Medicinal Chemistry

Medicinal Chemistry
Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry
and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal
chemistry involves the identification, synthesis, and development of new chemical entities suitable
for therapeutic use.
Introduction to Medicinal Chemistry

Medicinal chemistry emerged as a specialized area due to the development in chemistry and
biology; hence, it is considered a highly interdisciplinary science that combines a wide variety of
subjects, including organic chemistry, pharmacology, biochemistry, toxicology, pharmacognosy,
molecular biology, genomics, proteomics, computational chemistry, physical chemistry, and
statistics. Now, the growth of medicinal chemistry has reached a stage where the activity-guided
synthesis of compounds is possible rather than screening of synthesized compounds for different
biological activities. This field also penetrates the areas of gene therapy and biochemistry-based
virtual drug receptors with the help of computer-aided molecular modeling techniques.

Medicinal chemistry is a discipline at the intersection of chemistry and pharmacology that involves
the identification, synthesis, and development of new chemical entities that are suitable for medical
or pharmaceutical use. Medicinal chemistry is an interdisciplinary science combining a variety of
subjects such as organic chemistry, phytochemistry, pharmacology, toxicology, molecular biology,
biochemistry, computational chemistry, physical chemistry, and statistics. It also includes the study
of existing drugs, their pharmacological properties, toxic effects, and their quantitative structure-
activity relationships (QSARs).

Majority of the medicinal compounds, which are used as medicines are natural products and
synthetic organic compounds. However, metal-containing compounds are also found to be useful
as drugs. For example, the cisplatin series of platinum-containing complexes are used as anticancer
agents. These compounds are known as metal-based drugs.

The discipline of medicinal chemistry is devoted to the discovery and development of new
agents for treating diseases. Most of this activity is directed to new natural or synthetic organic
compounds. Paralleling the development of medicinal agents has come a better understanding of
the chemistry of the receptor. The latter has been greatly facilitated by low-cost computers
running software that calculates molecular properties and structure and pictures it using high-
resolution graphics. Development of organic compounds has grown beyond traditional synthetic
methods.

It now includes the exciting field of biotechnology using the cell’s biochemistry to synthesize
new compounds. Techniques ranging from recombinant DNA and site-directed mutagenesis to
fusion of cell lines have greatly broadened the possibilities for new entities that treat disease. The
pharmacist now dispenses modified human insulins that provide more convenient dosing
schedules, cell-stimulating factors that have changed the dosing regimens for chemotherapy,
humanized monoclonal antibodies that target specific tissues, and fused receptors that intercept
immune cell–generated cytokines.

Drug

Drugs are strictly defined as chemical substances used to prevent or cure diseases in humans,
animals, and plants. A drug's activity is its pharmacological effect on the subject, such as its
analgesic or b-blocker action.

Drugs act by interfering with biological processes, so no drug is completely safe. All drugs can
act as poisons if taken in excess. For example, overdoses of paracetamol can cause coma and
death. Furthermore, besides their beneficial effects, most drugs have non-beneficial biological
effects. Aspirin, which is commonly used to alleviate headaches, may also cause gastric irritation
and bleeding. The non-beneficial effects of some drugs, such as cocaine and heroin, are so
undesirable that the use of these drugs has to be strictly controlled by legislation. These
unwanted effects are commonly referred to as side effects.
Lead compound
A lead compound in drug discovery is a chemical compound that has pharmacological or biological
activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that
requires modification to fit better to the target; lead drugs offer the prospect of being followed by
back-up compounds.
Ligand
A ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The
etymology stems from Latin ligare, which means 'to bind'. In protein-ligand binding, the ligand is
usually a molecule that produces a signal by binding to a site on a target protein.
Drug candidate
The drug candidate is the molecule among several that has been shown to have sufficient target
selectivity and potency, and favorable medicine-like properties and justifies further development.

Chemical constitution and biological activity: (Receptor, Theory, Structure Activity

Relationships (SAR) and Drug Metabolism). The modern concept of rational drug design,
prodrug, combinatorial chemistry computer-aided drug design (CADD), and the concept of
antisense molecules.

The relationship between chemical constituents and biological activities is a central theme in fields
like pharmacology, biochemistry, and medicinal chemistry. Chemical constituents refer to the
specific chemical compounds found in natural or synthetic substances, while biological activities
refer to the effects those compounds have on living organisms or biological systems.
Relationship between chemical constituents and biological activities
1. Bioactive Compounds: Certain chemical constituents, such as alkaloids, flavonoids,
terpenoids, phenolics, and glycosides, are known to exhibit biological activity. These
compounds often interact with specific biological targets, such as enzymes, receptors, or
cell structures, resulting in a biological response. For example:
o Alkaloids (e.g., morphine, quinine) can have analgesic or anti-malarial effects.
 o Flavonoids (e.g., quercetin, catechins) exhibit antioxidant, anti-inflammatory, and
anti-cancer activities.
o Terpenoids (e.g., menthol, taxol) can have anti-inflammatory, antimicrobial, and
anticancer properties.
2. Mechanisms of Action: The biological activity of a compound depends on how it interacts
with the biological system. This interaction can involve:
o Enzyme Inhibition or Activation: Many drugs work by inhibiting or activating
specific enzymes. For example, acetylcholinesterase inhibitors (e.g., donepezil) are
used in Alzheimer's disease treatment.
o Receptor Binding: Some compounds act by binding to specific receptors,
mimicking or blocking natural ligands. Opioid drugs like morphine bind to opioid
receptors in the brain, producing analgesic effects.
o Antioxidant Activity: Many plant-derived compounds (e.g., flavonoids,
polyphenols) can scavenge free radicals, protecting cells from oxidative damage
and reducing the risk of diseases like cancer and cardiovascular diseases.
3. Structure-Activity Relationship (SAR): The structure of a chemical compound greatly
influences its biological activity. Small changes in the chemical structure can lead to
significant changes in potency, selectivity, or toxicity. This relationship is studied through
structure-activity relationship (SAR) analysis to optimize drug design.
4. Concentration-Dependent Effects: The biological activity of a compound is often dose-
dependent. At low concentrations, a compound might act as an antioxidant, while at higher
concentrations, it may become toxic. This principle is important in determining safe
therapeutic doses.
5. Synergistic Effects: In natural products, the combination of multiple chemical constituents
often produces a synergistic effect, where the overall biological activity is greater than the
sum of individual effects. This is seen in many traditional medicines, such as those used in
herbal remedies, where the whole plant or extract may have a broader range of biological
effects than any single compound isolated from it.
6. Toxicity and Side Effects: Not all chemical constituents are beneficial; some may have
toxic effects. Understanding the relationship between chemical structure and toxicity is
 crucial in developing safe therapeutic agents. For instance, compounds like cyanogenic
glycosides in certain plants can be toxic if not properly processed.
7. Pharmacokinetics: The absorption, distribution, metabolism, and excretion (ADME)
properties of a chemical constituent influence its biological activity. For instance, the
bioavailability of a compound (how much reaches the bloodstream and its target) depends
on its chemical properties such as solubility, stability, and ability to cross biological
membranes.
Examples of Chemical Constituents and Their Biological Activities:
• Curcumin (from turmeric): Exhibits anti-inflammatory, antioxidant, anticancer, and
antimicrobial activities. Its chemical structure allows it to modulate several signaling
pathways involved in inflammation and cancer.
• Capsaicin (from chili peppers): Known for its analgesic properties, capsaicin binds to the
TRPV1 receptor, which is involved in the sensation of pain and heat.
• Resveratrol (from grapes): A polyphenolic compound with antioxidant and anti-
inflammatory effects, often associated with cardiovascular health benefits.
• Saponins (from ginseng, quinoa): Have antimicrobial, anti-inflammatory, and immune-
modulating effects.
Receptor
Receptors are defined as proteins that recognize a molecule or molecules (ligands) with some
degree of specificity to initiate a biochemical signaling cascade that couples to secondary
messenger systems. The receptors are chemical structures, composed of protein, that receive
and transduce signals that may be integrated into biological systems. These signals are typically
chemical messengers which bind to a receptor and produce physiological responses such as change
in the electrical activity of a cell. For example, GABA, an inhibitory neurotransmitter, inhibits
electrical activity of neurons by binding to GABAA receptors.
Types of Receptor
1. Internal receptors.
2. Cell-Surface Receptors.
3. Ion Channel-Linked Receptors.
4. G-Protein Linked Receptors.
5. Enzyme-Linked Receptors
Receptor Theory
Receptor theory is the application of receptor models to explain drug behavior. Pharmacological
receptor models preceded accurate knowledge of receptors by many years. John Newport
Langley and Paul Ehrlich introduced the concept that receptors can mediate drug action at the
beginning of the 20th century. Alfred Joseph Clark was the first to quantify drug-induced
biological responses.
Receptor Theory is a foundational concept that explains how drugs interact with the body at the
molecular level. It revolves around the idea that the effects of drugs are mediated through
interactions with specific proteins or structures in the body known as receptors.
Key Concepts of Receptor Theory
1. Receptors
o Receptors are typically proteins found on the surface of cells or within cells that
bind to signaling molecules, such as neurotransmitters, hormones, or drugs.
o They are highly specific to certain ligands (molecules that bind to receptors), and
the binding often triggers a series of biochemical events within the cell, resulting
in a physiological effect.
2. Ligand-Receptor Binding:
o Drugs, hormones, and neurotransmitters are considered ligands when they bind to
a receptor.
o The strength and efficiency of this binding are influenced by factors like affinity
(the tendency of a ligand to bind to a receptor) and intrinsic activity (the ability of
a bound ligand to produce a physiological response).
3. Agonists and Antagonists:
o Agonists are substances that bind to a receptor and activate it, leading to a
biological response (e.g., morphine as an agonist at opioid receptors).

o Antagonists bind to receptors but do not activate them. Instead, they block the
receptor from being activated by other ligands (e.g., naloxone, which blocks opioid
receptors and can reverse opioid overdose).
4. Dose-Response Relationship:
o The relationship between the dose of a drug and the magnitude of its effect is often
described by a dose-response curve. The curve shows how increasing the drug
dose leads to a greater effect up to a certain point (maximum effect or Emax).
o This curve can also help determine the potency of a drug (the dose required to
produce a given effect) and its efficacy (the maximum effect achievable by the
drug).
5. Receptor Types:
o There are several types of receptors, including:
▪ Ion-channel receptors (e.g., nicotinic acetylcholine receptors).
▪ G-protein-coupled receptors (GPCRs) (e.g., beta-adrenergic receptors).
▪ Enzyme-linked receptors (e.g., insulin receptors).
▪ Intracellular receptors (e.g., steroid hormone receptors).
6. Receptor Occupancy Theory:
o This theory suggests that the response to a drug is directly proportional to the
number of receptors occupied by the drug. It assumes that once all receptors are
occupied, further increases in drug concentration will not produce a stronger effect.
o This concept is central to understanding how the concentration of a drug relates to
its pharmacodynamic effects.
7. Spare Receptors:
 o Some receptors in a system may remain unoccupied even when a full biological
effect is achieved. This suggests the presence of "spare" receptors, which means
that a lower concentration of agonist is needed to elicit a maximal response.
Mathematical Models:
• The Law of Mass Action is often used to describe receptor-ligand binding, which leads to
equations like the Langmuir equation or Hill equation that model the relationship
between drug concentration and receptor occupancy.
• The Hill coefficient is a parameter that can indicate the cooperativity of ligand binding —
whether the binding of one molecule affects the binding of others.
Postulates of receptor theory
• Receptors must possess structural and steric specificity.
• Receptors are saturable and finite (limited number of binding sites)
• Receptors must possess a high affinity for their endogenous ligand at physiological
concentrations
• Once the endogenous ligand binds to the receptor, some early recognizable chemical event
must occur.
Application of Receptor Theory:
• Receptor theory is critical for drug development, as understanding receptor interactions
helps in designing drugs with optimal potency, selectivity, and minimal side effects.
• It also aids in explaining why different drugs can have different effects, even if they act on
the same receptor type. For example, a drug may have a high affinity for a receptor but a
low intrinsic activity, leading to a partial agonist effect, whereas another drug might have
a higher intrinsic activity and produce a more potent response.
Structure-activity Relationships (SAR)
The structure-activity relationship is the relationship between the chemical structure of a molecule
and its biological activity. The structure-activity relationship (SAR) approach to drug discovery is
based on the observation that compounds with similar structures to a pharmacologically active
drug are often biologically active. This activity may be either similar to that of the original
compound but differ in potency and unwanted side effects or completely different from that
exhibited by the original compound. These structurally related activities are commonly referred to
as structure-activity relationships. A study of the structure-activity relationships of a lead
compound and its analogs may be used to determine the parts of the structure of the lead compound
that are responsible for both its beneficial biological activity, that is, its pharmacophore, and also
its unwanted side effects.
This information may be used to develop a new drug that has increased activity by selecting the
structure with the optimum activity, a different activity from an existing drug, and fewer unwanted
side effects.

Structure–activity relationship studies are usually carried out by making minor changes to the
structure of a lead to produce analogues and assessing the effect that these structural changes have
on biological activity. The investigation of numerous lead compounds and their analogues has
made it possible to make some broad generalizations about the biological effects of specific types
of structural changes. These changes may be conveniently classified as changing:

• the size and shape of the carbon skeleton

• the nature and degree of substitution
• the stereochemistry of the lead

The selection of the changes required to produce analogs of a particular lead is made by
considering the activities of compounds with similar structures and also the possible chemistry and
biochemistry of the intended analog.
Lipophilicity
Hydrophilicity
Micelle formation
It is believed that structural changes that result in analogs with increased lipid character may either
exhibit increased activity because of better membrane penetration or reduced activity because of a
reduction in their water solubility. However, whatever the change, its effect on water solubility,
transport through membranes, receptor binding and metabolism, and other pharmacokinetic
properties of the analog should be considered as far as possible before embarking on what could
be an expensive synthesis. Furthermore, changing the
structure of the lead compound could result in an analog that is too big to fit its intended target
site. Computer-assisted molecular modeling can alleviate this problem provided that the structure
of the target is known or can be simulated with some degree of accuracy. However, it is emphasized
that although it is possible to predict the effect of structural changes there will be numerous
exceptions to the predictions and so all analogs must be synthesized and tested.
Changing size and shape
The shapes and sizes of molecules can be modified in a variety of ways, such as:

• changing the number of methylene groups in chains and rings;

• increasing or decreasing the degree of unsaturation;
• introducing or removing a ring system.

Changing the number of methylene groups in chains and rings

Increasing the number of methylene groups in a chain or ring increases the size and the lipophilicity
of the compound. It is believed that any increase in activity with an increase in the number of
methylene groups is probably due to an increase in the lipid solubility of the analog, which gives
a better membrane penetration. Conversely, a decrease in activity with an increase in the number
of methylene groups is attributed to a reduction in the water solubility of the analogs. This
reduction in water solubility can result in the poor distribution of the analog in the aqueous media
as well as the trapping of the analog in biological membranes. A further problem with large
increases in the numbers of inserted methylene groups in chain structures is micelle formation.
Micelle formation produces large aggregates that, because of their shape, cannot bind to active
sites and receptors.
Introducing chain branching, different-sized rings, and the substitution of chains for rings, and vice
versa may also have an effect on the potency and type of activity of analogs. For example, the
replacement of the sulfur atom of the antipsychotic chlorpromazine by -CH2-CH2- produces the
antidepressant clomipramine.

Changing the degree of unsaturation

The removal of double bonds increases the degree of flexibility of the molecule, which may make
it easier for the analogue to fit into active and receptor sites by taking up a more suitable
conformation. However, an increase in flexibility could also result in a change or loss of activity.
The introduction of a double bond increases the rigidity of the structure. It may also introduce the
complication of E and Z isomers, which could have quite different activities. The analogues
produced by the introduction of unsaturated structures into a lead compound may exhibit different
degrees of potency or different types of activities. For example, the potency of prednisone is about
30 times greater than that of its parent compound cortisol, which does not have a 1–2 C––C bond.
The replacement of the S atom of the antipsychotic phenothiazine drugs by a -CH––CH- group
gives the antidepressant dibenzazepine drugs, such as protriptyline.
Introducing a C––C group will often give analogs that are more sensitive to metabolic oxidation.
This may or may not be a desirable feature for the new drug. Furthermore, the reactivity of the C–
–C frequently causes the analog to be more toxic than the lead.

Introduction or removal of a ring system

The introduction of a ring system changes the shape and increases the overall size of the analogue.
The effect of these changes on the potency and activity of the analog is not generally predictable.
However, the increase in size can be useful in filling a hydrophobic pocket in a target site, which
might strengthen the binding of the drug to the target. For example, it has been postulated that the
increased inhibitory activity of the cyclopentyl analog (rolipram) of 3-(3,4-dimethyloxyphenyl)-
butyrolactam towards cAMP phosphodiesterase is due to the cyclopentyl group filling a
hydrophobic pocket in the active site of this enzyme.
The incorporation of smaller, as against larger, alicyclic ring systems into a lead structure reduces
the possibility of producing an analog that is too big for its target site. It also reduces the possibility
of complications caused by the existence of conformers. However, the selection of the system for
a particular analog may depend on the objective of the alteration. For example, the antidepressant
tranylcypromine is more stable than its analog 1-amino-2-phenylethene.

The insertion of aromatic systems into the structure of the lead will introduce rigidity into the
structure as well as increase the size of the analogue. The latter means that small aromatic systems
such as benzene and five-membered heterocyclic systems are often preferred to larger systems.
However, the p electrons of aromatic systems may or may not improve the binding of the analogue
to its target site. Furthermore, heterocyclic aromatic systems will also introduce extra functional
groups into the structure, which could also affect the potency and activity of the analogue. For
example, the replacement of the N-dimethyl group of chlorpromazine by an N-methylpiperazine
group produces an analogue (prochlorperazine) with increased antiemetic potency but reduced
neuroleptic activity. It has been suggested that this change in activity could be due to the presence
of the extra tertiary amine group.
The incorporation of ring systems, especially larger systems, into the structure of a lead can be
used to produce analogues that are resistant to enzymic attack by sterically hindering the access of
the enzyme to the relevant functional group. For example, the resistance of diphenicillin to b-
lactamase is believed to be due to the diphenyl group preventing the enzyme from reaching the b-
lactam. It is interesting to note that 2-phenylbenzylpenicillin is not resistant to b-lactamase attack.
In this case, it appears that the diphenyl group is too far away from the b-lactam ring to hinder the
attack of the b-lactamase.
Many of the potent pharmacologically active naturally occurring compounds, such as the alkaloids
morphine and curare, have such complex structures that it would not be economical to synthesize
them on a large scale. Furthermore, they also tend to exhibit unwanted side effects. However, the
structures of many of these compounds contain several ring systems. In these cases, one approach
to designing analogs of these compounds centers around determining the pharmacophore and
removing any surplus ring structures. It is hoped that this will also result in the loss of any
unwanted side effects. The classic example illustrating this type of approach is the development of
drugs from morphine.
Introduction of new substituents
The formation of analogues by introducing new substituents into the structure of a lead may result
in an analogue with significantly different chemicals and hence different pharmacokinetic
properties. For example, the introduction of a new substituent may cause significant changes in
lipophilicity, which affect the transport of the analogue through membranes and the various fluids
found in the body. It would also change the shape, which could result in conformational restrictions
that affect the binding to the target site. In addition, the presence of a new group may introduce a
new metabolic pathway for the analogue. These changes will in turn affect the pharmacodynamic
properties of the analogue. For example, they could result in an analogue with either increased or
decreased potency, duration of action, metabolic stability, and unwanted side effects. The choice
of substituent will depend on the properties that the development team decides to enhance in an
attempt to meet their objectives. Each substituent will impart its characteristic properties to the
analog. However, it is possible to generalize about the effect of introducing a new substituent group
into a structure but there will be numerous exceptions to the predictions.
Methyl groups
The introduction of methyl groups usually increases the lipophilicity of the compound and reduces
its water solubility as shown by an increase in the value of the partition coefficient. It should
improve the ease of absorption of the analog into a biological membrane but will make its release
from biological membranes into aqueous media more difficult. The introduction of a methyl group
may also improve the binding of a ligand to its receptor by filling a pocket on the target site.

The incorporation of a methyl group can impose steric restrictions on the structure of an analogue.
For example, the ortho-methyl analogue of diphenhydramine exhibits no antihistamine activity.
Harmes et al. suggest this to be due to the ortho-methyl group restricting rotation about the C–O
bond of the side chain. This prevents the molecule from adopting the conformation necessary for
antihistamine activity. It is interesting to note that the para-methyl analogue is 3.7 times more
active than diphenhydramine.

The incorporation of a methyl group can have one of three general effects on the rate of metabolism
of an analogue.
It can result in either,
(1) an increased rate of metabolism due to oxidation of the methyl group,
(2) an increase in the rate of metabolism due to demethylation by the transfer of the
methyl group to another compound or
(3) a reduction in the rate of metabolism of the analogue.
A methyl group bound to an aromatic ring or a structure may be metabolized to a carboxylic
acid, which can be more easily excreted. For example, the antidiabetic tolbutamide is metabolized
to its less toxic benzoic acid derivative. The introduction of a reactive C–CH3 group offers a
detoxification route for lead compounds that are too toxic to be of use.

Demethylation is more likely to occur when the methyl group is attached to positively charged
nitrogen and sulfur atoms, although it is possible for any methyl group attached to a nitrogen,
oxygen, or sulfur atom to act in this manner. A number of methyl transfers have been associated
with carcinogenic action.
Methyl groups can reduce the rate of metabolism of a compound by masking a metabolically active
group, thereby giving the analog a slower rate of metabolism than the lead. For example, the action
of the agricultural fungicide nabam is due to it being metabolized to the active diisothiocyanate.
N-methylation of nabam yields an analog that is active because it cannot be metabolized to the
active di isothiocyanate.
Methylation can also reduce the unwanted side effects of a drug. For example, mono-and di-ortho-
methylation with respect to the phenolic hydroxy group of paracetamol produces analogs with
reduced hepatotoxicity. It is believed that this reduction is due to the methyl groups preventing
metabolic hydroxylation of these ortho positions.

Larger alkyl groups will have similar effects. However, as the size of the group increases the
lipophilicity will reach a point where it reduces the water solubility to an impractical level.
Consequently, most substitutions are restricted to methyl and ethyl groups.
Halogen groups
The incorporation of halogen atoms into lead results in analogues that are more lipophilic and so
less water soluble. Consequently, halogen atoms are used to improve the penetration of lipid
membranes. However, there is an undesirable tendency for halogenated drugs to accumulate in
lipid tissue.
The chemical reactivity of halogen atoms depends on both their point of attachment to the lead
and the nature of the halogen. Aromatic halogen groups are far less reactive than aliphatic halogen
groups, which can exhibit considerable chemical reactivity. The strongest and least reactive of the
aliphatic carbon–halogen bonds is the C–F bond. It is usually less chemically reactive than
aliphatic C–H bonds. The other aliphatic C–halogen bonds are weaker and so more reactive, their
reactivity increasing as one moves down the periodic table. They are normally more chemically
reactive than aliphatic C–H bonds.

Consequently, the most popular halogen substitutions are the less reactive aromatic fluorine and
chlorine groups. However, the presence of electron-withdrawing ring substituents may increase
their reactivity to unacceptable levels. Trifluorocarbon groups (-CF3) are sometimes used to
replace chlorine as these groups are of a similar size. These substitutions avoid introducing a very
reactive center and hence a possible site for unwanted side reactions into the analogue. For
example, the introduction of the more reactive bromo group can cause the drug to act as an
alkylating agent.
The changes in potency caused by the introduction of a halogen or halogen-containing group will,
as with substitution by other substituents, depend on the position of the substitution. For example,
the antihypertensive clonidine with its o,o-chloro substitution is more potent than its p,m-dichloro
analogue. It is believed that the bulky o-chlorine groups impose a conformational restriction on
the structure of clonidine that probably accounts for its increased activity.
Hydroxy groups
The introduction of hydroxy groups into the structure of a lead will normally produce analogues
with an increased hydrophilic nature and a lower lipid solubility. It also provides a new center for
hydrogen bonding, which could influence the binding of the analogue to its target site. For
example, the ortho-hydroxylated minaprine analogue binds more effectively to M1-muscarinic
receptors than many of its non-hydroxylated analogues.

The introduction of a hydroxy group also introduces a center that, in the case of phenolic groups,
could act as a bacterioside, whilst alcohols have narcotic properties. However, the presence of
hydroxy groups opens a new metabolic pathway that can either act as a detoxification route or
prevent the drug from reaching its target.

Basic groups
The basic groups usually found in drugs are amines, including some ring nitrogen atoms, amidines,
and guanidines. All these basic groups can form salts in biological media. Consequently, the
incorporation of these basic groups into the structure of a lead will produce analogues that have a
lower lipophilicity but an increased water solubility. This means that the more basic an analogue,
the more likely it will form salts and the less likely it will be transported through a lipid membrane.
The introduction of basic groups may increase the binding of an analogue to its target by hydrogen
bonding between that target and the basic group. However, a number of drugs with basic groups
owe their activity to salt formation and the enhanced binding that occurs due to the ionic bonding
between the drug and the target. For example, it is believed that many local anesthetics are
transported to their site of action in the form of their free bases but are converted to their salts,
which bind to the appropriate receptor sites.
The incorporation of aromatic amines into the structure of a lead is usually avoided since aromatic
amines are often very toxic and are often carcinogenic.
Carboxylic and sulphonic acid groups
The introduction of acid groups into the structure of a lead usually results in analogues with
increased water but reduced lipid solubility. This increase in water solubility may be subsequently
enhanced by in vivo salt formation. In general, the introduction of carboxylic and sulphonic acid
groups into a lead produces analogues that can be more readily eliminated.
The introduction of carboxylic acid groups into small lead molecules may produce analogues that
have a very different type of activity or are inactive. For example, the introduction of a carboxylic
acid group into phenol results in the activity of the compound changing from being a toxic
antiseptic to a less toxic anti-inflammatory salicylic acid.

Similarly, the incorporation of a carboxylic acid group into the sympathomimetic

phenylethylamine gives phenylalanine, which has no sympathomimetic activity. However, the
introduction of carboxylic acid groups appears to have less effect on the activity of large molecules.
Thiols, sulphides and other sulphur groups
Thiol and sulphide groups are not usually introduced into leads in SAR studies because they are
readily metabolised by oxidation (see Table 12.1). However, thiols are sometimes introduced into
a lead structure when improved metal chelation is the objective of the SAR study. For example,
the antihypertensive captopril was developed from the weakly active carboxyacylprolines by
replacement of their terminal carboxylic acid group with a thiol group, which is a far better group
for forming complexes with metals than carboxylic acids (see section 9.12.2).
The introduction of thiourea and thioamide groups is usually avoided since these groups may
produce goiter, a swelling on the neck due to enlargement of the thyroid gland.
Changing the existing substituents of a lead
Analogues can also be formed by replacing an existing substituent in the structure of a lead by a
new substituent group. The choice of group will depend on the objectives of the design team. It is
often made using the concept of isosteres. Isosteres are groups that exhibit some similarities in
their chemical and/or physical properties. As a result, they can exhibit similar pharmacokinetic and
pharmacodynamic properties. In other words, the replacement of a substituent by its isostere is
more likely to result in the formation of an analogue with the same type of activity as the lead than
the totally random selection of an alternative substituent. However, luck still plays a part, and an
isosteric analog may have a totally different type of activity from its lead.
Isosteres:
SH, NH2, and CH3 are isosteres of OH, whereas S, NH, and CH2 are isosteres of O. Isosteres can
be used to determine whether a particular group is an important binding group or not, by
altering the character of the molecule in as controlled a way as possible.
Replacing O with CH2, for example, will make little difference to the size of the analog, but will
have a marked effect on its polarity, electronic distribution, and bonding. Replacing OH with the
larger SH may not have such an influence on the electronic character, but steric factors become
more significant. Replacing OH with CH3 would completely eliminate and replacing OH with
NH2 would not.
Classical isosteres were originally defined by Erlenmeyer as being atoms, ions and molecules that
had identical outer shells of electrons. This definition has now been broadened to include groups
that produce compounds that can sometimes have similar biological activities. These groups are
frequently referred to as bioisosteres in order to distinguish them from classical isosteres.
A large number of drugs have been discovered by isosteric and bioisosteric interchanges. For
example, the replacement of the 6-hydroxy group of hypoxanthine by a thiol group gave the anti-
tumour drug 6-mercaptopurine whilst the replacement of hydrogen in the 5-position
of uracil by fluorine resulted in fluorouracil, which is also an anti-tumour agent. However,
not all isosteric changes yield compounds with the same type of activity: the replacement of
the -S- of the neuroleptic phenothiazine drugs by either -CH––CH- or -CH2CH2- produces the
dibenzazepines, which exhibit antidepressant activity

Non-classic isosteres: are groups which do not obey the steric and electronic rules used to define
classic isosteres, but which have similar physical and chemical properties.
They are all planar groups of similar size and basicity.

Drug Metabolism
Metabolism plays a central role in the elimination of drugs and other foreign compounds
(xenobiotics) from the body. A solid understanding of drug metabolic pathways is an essential
tool for pharmacists in their role of selecting and monitoring appropriate drug therapy for their
patients. Most organic compounds entering the body are relatively lipid soluble (lipophilic). To be
absorbed, they must traverse the lipoprotein membranes of the lumen walls of the gastrointestinal
(GIT) tract. Then, once in the bloodstream, these molecules can diffuse passively through other
membranes and be distributed effectively to reach various target organs and exert their
pharmacological actions. Because of reabsorption in the renal tubules. lipophilic compounds are
not excreted to any substantial extent in the urine. Xenobiotics then meet their metabolic fate
through various enzyme systems that change the parent compound to render it more water-soluble
(hydrophilic). Once the metabolite is sufficiently water soluble, it may be excreted from the body.
The statements above show that a working knowledge of the ADME (absorption, distribution.
metabolism, and excretion) principles is vital for the successful determination of drug regimens.
If lipophilic drugs. or xenobiotics were not metabolized to polar, readily excretable water-soluble
products, they would remain indefinitely in the body. eliciting their biological effect. Thus, the
formation of water-soluble metabolites enhances drug elimination and leads to compounds that are
generally pharmacologically inactive and relatively nontoxic. Consequently, drug metabolism
reactions have traditionally been regarded as detoxification (or detoxification) processes.'
Unfortunately, it is incorrect to assume that drug metabolism reactions are always detoxifying.
Many drugs are biotransformed to pharmacologically active metabolites, These metabolites may
have significant activity that contributes substantially to the pharmacological or toxicological
effect(s) ascribed to the parent drug. Occasionally, the parent compound is inactive when
administered and must be metabolically converted to a biologically active drug (metabolite). These
types of compounds are referred to as pro-
In addition, it is becoming increasingly clear that not all metabolites are nontoxic. Indeed, many
adverse effects e.g. tissue necrosis, and carcinogenicity. teratogenicity) of drugs and environmental
contaminants can be attributed directly to the formation of chemically reactive metabolites that are
highly detrimental to the body. This concept is more important when the patient has a disease state
that inhibits or expedites xenobiotic metabolism. Also, more and more drug metabolites are being
found in our sewage system.
These compounds may be nontoxic to humans but harmful to other animals or the environment
Drug metabolism reactions have been divided into two categories: phase I (functionalization) and
phase II (conjugation) reactions. Phase I, or functionalization reactions, include oxidative.
reductive, and hydrolytic biotransformations The purpose of these reactions is to introduce a
functional polar group(s) (e.g. OH. COOH, NH SH) into the xenobiotic molecule to produce a
more water-soluble compound. This can be achieved by direct introduction of the functional group
(e.g. aromatic and aliphatic hydroxylation) or by modifying or "unmasking" existing
functionalities (e.g. reduction of ketones and aldehydes to alcohols, oxidation of alcohols to acids:
hydrolysis of ester and amides
Drug Targets
Drugs are compounds that interact with a biological system to produce a biological response.
Drugs may be mere chemicals, but they are entering a world of chemical reactions with which they
interact. Therefore, there should be nothing odd in the fact that they can have an effect. The
surprising thing might be that they can have such specific effects. This is more a result of where
they act in the body—the drug targets.
The main molecular targets for drugs are proteins (mainly enzymes, receptors, and transport
proteins) and nucleic acids (DNA and RNA). These are large molecules (macromolecules) that
have molecular weights measured in the order of several thousand atomic mass units. They are
much bigger than the typical drug, which has a molecular weight in the order of a few hundred
atomic mass units.
The interaction of a drug with a macromolecular target involves a process known as binding. There
is usually a specific area of the macromolecule where this takes place, known as the binding site.
Typically, this takes the form of a hollow or canyon on the surface of the macromolecule allowing
the drug to sink into the body of the larger molecule. Some drugs react with the the binding site
and become permanently attached via a covalent bond that has a bond strength of 200–400 kJ
mol −1. However, most drugs interact through weaker forms of interaction known as
intermolecular bonds. These include electrostatic or ionic bonds, hydrogen bonds, van der Waals
interactions, dipole–dipole interactions, and hydrophobic interactions. (It is also possible
for these interactions to take place within a molecule, in which case they are called intramolecular
bonds ; see for example protein structure, sections 2.2 and 2.3.) None of these bonds is as strong
as the covalent bonds that make up the skeleton of a molecule, and so they can be formed and then
broken again. This means that an equilibrium takes place between the drug being bound and
unbound to its target. The binding forces are strong enough to hold the drug for a certain period of
time to let it have an effect on the target, but weak enough to allow the drug to depart once it has
done its job. The length of time the drug remains at its target will then depend on the number of
intermolecular bonds involved in holding it there. Drugs that have a large number of interactions
are likely

There are four primary target regulator proteins that are commonly involved in the drug
interactions to produce pharmacological actions. They are enzymes, carrier molecules, ion
channels, and receptors. The term receptor or a receptive substance was used to denote a small
region of macromolecule, which may be an isolable enzyme, a structural and functional compound
of a cell membrane, or a specific intracellular substance, such as a protein or a nucleic acid.
Occupation of a receptor by a drug molecule may or may not result in the activation of the receptor.
Activations result in tissue responses. Binding and activation represent the two steps in the
generation of receptor-mediated response by an agonist. If a drug binds to a receptor causing
activation, and thereby prevents the agonist from binding, it is termed as a receptor antagonist,
whereas the tendency for it once bound to activate the receptor is denoted by efficacy. Drugs with
intermediate levels of efficacy produces submaximal response even at 100% receptor occupation
are known as partial agonist. Those, which produce maximum response after 100% receptor
occupation, are called full agonist.
TYPES OF RECEPTORS
Receptors elicit many different types of cellular effect. Some of them are very rapid, that is, those
involved in synaptic transmission, operating within milliseconds, and other receptors for hormones
that operates after hours and days. There are four types of receptors.
Type 1: Ligand-gated ion channels
Type 2: G-protein-coupled receptors
Type 3: Kinase-linked receptors
Type 4: Nuclear receptors
Ligand-gated ion channels: The ligand-gated ion channels are also known as ionotropic
receptors. These are membrane proteins with a similar structure to other ion channels, but
incorporating a ligand-binding site (receptor), usually in an extracellular domain. Typically, these
are the receptors on which fast neurotransmitters act.
Examples: nicotinic acetylcholine receptor, GABAA receptor, and glutamate receptor of N-
methyl-D-aspartic acid (NMDA).
G-protein-coupled receptors: It is also called metabotropic receptors or seven-trans membrane
spanning receptors that act through a second messenger, which elicits an action. Second
messengers usually are cyclic adenosine monophosphate (cAMP) and inositol trisphosphate (IP3).
Examples: muscarnic receptors, beta adrenergic receptors, serotonin receptors and opioid
receptors.
Kinase-linked or enzyme-linked receptors: These constitute extracellular ligand-binding
domain that is linked to an intracellular domain by a single transmembrane helix. In many cases,
the intracellular domain is enzymatic in nature. Some times the receptor subunit may bind to an
enzyme called Janus-Kinase. Type 3 receptors include those for insulin and various cytokines.
Nuclear receptors: The nuclear receptors regulate the gene transcriptions, are located in the
cytosol, and migrate to the nuclear compartment when a ligand is present. The receptor protein is
inherently capable of binding to specific genes. These include the receptors of glucocorticoids and
thyroid hormone.
THEORIES OF RECEPTORS
Occupation Theory
Proposed by Gaddum and Clark, the theory states that the intensity of pharmacological effect is
directly proportional to the number of receptors occupied by the drug. The pharmacological
response of a drug molecule depends on the amount of dose, the total number of receptors
available, and its intrinsic activity that can be expressed as K1[R] × [A].
where K1 = association constant
R = concentration of the receptors not occupied by drugs
A = concentration of drug molecules or dose
Similarly, the rate of dissociation of the drug receptor complex is given by the expression K2 [RA].
K2 = dissociation constant
[RA] = concentration of receptors occupied by the drug
At equilibrium, K1[R] × [A] = K2[RA]
[R] + [RA] is equal to [r] = total concentration of the receptors.
Thus, K1[A] [r] – [RA] = K2 [RA] ----- (1)
or
[RA]/[r] = K1[A]/K1[A] + K2 = 1/1 + K2/K1[A] ----- (2)
K2/K1 can be replaced by KA = equilibrium constant.
It is the reciprocal of the drugs affinity for the receptors.
The term [RA]/[r] represent the fraction of the total number of receptors occupied by the drug.
When [RA] = [r], that is, all receptors are occupied and the response is, thus, proportional to its
intrinsic
activity Xn
Relative response = [RA]X/[r] = X/1 + KA/[A] ---- (3)
This theory does not rationalize partial antagonists.
Rate Theory
The rate theory explains that the pharmacological activity is a function of the rate of association
and dissociation of a drug with the receptor and is not the function of the number of occupied
receptors.
At equilibrium, the rates of combination and dissociation of drug-receptor reactions are same and
Eqn(1) can be written as
K1[A] ([r]-[RA])/[r] = K2 [RA]/[r]----(4)
or
Rate of receptor occupation = K2/1 + RA/[A] ---(5)
When the response is proportional to the number of receptors occupied, Eqn (3) is important and
when the response is proportional to the rate of receptors, Eqn (5) is important.
Induced Fit Theory
It is proposed by Koshland to give explanation for the action of enzymes and substrates. It explains
that the receptor (enzyme) need not necessarily exist in the same conformation that is required to
bind the drug (substrate). As the drug approaches the receptor, a conformational change is induced
for binding, which initiates the pharmacological activity.
Example: Acetylcholine interacts with the regulating protein and alters the normal forces that
stabilizes the structure of the protein and thereby producing a transient rearrangement in membrane
structure and a consequent change in its ion regulating property. These receptors are suggested to
be elastic and returns to the original conformation after the drug releases.
According to this theory, an agonist will bind by conformational change with intrinsic activity and
elicit a response, but an antagonist will bind by conformational change without intrinsic activity.
Macromolecular Perturbation Theory
According to this theory, the drug interaction with a receptor leads either to specific conformational
perturbations (SCPs) or to nonspecific conformational perturbations (NSCPs). An SCP will
produce a specific response from an agonist in which the drug possesses intrinsic activity. In NSCP,
no stimulant action, but may be antagonistic or blocking action will be produced. If a drug
possesses SCP and NSCP features, an equilibrium mixture of two complexes may result and leads
to partial agonistic action.
Example: Alkyl trimethyl ammonium ions C1 to C6, Alters receptor structure and produces
muscarinic agonistic action C8 to C12, Antagonistic action Heptyl and octyl derivatives—Partial
agonists (intermediate derivatives)
Activation–Aggregation Theory
According to this theory, even in the absence of drugs, a receptor is in a state of dynamic
equilibrium between an activated form (Ro), which is responsible for biological responses and an
inactive form (To). Agonists shift the equilibrium to activated form and antagonists shift the
equilibrium to inactivated form.
Partial agonists bind to both conformations during partial antagonistic action. The agonist-binding
site and antagonist-binding site conformation may be different.
FORCES INVOLVED IN DRUG RECEPTORS INTERACTION
Covalent Bonding
Covalent bonds are the one which are produced by a strong energy. These are produced only when
an irreversible antagonist inactivates the receptors. If a weak bond forms the drug receptor
complex, the complex formed will be a reversible type.
Example: Acetylcholinesterase is irreversibly inactivated by a number of phosphate esters
(organophosphorus compounds includes pesticides). The nitrogen mustards are irreversible
inhibitors of certain receptors.
Dipole-Dipole and Ion-Dipole Interactions
It is associated with electrostatic bonding. Molecules in which there is a partial charge separation
between adjacent atoms or functional groups can interact either with each other or with ions. The
carbon-X bonds in drugs and receptors (where X is an electronegative atom) will have asymmetric
distribution of electrons. This produces electronic dipoles. The dipoles in a drug molecule can be
attracted by ions (ion-dipole interaction) or by other dipole-dipole interaction (Fig. 2.1). Ion dipole
interactions are more powerful and has high energy.
Hydrogen Bonding
It forms a weak (energy from 7 to 40 KJ/mol) and easily breaking bond. Since drugs contain
hydroxyl, amino, carboxyl, and carbonyl groups it can form H bonds with the receptors. H-bonding
is a type of dipole-dipole interaction formed between the proton of a group X-H (X-is an
electronegative atom) and other electronegative atoms (Y) containing pairs of nonbonded
electrons. X removes electron density from hydrogen. Therefore, it has a partial positive charge,
which is strongly attached to nonbonded electrons of Y. Hydrogen bonding usually stabilizes the
structures by intramolecular bond formation. Such bond formation occurs in protein alpha helix
and in base pair of DNA.
Electrostatic Bonding
The opposite charged compound will interact with the opposite charged part of the receptor. The
positively charged quaternary N-acetylcholine may be attracted to the negative charge of an ionized
carboxyl group in the receptor.
Charge Transfer Complex
A dipole-dipole interaction is produced and a charge transfer complex is formed when any
molecule with electron-donating property comes near the electron-accepting group. Donor
molecules are electrons rich in heterocycles, for example, furan, thiophene, and aromatics with
electron-donating substituents, or compounds with free nonbonding electron pair. Acceptor
molecules are electron deficient systems such as purines and pyrimidines or aromatics with
electron-withdrawing substituents. Examples of charge transfer complex in drug receptor
interaction are antimalarials with their receptors and antibiotics intercalating the DNA. The energy
is not more than 30 KJ/mol.
Hydrophobic Forces
In the presence of nonpolar molecules, the surrounding water molecules orient themselves, and
therefore, are in a high-energy state, when two nonpolar receptor groups (one from the drug and
another from the receptor) approach disorder–ordered H2O molecules in an attempt to associate
with each other by increasing the enthalpy and decreasing the free energy to stabilize drug receptor-
complex.
van der Waal’s or London Dispersion Forces
Atoms in nonpolar molecular structure have a temporary nonsymmetrical distribution of electron
density, which results in the generation of a temporary dipole that creates an intermolecule
attraction called van der Waal’s force. However, this is a weak bond.
FACTORS AFFECTING THE DRUG-RECEPTOR INTERACTION
Isosterism: Groups of atoms that possess similar physical or chemical properties of a molecule
due to similarity in size, electronegativity, or stereochemistry are referred to as isosteres. The
existences of such groups in molecules are termed isosterism. For example, N2 and CO, both have
14 total electrons and no charges and show the same physical properties. In Sulphonamides, the
replacement of atoms or groups with various isosters, other analogues are developed. Potency of
these agents varied according their interaction with the target.
Steric features of a drug: The drug must possess stereoselective property to initiate a response at
a particular receptor. For example, trans-diethylstilbosterol is oestrogenic while cis-isomer is
almost inactive. Optical isomerism: Enantiomers, asymmetry, and chirality are important concepts
to give better receptor interaction with drugs. Although each enantiomer has some physical and
chemical properties, they may act in different ways and in different sites to produce variable
pharmacological action.
Computer aided drug design (CADD) involves all the computer-assisted techniques that are used
to discover, design, and optimize biologically active compounds with putative use as a drug having
the desired structure and properties.
The process of drug discovery and development is a long, tedious, and difficult one with the high
demand for drugs on one side and the complexity of various biological systems on the other side.
Occasionally, new drugs are discovered by accident, more frequently, they are developed as a part
of an organized effort to discover new ways to treat specific diseases. The trial-and-error method
usually employed for new drug developments are highly uneconomical, as they require various
predictions, such as pharmacokinetic, pharmacodynamic, and toxic properties before the synthesis
of a chemical compound. Finally, after these, it is observed that out of the several thousand
compounds synthesized and tested, hardly one, two, or even none clicks. Today, the emphasis is
not just finding new ways to treat human disease, but also on improving the quality of life in
general. Computer-based drug design techniques have the ability to accomplish both these goals
and improve the efficiency of the process as well.
The drug discovery and lead optimization process is currently dominated by developments in two
fi elds, a rational design based on structural information and sophisticated computational methods
to elucidate the structural prerequisites that are important for binding to a particular target.
The rational drug design processes have changed the way in which potential new drugs are
discovered.
The rational drug design process starts with an understanding of the fundamental physiological
and biochemical aspects of the disease or target, rather than a random screening process. One
method to bring about cost-effectiveness in the drug design process is by applying both the
knowledge of the mechanistic basis of a target disease and the molecular characteristics of the
compounds to have an effect on the disease state. This approach to therapeutic development is
called the rational drug design approach.
CADD is a specialized branch that covers computational methods of calculation, and graphics
techniques give information about drug-receptor interactions. CADD methods are closely linked
to bioinformatics applications and databases

Synthesis
Drug synthesis may be accomplished by the actual preparation of a wide variety of compounds
involving a representative careful selection of typical documented reaction processes and the latest
techniques. Perhaps, logically and justifiably the prospective budding ‘medicinal chemists’ on the
strong foot-hold of good theoretical knowledge and the various chemical, physical, and
spectroscopical aspects may begin to understand more vividly and explicitly the cardinal factors
that essentially attribute their reactivity vis-a-vis biological activity.
‘Drug design’ or ‘tailor-made compound’ particularly aims at developing a drug with a very high
degree of chemotherapeutic index and specificity of action. With the advent of latest concepts and
tools evolved in ‘Computer Aided Drug Design (CADD)’ one may logically design a new drug
molecule on as much a rational basis as possible.
It is, however, pertinent to mention here that ‘medicinal chemists’ have traditionally adopted
synthesis as the ultimate-concrete-evidence of molecular structure(s) of natural products
meticulously isolated from plant and animal sources. Over the years it has been universally
accepted as an authentic and genuine proof-of-identity between an isolated natural substance and
the compound produced by total-synthesis eventually confirmed the molecular structure arrived at
through various physicochemical methods of analysis.
Therefore, a thorough basic concept and knowledge of ‘drug synthesis’ may ultimately help a
medicinal chemist to produce life-saving drugs, such as : penicillin, quinine, prostaglandins,
steroids, anti-neoplastic agents. In short, synthetic medicinal chemistry, with the skill, wisdom and
effort, has proved to be a major endeavor not only confined to the laboratories of Universities in
general, but also to the bulk-drug industry in particular
Concept of Synthesis
In the past one century and a half ‘research chemists’ across the globe have evolved an
innumerable, viable and potential synthetic routes for the preparation of any conceptualized
‘target-drug-molecule’. Interestingly, in the last four decades or so the very emergence of
the creation of piecing together a logical philosophy and a well-conceived theoretical design
have, in fact, made the entire task of complicated and strategic ‘drug design’ into a rather
easier and viable proposition. With the advent of computer-assisted-drug-design (CADD)* the
overall cost of drug development may, therefore, be reduced drastically by minimizing the number
of drug candidates that are synthesized and screened biologically route to each successful or
computerized-molecular-modeling based ‘target-drug molecules’. The computerized molecular
graphics allow a research chemist to make optimum utilization of the ability of computer software
to quantify an elaborated measurement of molecular geometry, conformation, electron
densities, electrostatic potential energies, and above all the direct comparisons of key structural
features of a wide range of biologically, potent active structure(s). The power of the human eye
together with the ‘brain’ can interact directly and intimately with the data processing
capability of the computer.
There are a number of important considerations that have got to be followed sequentially,
artistically, meticulously, and above all an individual’s own skill and wisdom in accomplishing
the ‘target-drug-molecule’ as stated below :

a. Prime considerations in designing synthesis,

b. The Synthon Approach,
c. The Retro-Synthetic Approach,
d. Materials required,
e. Reaction specificity,
f. Purity and yield.

2.2.1 Prime Considerations in Designing Synthesis

The first and foremost objective is to conceptualize any given ‘target-drug-molecule’ based
theoretically upon pharmacophoric entities or various clues and indicators derived from
biologically active prototypes after a vigorous and thorough survey of a wide range of literatures
available. Presently, any reasonably well-equipped library should have an easy access to online
latest scientific journals and CD-Rom facilities so that a research chemist may reach to the bottom
of the ocean of copious volumes of subject-related topics published in the world.
From a close-look of the target-drug-molecule the researcher may logically ponder over the ways
and means to accomplish their objective through the kinds of reaction(s) to make use in a sequential
manner.
In other words, the strategic attack on the target-drug-molecule may be conveniently and formally
divided into two major components, namely:
(a) Basic Carbon Skeleton. The importance of the basic carbon skeleton present in the conceived
and proposed target-drug-molecule structure in any synthesis, cannot be ruled out. It may be
accomplished through a series of reactions that eventually form the vital links to the newly
proposed carbon skeleton. Therefore, the adequate planning on the board for the logical creation
of carbon-carbon bonds, frequently termed as the construction reactions, is regarded as the
backbone and obviously the most crucial step in designing a synthesis.
(b) Inclusion of Functional Moieties. Invariably, the necessary and required functional groups
are most carefully and strategically positioned at various specific locations on the proposed target
skeleton. These are usually dealt within a specific way, and hence could be the possible outcome
of last reactions in the synthesis. They may also be carried out successfully either by means of
aforesaid construction reactions or through functional alteration reactions. However, the latter
operation(s) exclusively alter the ‘functional moieties’ without affecting the basic carbon-carbon
skeleton. The exact nature of the functional moieties present in the target-drug-molecule may,
therefore, guide one precisely about what chemical reactions might be opted for.

In actual practice, one may also observe that a criterion of selecting organic reactions important in
designing a synthesis is that the reactions usually occur at or adjacent C-atoms having the
functional moieties. In other words, the very C-atoms which essentially bear functional moieties
in the target shall normally also possess allied functions either in the starting products or
intermediates of any synthetic sequence of reactions. Besides, it has also been observed that there
are substantially very few reactions which might incorporate a functional moiety directly onto a
hydrocarbon site located apart from another functional moiety; and there are certain construction
reactions wherein a functional moiety altogether vanishes from a C-atom. Bearing in mind the
above vital observations and findings one may safely infer that—“the location of the functional
moieties present in target-drug-molecule structure is much more important than their actual
nature”.
Summarily, there could be several genuine and possible reasons of undertaking the herculean-task
for the total laboratory synthesis of an organic target-drug-molecule ab initio from simple
precursors. Evidently, the pharmaceutical industry, looks for newer organic drug molecules that
are particularly designed and synthesized with a possible hope that some of them may evolve as a
potential useful ‘new drug’ to combat the human sufferings and ailments. In short, the ultimate
successful route of synthesis is indeed acclaimed as a highly creative and dedicated research output
which is sometimes pronounced and described by such subjective terminologies as beautiful or
elegant or superb.
The Synthon Approach
A synthon may be defined as—‘a structural unit that becomes an idealized fragment as a result
of disconnection of a carbon-carbon or carbon-heteroatom bond in a retrosynthetic step
(transform)’.
Therefore, one would broadly imagine that an open-chain structure while undergoing a single-
disconnection step would ultimately yield two synthons. Further, an alike disconnection of a bond
joining a functional group to a cyclic structure would also give rise to two synthons. Interestingly,
the synthons being obtained from single bond disconnections could be either ions (cations or
anions) or radicals exclusively depending on the fact whether the cleavage encountered to the
bond is heterolytic or homolytic. Invariably, they do not behave