QSAR?
12. What is the difference between SAR and QSAR?
13. What are the advantages of good drug-like properties?
14. What is Lipinski’s rule?
15. What is Lipinski’s rule of five?
16. What is Veber rule?
17. How you can apply Lipinski and Veber rule for single drug molecule?
18. What are the modern approaches of research and development strategies for better
drug-like processes?
19. What is SAR paradox?
20. What do you mean by partition coefficient and how we can measure the lipohilicity?
21. What are bioisosteres? Explain.
22. Explain the role of stereochemistry in drug discovery programme.
2
Basic Retrosynthetic Approach
2.1 INTRODUCTION
A huge number of complex compounds having diversified properties are produced by
various microorganisms (viz., biomolecules, antibiotics, steroids, alkaloids, perfumes,
rubber, etc.), animals and plants. Chemists have been involved in the isolation, purification,
analyses and determination of the structures of these complex compounds using
retrosynthetic approaches. Thereafter, we found various applications for these substances,
viz., medicine, electronics, paints, plastics, textiles, etc. Later on, the synthesis of these
valuable compounds became important for specific reasons:
(1) For the synthesis of numerous scaffolds and products, many simple starting
materials can be used by applying predictable regioselectivity, stereochemistry,
similar product forming sequences, etc.
(2) The natural products are very costly and found in very small quantities. Synthesis
is another way for the production of these natural products but still in very less
quantities due to a series of reactions. Retrosynthetic approach leads to cheap mass
production and can be applied for the benefit of mankind as a medicine.
(3) Structural modification in the natural product may lead to more potent and useful
molecules.
(4) Excellent planning and deep knowledge of reaction with mechanism is required for
the synthesis of various complex natural scaffolds. This is an important and
extremely challenging part of synthesis and provides immense intellectual
satisfaction to the chemist.
Till 1950s, scientists were busy in the synthesis of the homogeneous species or scaffolds
by choosing an appropriate starting material after failures and success of many structural
resemblances to the molecule to be synthesized. Thus, many attempts were made by
scientists to convert the starting material to the required scaffolds through various reactions
specially by using common laboratory reagents. Overall synthesis of structurally complex
scaffolds has been a challenging task. Simple compounds can be synthesized by the
strategic synthetic routes in a few reaction steps, while complicated molecules may require
a lengthy strategic plan of numerous sequential reactions which is known as multistep
synthesis. It is very difficult to execute or attempt such multistep syntheses. Earlier,
Basic Retrosynthetic Approach 29
designing the synthesis of reaction sequences was based on imaginary associative thinking
processes using the following:
(a) Association with similar compounds having existing synthesis.
(b) Association with available starting material(s).
(c) Association with an imaginary and hypothetical intermediate.
By using these thinking processes, the designing problems of synthetic reactions
sequences can be reduced; however, the choice of an appropriate intermediary structure is
still a highly imaginary spontaneous process. Use of associative approach for the synthetic
reactions sequences becomes less practical due to the complexity problem, hence the
synthetic steps were required to be increased and there was no economic planning for the
etarget material.
2.2 RETROSYNTHETIC ANALYSIS: THE CONCEPTS
It is an imaginary approach to understand the reverse disconnection approach of the target
molecule which lead to simpler, suitable and economically feasible chemical structures.
Thus, the backward disconnection approach is known as retrosynthetic approach or
UHWURV\QWKHWLFDQDO\VLV7KLVFRQFHSWZDVÀUVWGHYHORSHGE\3URI(-&RUH\IURP+DUYDUG
University. The resulting simpler structures can be synthesized using retrosynthetic
approach or the simpler structures can also be purchased commercially.
Example: Diels-Alder reaction: Cycloaddition reaction between dienophile (symmetrical)
and 1,3-diene: The disconnection approach is readily recognised by making simpler
structures.
h
P
Antithetical
reaction
O
FGI FGI
Ph
OH
OH
disconnection
Ph
O
O
DielsAlder
O
Ph
1-phenyl-1,3-
butadiene
+
anhydride
O
O
O
Maleic
The disconnection approaches to reveal two imaginary fragments are also known as
synthons which carry a positive or negative charge on the synthon species. Afterwards, it
is necessary to identify the real (non-imaginary) reactive or chemical intermediate scaffolds.
These scaffolds must be synthetic equivalents of the synthons identified previously.
Antithetical
reaction
+
OH OH
disconnection
BrMg
O
Synthon
Synthetic equivalent
30 Pharmaceutical Chemistry
2.2.1 Retrosynthetic (Antithetic) Analysis and the Disconnection Approach
It can be easily explained by the reverse synthetic reaction process without any assumptions
regarding the starting materials. Here the target structure is subjected to a disconnection
that led to simpler structure known as synthons. Each precursor obtained from
disconnection is then examined, and the synthetic process is repeated until economically,
structurally simpler, and commercially available starting materials are obtained.
Retrosynthetic analysis (RA) has great advantages, which may lead to the possibility of
identifying numerous commercially and economically available starting materials,
numerous possible synthetic routes or alternate routes. All possible alternative routes may
lead to one cheaper, short-time and successful synthesis. All precursors by which the target
molecules may be assembled are known as synthons. The target molecule can also be
synthesized by assembling the synthons, known as convergent synthesis. Using the
disconnection approach, chemists may reduce the time (which is required to achieve the
synthesis) and yield of the product. Convergent synthesis is a much better approach than
linear synthesis (Figs. 2.1 & 2.2).
ABCDEF
ABCD + EF
convergent
AB + CD , E + F
A + B , C + D
Fig. 2.1: Linear vs. convergent synthesis
Linear:
Convergent: The purely convergent synthesis is ideal.
AAB
ABCD
CCD
EEF
80% 64%
Fig. 2.2: Linear vs. convergent synthesis separately
ABCDEF
G...K
L...P
51% 40% 32%
ABCDE + F
ABCD + E
ABC + D
AB + C
A+ B
linear
A...K
A......P
Basic Retrosynthetic Approach 31
Example: Retrosynthetic analysis approach of chloramphenicol
Disconnection
ClO
O2N
HOH2C
NH
OH
Disconnection
Cl
-ClCOCHCl
2
O2N
HOH2C
OH
NH
2
-HCHO
O2N
OH
NH
2
D(-)Chloramphenicol
FGI
O2N
Acetophenone
Disconnection
Disconnection
NH
2
O
CH
3
O
O2N
Benzene
CH
O
+
Cl CH
Disconnection
3
O
O2N
Nitrobenzene
3
O
HO CH
Acetic acid
O
+
Cl CH
Acetyl chloride
3
3
Retrosynthetic analysis always leads to useful results if they are directed towards some
specific goals. The basic goal of retrosynthetic analysis is to generate precursors that have
close resemblance with the starting materials. It is very difficult to start a reaction with
simpler molecules to make very complex molecules, thus we have to look for the possible
precursors or immediate precursors. Thus, the basic goal becomes much easier after the
generating precursors for the synthesis of target scaffolds and in simpler way, we can say
retrosynthetic analysis is directed towards molecular simplification (Fig. 2.3).
Corey has explained five types of strategies for the desired simplification which are as
follows:
(1) Strategies based on functional groups: Functional groups (viz., double bonds,
carbonyl, hydroxyl and fused ring, etc.) can be useful in identifying appropriate
points for disconnection. Functional groups in the target structure may direct the
transform search in the following ways:
(DV\UHPRYDORIUHDFWLYHDQGPDVNHGIXQFWLRQDOLW\
/RFDWLRQRIIXQFWLRQDOJURXSVPD\EHGLVFRQQHFWLRQSRLQWV
5HFRQQHFWLRQRIIXQFWLRQDOJURXSVWRIRUPULQJVUHWURV\QWKHWLFDOO\
Strategic rules may be operated for the re-connective strategy, as we know to
attempt every possible reconnection is not possible.