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2 General Terms and Concepts in Synthetic Organic Chemistry38
2.39 Solid-phase Synthesis
Solid-phase synthesis is a technique where molecules are covalently attached to a
solid support material and synthesized sequentially in a single reaction vessel using
selective protecting group chemistry. This approach is widely employed for the syn-
thesis of peptides [60, 61], deoxyribonucleic acid (DNA), ribonucleic acid (RNA),
and other molecules that require precise sequential assembly [62]. In recent years,
it has also found applications in combinatorial chemistry and various synthetic
processes. The method was pioneered in the 1950s and 1960s by Robert Bruce
Merrifield, who developed it specifically for synthesizing peptide chains [63]. His
groundbreaking work earned him the 1984 Nobel Prize in Chemistry.
In peptide synthesis, an amino-protected amino acid is first attached to a
solid-phase material or resin, typically low cross-linked polystyrene beads, forming
a covalent bond—often an amide or ester linkage—between the carbonyl group of
the amino acid and the resin [64]. The amino group is then deprotected and reacted
with the carbonyl group of the next N-protected amino acid, resulting in a dipep-
tide bound to the solid support. This cycle is repeated iteratively to build the desired
peptide chain. Once the synthesis is complete, the peptide is cleaved from the resin.
The process can be illustrated through the synthesis of a dipeptide, as outlined in
the following scheme [60].
2.40 Combinatorial Chemistry
Combinatorial chemistry involves chemical synthesis techniques designed to
produce a vast number of compounds—ranging from tens to thousands, or even
millions—in a single procedure. This approach was pioneered by Árpád Furka
from Eötvös Loránd University in Budapest, Hungary. The core principle of com-
binatorial chemistry is to synthesize a multicomponent compound mixture, known
Polystyrene
Cl
NHCbz
Polystyrene
HBr-HOAc
NHCbz
O
O
NHCbz
NO
2
Polystyrene
O
O
Polystyrene
O
O
H
N
O
NHCbz
HBr-HOAc
Deprotection
Cbz
Covalent bond
formation
Deprotection
Cbz
Couple with 2nd
amino acid
Polystyrene
O
O
H
N
O
aq. NaOH
H
N
O
HO
O
Polystyrene
OH
Cleave from
polymer
dipeptide
HO
2
C
R
1
NO
2
R
1
NO
2
NH
2
R
1
HO
2
C
R
2
NO
2
R
1
R
2
NO
2
R
2
R
1
NH
2
NO
2
R
1
R
2
NH
2
2.41 Process Chemist versus Medicinal Chemist 39
as a combinatorial library, through a single stepwise process. This library is then
screened to identify potential drug candidates or other useful compounds. A key
innovation of this method is the use of mixtures during both synthesis and screen-
ing, which significantly enhances the efficiency and productivity of the process. The
motivations behind the development of combinatorial chemistry were detailed in a
publication in 2002 [65].
Combinatorial chemistry began to gain significant traction in the industrial sector
starting in the 1990s [66] and has since become a crucial component of early-stage
drug discovery for over 20 years. To date, only one drug developed through de novo
combinatorial chemistry synthesis has received FDA approval for clinical use:
sorafenib, a multikinase inhibitor used to treat advanced renal cell cancer [67].
2.41 Process Chemist versus Medicinal Chemist
Process chemistry plays a crucial role in medicinal chemistry, yet the responsibil-
ities of process chemists and medicinal chemists (also known as discovery
chemists) differ significantly. These differences can be summarized in the follow-
ing key aspects:
• Number of Synthesized Compounds: Medicinal chemists focus on synthe-
sizing a large number of compounds within a given project to screen for bio-
activity and conduct structure-activity relationship (SAR) studies. In contrast,
process chemists typically synthesize a single compound, which is intended for
use in clinical studies or as an API in a marketed drug.
• Quantity of Synthesized Compounds: Medicinal chemists usually produce
small quantities of each target compound, typically in the range of 5–10 mg,
which is sufficient for preliminary bioactivity screening. Process chemists,
however, work on a much larger scale, synthesizing compounds in kilogram
or even ton quantities to meet the demands of clinical trials and commercial
production.
• Synthetic Methods and Reaction Conditions: Medicinal chemists priori-
tize speed and diversity in synthesis, often employing divergent strategies to
generate numerous compounds from common intermediates (scaffolds). The
synthetic routes and reaction conditions are generally not optimized, and
factors such as yield, purification convenience, cost, and green chemistry are
not their primary concerns. If a compound lacks bioactivity, the elegance of its
synthesis becomes irrelevant. In contrast, process chemists focus on optimizing
synthetic routes to ensure high yield, safety, cost-effectiveness, labor efficiency,
environmental sustainability (“greenness”), and robustness. As a result, the
final synthetic route developed by process chemists often differs significantly
from that used by medicinal chemists.
• Involvement in Drug Discovery Stages: Medicinal chemists are primarily
involved in the early stages of drug discovery, synthesizing a large number of
compounds for activity screening. Once a promising drug candidate is identi-
fied, the synthesis must be scaled up to gram or hundred-gram quantities for
2 General Terms and Concepts in Synthetic Organic Chemistry40
preclinical studies. At this stage, process chemists step in to ensure the drug
candidate is synthesized in the required quantities and quality, adhering to
project timelines. Additionally, process chemists play a critical role in devel-
oping robust synthetic processes for producing the drug candidate or API on a
kilogram scale during clinical studies and commercial production.
• Quality Requirements for Final Products: The purity requirements for
compounds synthesized by medicinal chemists are relatively modest, typically
around 98% (and sometimes as low as 95%) for preliminary screening purposes.
In contrast, process chemistry demands much higher purity standards for its
products [68]. Certain impurities must be controlled to levels below specified
thresholds. For APIs, if an impurity exceeds 0.1%, its structure must be identi-
fied and characterized.
In summary, while medicinal chemists and process chemists both contribute to
drug development, their roles, priorities, and methodologies differ significantly,
reflecting the distinct requirements of early-stage discovery versus late-stage
development and production.
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Some basic concepts, principles, and approaches in medicinal chemistry and drug
discovery are collected in this chapter.
3.1 What Is a Drug?
A drug is any chemical substance that, when taken, causes changes in the physi-
ology of an organism, including its psychology (if applicable) [1, 2]. Typically drugs
are molecules used as drugs or pharmaceutical ingredients to diagnose, cure, miti-
gate, treat, or prevent disease. Medications are generally distinguished from foods
and other substances that provide nutritional support. The drug may be consumed
by inhalation, injection, smoking, ingestion, eye or nose drops, via skin patches,
suppositories, or by dissolving under the tongue. Traditionally, drugs were obtained
through extraction from medicinal plants, but in modern times an increasing
number of drugs are obtained through organic synthesis [3]. Medications can be
used for a limited time, or on a regular basis to treat chronic conditions.
3.2 Drug Discovery
Drug discovery is the process of discovering new drugs.
Historically, drugs were discovered by identifying active ingredients from tra-
ditional remedies or by serendipitous discovery. More recently, chemical libraries
of synthetic small molecules, natural products, or extracts are screened in intact
cells or whole organisms to identify substances with desirable therapeutic effects
in a process known as classical pharmacology. After the sequencing of the human
genome allowed rapid cloning and synthesis of large quantities of purified proteins,
high-throughput screening (HTS) using large libraries of compounds against iso-
lated biological targets that were hypothesized to ameliorate disease has become
common practice in a process known as reverse pharmacology. The hits from these
screens are then tested in cells and then in animals for efficacy.
3
General Terms and Concepts in Medicinal Chemistry
3 General Terms and Concepts in Medicinal Chemistry44
In modern drug discovery, target molecules, such as proteins, related to disease
processes are identified. Once a target molecule is validated, scientists initiate a dis-
covery process to find other molecules or substances that act on the target. The pro-
cess of finding molecules that act on a target (i.e., lead molecules) can be arduous;
thousands of compounds may need to be screened to find one or more promising
leads. Once a lead molecule is identified, it can be chemically modified to increase
its efficacy against the target molecule.
Drug discovery is a multifaceted process that begins with the identification of
potential screening hits [4], followed by medicinal chemistry [5] efforts to refine
these hits. The goal is to optimize their properties, including affinity, selectivity
(to minimize side effects), efficacy/potency, metabolic stability (to extend half-life),
and oral bioavailability. Once a compound meets these criteria, it advances to the
drug development phase. If it proves viable, clinical trials are initiated.
Modern drug discovery is a highly capital-intensive endeavor, requiring substan-
tial investments from pharmaceutical companies and governments alike. Despite
technological advancements and a deeper understanding of biological systems, the
process remains lengthy, costly, and challenging, with a low success rate for discov-
ering new treatments [6]. In 2018, the research and development costs for a new
molecular entity ranged from approximately 318 million to 2.8 billion [7]. In the
twenty-first century, early-stage discovery research is primarily funded by govern-
ments and philanthropic organizations, while later-stage development is typically
financed by pharmaceutical companies or venture capitalists. To gain approval for
market release, a drug must successfully navigate multiple phases of clinical trials
and undergo a rigorous regulatory review process, such as the New Drug Application
(NDA) in the United States.
3.3 Medicinal Chemistry
Medicinal chemistry is an interdisciplinary field that bridges chemistry and phar-
macy, focusing on the design, discovery, and development of therapeutic drugs.
This discipline encompasses the identification, synthesis, and optimization of new
chemical compounds for medical use, as well as the investigation of the biological
effects and structure–activity relationships (SAR) of existing drugs. These studies
often involve quantitative structure–activity relationship (QSAR) analyses to under-
stand how chemical structures influence biological activity [8, 9].
As a highly integrative science, medicinal chemistry draws on principles and
techniques from organic chemistry, biochemistry, computational chemistry, phar-
macology, molecular biology, statistics, and physical chemistry.
The compounds utilized as drugs can be classified into several broad categories,
each with distinct characteristics and applications.
1. Organic compounds
1a. Small organic molecules (e.g., simvastatin, dexamethasone, imatinib)
1b. “Biologics” (erythropoietin, insulin glargine, talquetamab), which are
usually protein pharmaceuticals (natural and recombinant antibodies,
hormones, etc.)
3.5 Enzyme 45
2. Inorganic and organometallic compounds [10, 11], commonly known as metal-
lodrugs, include agents such as cisplatin (platinum-based), lithium carbonate
(lithium-based), and gallium nitrate (gallium-based).
Medicinal chemistry, particularly in its most prevalent form—centered on small
organic molecules—encompasses synthetic organic chemistry, natural products,
and computational chemistry. It is deeply intertwined with chemical biology, enzy-
mology, and structural biology, collectively striving to discover and develop new
drugs. This field involves investigating the synthetic and computational dimen-
sions of both existing drugs and those in development, with a focus on their
bioactivity and properties. A key aspect is understanding SARs to optimize drug
efficacy. Additionally, medicinal chemistry plays a critical role in pharmaceutical
quality control, ensuring the safety and effectiveness of drug products [12].
3.4 Drug Target
A drug target is a molecule in the body, usually a protein, that is intrinsically asso-
ciated with a particular disease process and that could be addressed by a drug via
interaction with the target to produce a desired therapeutic effect. Drug targets can
be classified as enzymes, receptors, and nucleic acids. In modern drug discovery,
most of the new approved drugs are targeted drugs. For example, in 2023, the Food
and Drug Administration (FDA) approved 55 novel drugs, 47, or 85.5%, were tar-
geted therapies, reflecting a clear trend toward more personalized and effective
treatment options [13].
3.5 Enzyme
Enzymes are specialized proteins that function as biological catalysts—substances
that accelerate chemical reactions without being consumed in the process. Without
enzymes, the chemical reactions within cells would either proceed too slowly or fail
to occur at all. The specific molecule upon which an enzyme acts is referred to as a
substrate, and the enzyme transforms the substrate into different molecules called
products. Nearly all metabolic processes in cells depend on enzyme catalysis to pro-
ceed at rates sufficient to support life. Metabolic pathways are driven by enzymes,
which facilitate multiple steps in these processes. The scientific study of enzymes is
known as enzymology.
Enzyme activity may be affected by other molecules: inhibitors are molecules
that reduce enzyme activity, and activators are molecules that increase enzyme
activity.
Drugs that function as enzyme inhibitors constitute a significant portion of the
orally bioavailable therapeutic agents that are in clinical use today. Likewise, much
of drug discovery and development efforts at present are focused on identifying and
optimizing drug candidates that act through inhibition of specific enzyme targets
[14, 15]. Lovastatin is an inhibitor of 3-hydroxy-3-methylglutaryl (HMG) coenzyme
A (HMG-CoA) reductase used in the treatment of hypercholesteremia [16].
3 General Terms and Concepts in Medicinal Chemistry46
Protein kinases are enzymes that phosphorylate proteins (add a phosphate or PO
4
group) and regulate their function and are important drug targets for the treatment
of certain diseases, especially cancer. As of September 2021, the FDA has approved
73 small-molecule kinase inhibitor drugs [17].
Paxlovid is a medication specifically designed to treat COVID-19 [18]. It consists of
two antiviral drugs, nirmatrelvir and ritonavir, co-packaged together. Nirmatrelvir
works by inhibiting the main protease of SARS-CoV-2, the virus responsible for
COVID-19. Ritonavir, on the other hand, acts as a potent CYP3A inhibitor, which
slows down the metabolism of nirmatrelvir, thereby enhancing its effectiveness.
3.6 Receptor
In the fields of biochemistry and pharmacology, receptors are protein-based
chemical structures that receive and transmit signals, which can then be integrated
into biological systems. These signals are usually chemical messengers that bind to
receptors, triggering physiological responses, such as alterations in a cell’s electrical
activity. The actions of receptors can be categorized into three primary functions:
signal relay, amplification, and integration. Signal relay involves transmitting the
signal forward, amplification enhances the impact of a single ligand, and integration
enables the signal to be incorporated into other biochemical pathways. Receptors
are, by a significant margin, the most critical drug targets in medical science [19].
Receptor proteins are categorized based on their location within the cell.
Cell surface receptors, also referred to as transmembrane receptors, encom-
pass ligand-gated ion channels, G protein-coupled receptors (GPCRs), and
enzyme-linked hormone receptors. Intracellular receptors, on the other hand,
are located inside the cell and include cytoplasmic receptors and nuclear
receptors. A ligand is a molecule that binds to a receptor, which can be a protein,
peptide, or a small molecule such as a neurotransmitter, hormone, pharmaceutical
drug, toxin, calcium ion, or components of a virus or microbe’s outer structure.
A naturally occurring substance that binds to a specific receptor is known as
its endogenous ligand. For example, acetylcholine is the endogenous ligand for
the nicotinic acetylcholine receptor, though this receptor can also be activated by
N
H
H
O
H
N
F
O
F
F
H
N
NH
O
N
O
Nirmatrelvir
HN
H
N
OH
O
O
S
N
O
HN
N
O
N
S
Ritonavir
3.7 Inhibitor 47
nicotine and inhibited by curare. Each type of receptor is connected to distinct
cellular biochemical pathways that align with the signal it receives. Although most
cells contain a variety of receptors, each receptor is selective and will only bind
to ligands with a specific structure. This specificity is often likened to a lock that
only opens with a uniquely shaped key. When a ligand binds to its corresponding
receptor, it either activates or inhibits the receptor’s associated biochemical pathway,
which is often highly specialized in its function.
GPCRs and G protein-linked receptors are a class of cell surface receptors that
sense extracellular molecules and initiate intracellular signaling pathways. These
receptors are associated with G proteins, which facilitate the transmission of signals
into the cell. GPCRs represent a critical target for pharmaceutical development, and
as of 2018, around 34% of all drugs approved by the U.S. FDA act on 108 members
of this receptor family [20].
Drugs that mimic the natural messengers and activate receptors are known as
agonists. Drugs that block receptors are known as antagonists. Antagonist still
binds to the receptor, but it does not activate it. However, because it is bound to the
receptor, it prevents the natural messenger from attaching and activating it.
Cortisol is used as anti-inflammatory agent and acts as an agonist at the glucocor-
ticoid receptor. Raloxifene is an antagonist of the estrogen receptor and is used for
the treatment of hormone-dependent breast cancer.
Chemokine receptor 5 (CCR5) and CXCR4 serve as the primary receptors facili-
tating the entry of human immunodeficiency viruses (HIV) into cells. These recep-
tors are part of the GPCR family. CCR5 receptor antagonists are a group of small
molecules designed to block the CCR5 receptor. As a result, these antagonists act as
entry inhibitors and hold promise for therapeutic use in managing HIV infections.
Maraviroc, which was discovered and developed by Pfizer, became the first CCR5
antagonist to receive FDA approval in August 2007 [21].
3.7 Inhibitor
An enzyme inhibitor is a molecule that attaches to an enzyme and disrupts
its function. Enzymes are proteins responsible for speeding up and enabling the
chemical reactions essential for life, where substrates are transformed into prod-
ucts. They achieve this by binding substrates to their active site, a specialized area
on the enzyme that accelerates the most challenging steps of the reaction. Enzyme
inhibitors hinder this process by either binding to the enzyme’s active site (prevent-
ing the substrate from attaching) or attaching to another part of the enzyme, thereby
blocking its catalytic activity.
H
H
H
OH
O
HO
OH
O
Cortisol
S
HO
OH
O
O
N
Raloxifene
N
H
O
N
F
F
N
N
N
Maraviroc