have reported the synthesis of a range of fluoroquinolone derivatives with 4-(carbopiperazin-1-yl)piperazinyl moieties at the C-7 position and the results indicated that a 7-[4-(4-(benzoyl)carbopiperazin-1-yl)]piperazinyl derivatives and two 7-[4-(4-(benzenesulfonyl)carbopiperazin-1-yl)]piperazinyl derivatives are showed more have synthesize novel 1,7-disubstituted-6-nitroquinolones. The new derivatives were tested against Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) as well as against both Gram positive and Gram negative bacteria. Some derivatives were also found more potent

1. MEDICINAL CHEMISTRY
Introduction
Dr. Mehul Patel
Assistant Professor, RPCP

2. Definition
• Medicinal chemistry
• is a chemistry-based discipline, involving aspects of
biological, medical and pharmaceutical sciences.
• It is concerned with the invention, discovery, design,
identification and preparation of biologically active
compounds,
• The study of their metabolism, the interpretation of
their mode of action at the molecular level and the
construction of structure-activity relationships
(SARs).

3. • In particular, Medicinal chemistry also involves
the discovery of new chemical entities for the
treatment of diseases and the systematic study
of the structure-activity relationships of the
active compounds.
• Such studies provide the basis for development
of better medicinal agents from lead
compounds found via random screening,
systematic screening and rational design.

4. • Drug is any substance presented for treating,
curing or preventing disease in human beings
or in animals. It may also be used for restoring,
correcting, or modifying physiological functions.

5. • Structure-activity relationship (SAR) is the
relationship between chemical structure and
pharmacological activity for a series of
compounds.
• Lead compound is a compound that has a
desirable biological activity with therapeutic
relevance

6. The important role of
drugs in human society
• Drugs have irrevocably changed the fabric of
society by improving both the individual quality
of life and life expectancy.
• Some examples are shown as follows:

7. 1. Bacterial and virus infections: polio, smallpox,
tuberculosis and related diseases have, to a very major
extent, become minor public health concerns.
2. An increase in life expectancy resulting from drug
therapy has also led to a shift in population
demographics toward a more healthy, elderly population.
3. Drug regimens for birth control have improved individual
life choices and the quality of life.
4. HIV protease and reverse transcriptase inhibitors for the
treatment of HIV infections have changed a disease
with a fatal prognosis to a potentially chronic one.
5. Cancer is also being viewed as a potentially chronic,
rather than fatal disease with newer, non-cytotoxic
approaches.

8. Origins of Medicinal Chemistry
1. Early investigations of natural products
• 1.1.In the so-called pre-scientific era
• Natural products having a history as folk
remedies were in use. Fore examples, opium,
belladonna, cinchona bark, etc. Many drugs
originally used as folk remedies, nowadays,
have been abandoned.

9. • 1.2. In the late eighteenth and early nineteenth
centuries, chemical experimentation led
ultimately to its use in the discovery of new drugs.
• In 1853, Henry How conceived the idea that
functional groups in natural products might be
modified by chemical reagents.
He heated morphine with methyl iodide, hoping to
convert the alkaloid to codeine. He obtained, however, a
new substance of the quaternary salt of morphine.
HO O
H OH
N

10. • In 1898, the first commercially available
semisynthetic morphine derivative (ethyl ether)
was introduced as a cough sedative in preference
to codeine or other opiates.
• Meanwhile, diacetylmorphine was introduced as a
safer pain reliever than morphine. It quickly
became popular throughout the world.
• Four years passed before its addictive properties of heroin
were recognized. Laws were later passed by governments
to restrict its use.

11. • During the 1840s, the first use of synthetic organic
chemicals were introduced for anesthesia during a
tooth removal, such as nitrous oxide, ether, and
chloroform.
• In 1864, barbituric acid had been synthesized as a
useful hypnotic.
• In 1875, salicylic acid was introduced as a possible
cure for typhoid fever. It was found to be an effective
antipyretic.
• In 1899, Aspirin was marketed as an antipyretic
without the unpleasant side effects. This indicated
that the chemical structures from natural products
were changed into better drugs.
• Medicinal Chemistry began.

12. 2. Fast Development from 1900’s to 1960’s
• 1920’s~1930’s: Anesthetics, Hypnotics, Analgesics
were used extensively. In research for functional
“pharmacophore”, structure-function relationship
was investigated gradually.

13. • After 1930’s: The development of new drugs was
speeded greatly by the close combination of
Medicinal Chemistry and Experimental
Pharmacology.
• Theory of antimetabolite was formed by using
metabolic products as lead compounds.
• Discovery of penicillin which is the first antibiotics
is an epoch-making achievement.
• Afterward, tetracycline, streptomycin, chloramphenicol,
erythromycin were introduced one after another.

14. • In 1940’s, the first drug used for treating cancer
as a biological alkylating agent was nitrogen
mustard, which began tumor chemical therapy.
• In 1960’s, oral steroidal contraceptive agents
were discovered. Corticosteroids have become an
important drugs.

15. • After 1950’s, aging disease, cerebrovascular and
cardiovascular diseases became first reason for
human death. New drugs design based on enzymes
or receptors as drug targets.
• In 1964, first β-Adrenergic blocking agent,
Propranolol, was marketed.
• In 1979, Nifedipine, Calcium Channel Blocker was
marketed.
• In 1981, Captopril, Angiotensin Converting Enzyme
(ACE) Inhibitor was launched.

16. Future of Medicinal Chemistry
• New drugs will be discovered
or invented by investigating
human genomics and human
disease genomics.

17. 3. Drug Target and Drug Design
• Mechanism based drug design
• Structure based drug design
• Known targets: 480，receptors: 45%; enzymes: 28%
(See p5~6)

18. 3.1. Receptor Used as Drug Target
• Receptors: M acetylcholine receptor; adrenergic
receptor; angiotensin receptor; dopamine receptor;
serotonin receptor; opioid receptor etc.
• Drugs effecting on receptors：
• Agonist；Antagonist
Drug
Receptor

19. • Agonist is an endogenous substance or a drug
that can interact with a receptor and initiate a
physiological or a pharmacological response
(contraction, relaxation, secretion, enzyme
activation, etc.).
• Antagonist is a drug or a compound that
opposes the receptor-associated responses
normally induced by another bioactive agent.
• Partial agonist is an agonist which is unable to
induce maximal activation of a receptor population,
regardless of the amount of drug applied.

20. 3.2. Enzyme Used as Drug Target
• Enzyme: Angiotensin Converting Enzyme (ACE),
Cycloxygenase （ COX2 ） ， β-Lactamase,
Acetylcholine Esterase etc.
• Drugs effecting on enzyme: Enzyme Inhibitor

21. 3.3. Ion Channal Used as Drug Target
• Ion Channal: Calcium Ion Channal, Potassium Ion
Channal, Sodium Ion Channal, Chloride Ion
Channal, etc.
• Drugs effecting on Ion Channal: Calcium Channal
Blocker, Potassium Channal Blocker, Sodium
Channal Blocker, etc.

22. SAR
• Structure-activity relationship (SAR) is the relationship between the chemical or three-
dimensional structure of a molecule and its biological activity.
• The analysis of SAR enables the determination of the chemical groups responsible for
evoking a target biological effect in the organism.
• This allows modification of the effect or the potency of a bioactive compound (typically a
drug) by changing its chemical structure.
• Medicinal chemists use the techniques of chemical synthesis & computational drug design
to insert new chemical groups into the biomedical compound and test the modifications
for their biological effects.
• This method was refined to build mathematical relationships between the chemical
structure and the biological activity, known as quantitative structure-activity relationships
(QSAR).

23. SAR Examples

27. Questions
Definitions:
medicinal chemistry, drug, structure-activity
relationship, lead compound, Antisense drugs.
To be familiar with main research contents of
medicinal chemistry.
To understand orgins of medicinal chemistry.