INTRODUCTION

TO
MEDICINAL CHEMISTRY

Amity Institute of Pharmacy

Dr. SATHISH KUMAR M
BP402T. MEDICINAL CHEMISTRY – I (Theory)
45 Hours
Scope: This subject is designed to impart fundamental knowledge on the structure,
chemistry and therapeutic value of drugs. The subject emphasizes on structure
activity relationships of drugs, importance of physicochemical properties and
metabolism of drugs. The syllabus also emphasizes on chemical synthesis of
important drugs under each class.
Objectives: Upon completion of the course the student shall be able to
1. understand the chemistry of drugs with respect to their pharmacological activity
2. understand the drug metabolic pathways, adverse effect and therapeutic value of
drugs
3. know the Structural Activity Relationship (SAR) of different class of drugs
4. write the chemical synthesis of some drugs
Course Content:
Study of the development of the following classes of drugs, Classification, mechanism of action, uses of
drugs mentioned in the course, Structure activity relationship of selective class of drugs as specified in the
course and synthesis of drugs superscripted (*)
UNIT- I 10 Hours

Introduction to Medicinal Chemistry

History and development of medicinal chemistry
Physicochemical properties in relation to biological action
Ionization, Solubility, Partition Coefficient, Hydrogen bonding, Protein
binding, Chelation, Bioisosterism, Optical and Geometrical isomerism.
Drug metabolism
Drug metabolism principles- Phase I and Phase II.
Factors affecting drug metabolism including stereo chemical aspects.
UNIT- II 10 Hours
Drugs acting on Autonomic Nervous System
Adrenergic Neurotransmitters:
Biosynthesis and catabolism of catecholamine.
Adrenergic receptors (Alpha & Beta) and their distribution.
Sympathomimetic agents: SAR of Sympathomimetic agents
Direct acting: Nor-epinephrine, Epinephrine, Phenylephrine*,
Dopamine, Methyldopa, Clonidine, Dobutamine, Isoproterenol,
Terbutaline, Salbutamol*, Bitolterol, Naphazoline, Oxymetazoline and
Xylometazoline.
 Indirect acting agents: Hydroxyamphetamine, Pseudoephedrine,
Propylhexedrine.
 Agents with mixed mechanism: Ephedrine, Metaraminol.
Adrenergic Antagonists:
Alpha adrenergic blockers: Tolazoline*, Phentolamine,
Phenoxybenzamine, Prazosin, Dihydroergotamine, Methysergide.
Beta adrenergic blockers: SAR of beta blockers, Propranolol*,
Metibranolol, Atenolol, Betazolol, Bisoprolol, Esmolol, Metoprolol,
Labetolol, Carvedilol.
UNIT-III 10 Hours
Cholinergic neurotransmitters:
Biosynthesis and catabolism of acetylcholine.
Cholinergic receptors (Muscarinic & Nicotinic) and their distribution.
Parasympathomimetic agents: SAR of Parasympathomimetic agents
Direct acting agents: Acetylcholine, Carbachol*, Bethanechol,
Methacholine, Pilocarpine.
Indirect acting/ Cholinesterase inhibitors (Reversible & Irreversible):
Physostigmine, Neostigmine*, Pyridostigmine, Edrophonium chloride,
Tacrine hydrochloride, Ambenonium chloride, Isofluorphate, Echothiophate
iodide, Parathione, Malathion.
Cholinesterase reactivator: Pralidoxime chloride.
Cholinergic Blocking agents: SAR of cholinolytic agents
Solanaceous alkaloids and analogues: Atropine sulphate, Hyoscyamine
sulphate, Scopolamine hydrobromide, Homatropine hydrobromide,
Ipratropium bromide*.
Synthetic cholinergic blocking agents: Tropicamide, Cyclopentolate
hydrochloride, Clidinium bromide, Dicyclomine hydrochloride*,
Glycopyrrolate, Methantheline bromide, Propantheline bromide,
Benztropine mesylate, Orphenadrine citrate, Biperidine hydrochloride,
Procyclidine hydrochloride*, Tridihexethyl chloride, Isopropamide iodide,
Ethopropazine hydrochloride.
UNIT- IV 08 Hours
Drugs acting on Central Nervous System
A. Sedatives and Hypnotics:
Benzodiazepines: SAR of Benzodiazepines, Chlordiazepoxide, Diazepam*,
Oxazepam, Chlorazepate, Lorazepam, Alprazolam, Zolpidem
Barbiturtes: SAR of barbiturates, Barbital*, Phenobarbital, Mephobarbital,
Amobarbital, Butabarbital, Pentobarbital, Secobarbital
Miscelleneous:
Amides & imides: Glutethmide.
Alcohol & their carbamate derivatives: Meprobomate, Ethchlorvynol.
Aldehyde & their derivatives: Triclofos sodium, Paraldehyde.
B. Antipsychotics
Phenothiazeines: SAR of Phenothiazeines - Promazine hydrochloride,
Chlorpromazine hydrochloride*, Triflupromazine, Thioridazine hydrochloride,
Piperacetazine hydrochloride, Prochlorperazine maleate, Trifluoperazine
hydrochloride.
Ring Analogues of Phenothiazeines: Chlorprothixene, Thiothixene, Loxapine
succinate, Clozapine.
Fluro buterophenones: Haloperidol, Droperidol, Risperidone.
Beta amino ketones: Molindone hydrochloride.
Benzamides: Sulpieride.
C. Anticonvulsants: SAR of Anticonvulsants, mechanism of anticonvulsant
action
Barbiturates: Phenobarbitone, Methabarbital. Hydantoins:
Phenytoin*, Mephenytoin, Ethotoin Oxazolidine diones:
Trimethadione, Paramethadione Succinimides:
Phensuximide, Methsuximide, Ethosuximide* Urea and
monoacylureas: Phenacemide, Carbamazepine*
Benzodiazepines: Clonazepam Miscellaneous: Primidone, Valproic acid ,
Gabapentin, Felbamate
UNIT – V 07 Hours
Drugs acting on Central Nervous System
Inhalation anesthetics: Halothane*, Methoxyflurane, Enflurane,
Sevoflurane, Isoflurane, Desflurane.
Ultra short acting barbitutrates: Methohexital sodium*, Thiamylal
sodium, Thiopental sodium.
Dissociative anesthetics: Ketamine hydrochloride.*
Narcotic and non-narcotic analgesics
Morphine and related drugs: SAR of Morphine analogues, Morphine
sulphate, Codeine, Meperidine hydrochloride, Anilerdine hydrochloride,
Diphenoxylate hydrochloride, Loperamide hydrochloride, Fentanyl citrate*,
Methadone hydrochloride*, Propoxyphene hydrochloride, Pentazocine,
Levorphanol tartarate.
Narcotic antagonists: Nalorphine hydrochloride, Levallorphan tartarate,
Naloxone hydrochloride.
Anti-inflammatory agents: Sodium salicylate, Aspirin, Mefenamic acid*,
Meclofenamate, Indomethacin, Sulindac, Tolmetin, Zomepriac, Diclofenac,
Ketorolac, Ibuprofen*, Naproxen, Piroxicam, Phenacetin, Acetaminophen,
Antipyrine, Phenylbutazone.
INTRO
• It is a discipline or intersection of chemistry especially
synthetic organic chemistry & pharmacology.

• Medicinal chemistry involves discovery,

development, identification & interpretation of
Mode of action of biologically active compounds at
molecular level.
 Medicinal chemistry is a branch or subject that uses both chemistry
and pharmacology.
 It deals with identification, synthesis and development of new
molecules that can be used for medicine.
 It also includes the study of existing drugs called as structure activity
relationship.
 It is also concerned with the identification and synthesis of
metabolites of the drugs.
 So, we can say that medicinal chemistry is concerns with new drug
discovery and its development.
Medicinal chemistry mainly deals with the identification, synthesis and development
of new chemical entities suitable for therapeutic use.
Studies in pharmacology, toxicology, microbiology, biochemistry,
biophysics, molecular biology etc. are necessary
Pharmaceutical chemistry is to do with the discovery and development of new and
better drugs through organic synthesis, analytical study and some physical
characterization. It involves organic synthesis, complete analytical characterization
including spectroscopy, identification of physical and chemical properties,
computational analysis, combinatorial approach etc.
Pharmaceutical chemistry - Medicinal chemistry
Synthesis of compounds which could show biological activity as a drug
Structural identification
Study of structure activity relationship
Mechanism of action of a drug molecule
Drug Discovery, Design and Development
Pure organic compounds are the chief source of agents for the cure, reduction or the
prevention of disease.
These drugs could be classified according to their origin:
Natural compounds:
materials obtained from both plant and animal, e.g. vitamins, hormones, amino acids,
antibiotics, alkaloids, glycosides…. etc.).
Synthetic compounds:
either purely synthetic or synthesis of naturally occurring compounds (e.g. morphine,
atropine, steroids and cocaine) to reduce their cost.
Semi-synthetic compounds:
Some compounds either can not be purely synthesized or can not be isolated from natural
sources in low cost. Therefore, the natural intermediate of such drugs could be used for
the synthesis of a desired product (e.g. semi synthetic penicillins).
The average cost to research and develop each successful drug is estimated to be
$800 million to $1 billion. Time it takes is 10-15 years.
 What do drugs/medication do?
Drugs are substances that alter biochemical processes in the body.

If a drug has beneficial effects it is a medicine.

Medicines usually contain the active ingredient (drug) and other ingredients.
 Stages of new drug discovery and its development
1. Discovery
It involves identification of new active molecules, which are called as ‘hits’ or ‘leads’. They
are found naturally (such as from plants, animals or microorganisms) or synthetically.

2. Optimization
It involves chemical changes in hits or leads to improve their biological, physicochemical and
pharmacokinetic properties and their stabilities.
It also includes pharmacophore (part of hits or leads responsible for activity) identification.
This helps in finding the lead compounds, which exhibit the most potent activity, best
pharmacokinetics and least toxicity.
3. Development
In this stage, optimized leads undergo clinical trials (first tested on animals
and then on humans).
The lead compound which successfully passes from clinical trials is called as
new drug.
Then suitable synthetic route is found out for bulk production of new drug
and preparation of suitable drug formulation.
Then, finally it enters into the market.
 Paracetamol
Paracetamol works as a painkiller by affecting chemicals in the body called
prostaglandins.

Prostaglandins are substances released in response to illness or injury.

Paracetamol blocks the production of prostaglandins, making the body less aware of
the pain or injury.

H
N CH3

O
HO
What kind of compound can become a drug?
Most effective oral drugs follow the Lipinski’s rule of five.
A compound should have a molecular weight less than 500
Daltons.
It should have no more than five H-bond donating groups.
It should have no more than ten H-bond accepting groups.
It should have octanol-water partition coefficient (logP) no
more than 5.
•Medicinal chemistry includes synthetic & computational aspects
of the study of existing drugs and agents in development in
relation to their bioactivities i.e., understandings a
SARs (Structure Activity Relationships).
 HISTORY
History and evolution of medicinal chemistry studied under four head

Dugs of Antiquity

The Middle Age

The 19th Century

The 20th Century

 Dugs of Antiquity

The oldest records of use of therapeutic plants and minerals were

derived from ancient civilzations of the Chinese, the Hindus, the
Mayans of central America and Mediterran
peoples of antiquity. (Cannabis, Opium, Alcohol)
 There is a long history of plants being used to treat various
diseases. They figure in the records of early civilizations in
Babylon, Egypt, India and China. The therapeutic properties of
plants were described by the Ancient Greeks and by the Romans
and are recorded in the writings of Hippocrates and Galenus.
Some metals and metal salts were also used at that time.
 In the Middle Ages various 'Materia Medica and pharmacopeas
brought together traditional uses of plants. The herbals of John
Gerard (1596), John Parkinson (1640) and Nicolas Culpeper
(1649) provide an insight into this widespread use of herbs.
Exploration in the seventeenth and eighteenth centuries led to
the addition of a number of useful tropical plants.
 The Middle Age

• Paracelsus (1493-1541), a Swiss physician used

Antimony and its salts of heavy metals to cure the
diseases.
• He was a German-Swiss physician and
Renaissance man who pioneered the use of
chemicals in medicine.
• To treat digestive issues, he gave an ointment containing iron,
antimony, and zinc oxide
• To treat leprosy, he promoted an "oil of antimony", a known
poison used in metal alloys
• He recommended mercury in its inorganic compound form to
treat syphilis
• He also used lead and arsenic in his medicine

• He reformed medical education by introducing chemical agents

• He preferred observing nature over studying ancient texts to
find treatments for diseases
• He is often called the "father of toxicology"
 The 19th Century

Age of innovation and chemistry

The isolation of morphine by Steruner in 1803, emetine from

ipecac by Pelletier in 1816 and Purifcation of caffine, quinine
and cochicine contributed to the increased use of pure substances
as therapeutic agent.

Pharma industry came to existence at end of 19 century.

Medicinal chemistry received formal recognition in

academics in pharmacy in 1932.
 The 20th Century

• Domangk
• Penicillin
• Various classes of compounds like hormones, steroids,
anesthetics, anticonvulsants, cardiac drugs, and renal drugs.
HISTORY OF MEDICINAL CHEMISTRY

 The nineteenth century saw the beginnings of modern organic

chemistry and consequently of medicinal chemistry.
The alkaloids like morphine (1805), quinine (1823) and atropine
(1834) were isolated from crude medicinal plant extracts.
General anaesthetics were introduced in surgery from 1842
onwards (diethyl ether (1842), nitrous oxide (1845) and
chloroform (1847)).
Antiseptics such as iodine (1839) and phenol (1860) also made
an important contribution to the success of surgery.
The hypnotic activity of chloral (trichloroethanal) (1869) was
reported.
The analgesic activity of willow bark’s constituents salicin (Salix and Populus)
and salicylic acid was found out in the 1860s and 1870s respectively.
p-hydroxyacetanilide (paracetamol) and phenacetin (1886) were also
recognized as pain-killers.
Acetylation of salicylic acid to reduce its harmful effect on the stomach led to
the introduction of aspirin in 1899. However, its mode of action was not
established until 1971.
In 1860, alkaloid cocaine was isolated from cocoa leaves for its local
anaesthetic activity.
The barbiturates – barbital (1903) and phenobarbital (1911) were introduced
as sleeping tablets.
Barger and Dale (1910) examined the response of various tissues to
acetylcholine agonists and showed that there were different receptor sub-
types; some responding to muscarine and others to nicotine.
The 1920s and 1930s saw the recognition of vitamin deficiency diseases and the
elucidation of the structure of various vitamins.
 In 1935 Domagk observed the anti-bacterial action of prontosil red dye, from
which the important family of sulfonamide anti-bacterial agents were developed.
 In 1929 Alexander Fleming had observed that a strain of Penicillium notatum
inhibited the growth of a Staphylococcus.
 In 1940-1941 Chain, Florey and Heaton isolated antibacterial agent
benzylpenicillin from P. notatum.
 The beneficial effect of steroidal hormone cortisone in alleviating inflammation
was observed in 1949.
 A number of anti-inflammatory semi-synthetic corticosteroids such as
prednisolone, betamethasone and triamcinolone became available in the late
1950s and 1960s.
 The development of histamine antagonists during the 1960s for the treatment
of peptic ulcers led to the development of cimetidine (1976) and then ranitidine
(1981).
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