Introduction to Environmental Science

& Engineering (GE 111)

Dr. Asit K. Chakraborti, FRSC, FASc, FNA

Visiting Professor, Department of Chemistry
[Former Professor and Head, Dept Medicinal Chemistry, NIPER, S. A. S. Nagar (Mohali), Punjab]

Room No. 216 (First Floor), S. S. Bhatnagar Block, Main Campus

Email: chakrabortiak@iitrpr.ac.in; akchakraborti@niper.ac.in
akchakraborti@rediffmail.com;
Website: http://akcresearchgroup.weebly.com/
Phone: +91-XXXX-XXXXXX (Off); +91-9417770515 (M)
 GE 111 Course Contents: Module - 1
▪ Impact of Drugs and Pharmaceuticals on the Environment

▪ Sustainable Development and Green Chemistry

▪ Green Chemistry Principles

▪ Green Chemistry Metrics

▪ Alternatives to VOCs/VOSs

▪ Green Technologies

▪ A Few Case Studies

Ref: Details of resource materials will be provided in the respective slides
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Scopes of Education in
the Fields of Sciences

Engineering
Basic
Sciences and
Sciences
Technology

Interdisciplinary
Sciences
Disciplines of Basic Science…….

Physical Science Life Science

Physics Botany
Chemistry
Mathematics Zoology

Earth and Space Science Genetics

Geology
Astronomy Ecology
Meteorology
Oceanography

Interdisciplinary Science
Biotechnology & Pharmaceutical science
Necessities in Life
Can’t Imagine Life without…………
 What is Drug (Medicine) ?

A drug, broadly speaking, is any substance that, when

absorbed into the body of a living organism, alters normal
bodily function
A drug is any kind of substance that alter body functions upon intake

A medicine, on the other hand, is a classification of drug that only alters

body function to the consumer's health benefit

Different Dosage Forms

Sources of Drugs
Why it is So Difficult to Make Drugs?
 Pharmaceutical Sciences

How are Drugs Discovered and Developed?

Step 1: Choosing A Disease

Most research is carried out on diseases which affect

global population (cancer, cardiovascular diseases,
depression, diabetes, flu, migraine, obesity)
Step 2: Target Identification

Selectivity is Important!
Step 3: Synthesis

Nobel Prize 2010: Palladium Crossed Couplings in Organic Synthesis

❑ Organic Synthesis is a (the) bottleneck in New Drug

Discovery

❑ Organic synthesis specialization is absolutely essential for

best results

❑ Outsourcing with the right partner will drive R&D, not hinder it
Step 4: Animal Study

Determine toxicity and efficacy in animal models

Step 5: Metabolism of Drugs

The body considers drugs as foreign substances.

Step 6: Manufacture of Drugs

Pharmaceutical companies must make a profit to continue to

exist. Therefore, drugs must be sold at a profit.

One must have readily available, inexpensive starting materials.

One must have an efficient synthetic route to the compound.

Post-marketing Surveillance:

Pharmacy Practice:
Pharmacovigilence
Thalidomide Tragedy
 Post-marketing Surveillance:

Cardiovascular side effects of NSAIDS for long-

term treatment (Rheumatoid Arthritis):
Withdrawal of Rofecoxib and Valdecoxib from the market
Wealth through Education in Science ?
 Intellectual Property Rights

Design structure which is similar to existing lead, but

different enough to avoid patent restrictions
Step 2: Target Identification

Selectivity is Important!

Think differently!
Implication of Stereochemistry of Drug
in Pharmacological Action

23
 Stereoisomers in the Context of
Chemistry and Pharmacology
• Stereochemistry deals with the three dimensional structure of
molecules
• Stereoisomers are those molecules in which bond connectivity is
same but the arrangement of atoms in 3D space is different

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Chiral: Molecule/object that is different from its mirror image
(Enantiomers are chiral)

Achiral: Molecule/object that is the same as its mirror image

26
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 Foundation of Stereochemistry
THE CHILDISH FANTASY ???
NOT LONG AGO, I EXPRESSED THE VIEW THAT THE LACK OF GENERAL
EDUCATION AND OF THOROUGH TRAINING IN CHEMISTRY WAS ONE CAUSE OF
DETERIORATION OF CHEMICAL RESEARCH IN GERMANY. WILL ANYONE TO
WHOM MY WORRIES SEEM EXAGGERATED PLEASE READ, IF HE CAN, A RECENT
MEMOIR BY A HERR VAN’T HOFF ON “ THE ARRANGEMENT OF ATOMS IN
SPACE,” A DOCUMENT TO HILT WITH THE OUTPOURING OF A CHILDISH
FANTASY. THIS DR. J. H. VAN’T HOFF, EMPLOYED BY THE VETERINARY
COLLEGE AT UTRECCHT, HAS, SO IT SEEMS, NO TASTE FOR ACCURATE
CHEMICAL RESEARCH. HE FINDS IT MORE CONVENIENT TO MOUNT HIS
PEGASUS (EVIDENTLY TAKEN FROM THE STABLES OF THE VETERINARY
COLLEGE) AND TO ANNOUNCE HOW, ON HIS FLIGHT TO MOUNT PARNASSUS, HE
SAW THE ATOMS ARRANGED IN SPACE.

Reaction of Hermann Kolbe (University of Leipzig), one of the most eminent organic chemists
of the time, in 1877 (nearing the end of his career) to a publication of a 22 year old Dutch
scientist.

VAN’T HOFF RECEIVED THE FIRST NOBLE PRIZE IN CHEMISTRY IN 1901.

 Chemical Terminologies
1. Stereocenter – Carbon atom bearing 4 different substituents.
2. Enantiomers – Two stereoisomers, each a non-superimposable
mirror images of the other.
3. Mirror Plane – Chiral molecules does not have a mirror plane.
4. Diastereomers – Stereoisomers not related to each other as mirror
images.
5. Epimerization- changing the configuration at one chiral center in a
molecule with >1 chiral centres produces a compound which is not
a mirror image.
6. Two Stereocenters in a Molecule – Create up to 4 stereoisomers: 2
diastereomerically related pairs of enantiomers. If the 2
stereocenters generate a mirror plane in the molecule, the
molecule is known as a meso compound and is achiral.
7. Physical Properties of Stereoisomers – Most are the same except
for the rotation of plane polarized light. One enantiometer rotates
the plane of polarization to the right, the other to the left. This
rotation is expressed as the specific rotation, [].
 Chemical Terminologies

8. Absolute Configuration - Determined by X-ray diffraction.

Assignment of R or S, as determined by the Cahn, Ingold, and
Prelog sequence rules.
9. Stereoselectivity - Preference for the formation of one
stereoisomer when several are possible.
10. Resolution – Separation of enantiomers.
i. Reaction with a pure enantiomer of a second chiral
compound and separation of the diastereomers.
ii. Chiral chromatography.
Terminologies with Respect to Drug Action

• Eutomer is the bioactive isomer or isomer having higher

pharmacological activity.
• Distomer is the bio-inactive isomer or isomer having less
pharmacological activity.
• Eudismic ratio is the ratio of pharmacological activity of a
eutomer to pharmacological activity of a distomer.
• Eudismic ratio indicates the potency of one stereoisomer
with respect to other.
• Agonist is a substance that initiates a physiological
response when binds/interact with a receptor.
• Antagonist is a substance that interferes with or inhibits
the physiological action of another.

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Pharmacological Aspects of Drug Action

Pharmacological
aspects

Pharmacodynamics
Pharmacokinetics

Therapeutic Absorption Distribution Metabolism Excretion

action

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 Implication of Chirality

(R)-Carvone (S)-Carvone (R)-Thalidomide (S)-Thalidomide

spearmint dill, caraway sleep aid, antiemetic teratogen

INTERESTING
IMPORTANT

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 The Nose Knows!
Receptors, protein that binds to a particular molecule, are also chiral - allow selective
binding of enantiomers
Receptors in the nose are able to distinguish between 10,000 different smells -
each enantiomer fits into a different receptor

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The Tongue Decides How Sweet it is!

Aspartame
O O

H O H O
O H O H
N CH3 N CH3
H3N O H3N O

O H O H

(S,S) (R,R)

160 Times Sweeter Bitter!!

than Sugar
Pharmacological Aspects of Drug Action

Pharmacological
aspects

Pharmacodynamics
Pharmacokinetics

Therapeutic Absorption Distribution Metabolism Excretion

action

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 How Drugs Work:
Theories of Drug-receptor Interaction
• Lock and Key theory
“ The drug molecule must fit into the receptor
like a key fits into the lock”

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Different drug effects
• Biomolecules, thus, can discriminate between
enantiomers (isomers) of a given drug molecule.

• The net result is same or different pharmacologic/

pharmacokinetic/ toxicologic activities
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IMPORTANCE OF STREOCHEMISTRY IN DRUG RECEPTOR INTERACTION

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 Theories of Drug-receptor interaction
• Lock and Key Hypothesis
“ The drug molecule must fit into the receptor like a key fits into the
lock”
Known as the Intrinsic Activity.
• Occupancy theory: Ariens and Stephenson
Effectiveness of a drug lasts as long as the receptor is occupied. Many
substance possess different effect, some have high affinity for the receptor,
some have low affinity and some are not effective, and those ineffective
substances block or inhibit the receptor.
• Induced fit theory
Contradictory to Lock and Key concept, This concept states that binding of
drug/ligand receptor is a dynamic process and receptor organize itself to
promote facilitate maximum binding of drug.
• Rate theory
Rate theory suggests that the pharmacological activity is a function of
the rate of association and dissociation of the drug with the receptor.

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POINTS OF ATTACHMENT OF DRUG TO RECEPTOR

2 POINTS 3 POINTS
ATTACHMENT ATTACHMENT

✓ For maximum biological response 3 point attachment

of drug to receptor is necessary
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Pharmacological Aspects of Stereo-defined/Chiral Drugs

Pharmocokinetic Pharmacodynamic
(ADME/T) aspects aspects

Absorption Drug action

Distribution/
Disposition

Metabolism

Excretion

41
STERODIFFERENTIATION OF
PHARMACODYNAMIC PROCESS
Racemic Drugs

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 Relative Pharmacodynamic Potency of
Enantiomers of a Few Selected Chiral Drugs
Chiral Drug Relative Activity Biological Response
terbutaline - > + (3000:1) trachea relaxation
propranolol S > R (100:1) block tachycardia
pindolol - > + (200:1) inhibit tachycardia
methadone - > + (3:1) respiratory depression
Ketamine S > R (4:1) anesthesia
tocainide R > S (3:1) antiarrhythmic
flecainide +=- antiarrhythmic
propafenone +=- antiarrhythmic
disopyramide S>R antiarrhythmic
disopyramide S>R anticholinergic
warfarin S > R (8:1) anticoagulant
verapamil - > + (5-18:1) block AV conduction

Data from: Jamali F, et al. J Pharm Sci 78:695, 1989.

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 Group 1.
Racemic drugs with one major bioactive enantiomer

i. β- Adrenergic receptor blockers

• For all β-blockers levo isomer is more active than
dextro isomer
• e.g, propranolol S(-)-isomer is 100 times more
active than R(+)-isomer
• Exception : Timolol

ii. β- Adrenergic receptor agonists

• Bronchodilators: Albuterol (salbutamol),

salmeterol and terbutaline
• R(-) > S(+)
albuterol
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 ACE ENZYME-Captopril binding
iii. ACE inhibitors
• Captopril, Benazepril, Enalapril, Idapril
• S(-) form is most effective and all are marketed as
single enantiomeric form

iv. I n neurology and psychiatry

• Hypnotics like Secobarbital, hexobarbital S(-) > R(+)
• Local anesthetics like Ketamine, Isoflurane S(-) > R(+)
isoflurane
• Methadone R(-) > S (+)

v. Anti-arrythm ics and local anaestheitcs

• Propafenone, disopyramide, prilocaine, tocainide

Propafenone
vi. Anti-hyperlipidem ic
• Atorvastatin, Lovastatin
• R>S

Atorvastatin
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 vii. Psychostim ulants

• Amphetamine, Metamphetamine

viii. T ranquilizers
• Oxazepam, Lorazepam, Temazepam
• S(+) > R(-)

Lorazepam

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Group 2. Enantiomers with Opposite Biological Activities
Barbiturates

l-isomer is depressant
and
d-isomer is convulsant

Dobutamine
• l-isomer is α-adrenoceptor agonist
• d-isomer is α-adrenoceptor antagonist

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 Group 3. Distomer Possessing Adverse Effects
• Thalidomide: Thalidomide is racemic. One enantiomer is
effective against morning sickness, whereas the other
is teratogenic. However, the enantiomers are converted into each
other in vivo.
• Ethambutol: One enantiomer (R) is used to treat tuberculosis,
the other causes blindness.
• Naproxen: One enantiomer (S) is used to treat arthritis pain, but
the other (R) causes liver poisoning with no analgesic effect.
• (d,l)- Dopa: Owing to the grave toxicity (agranulocytosis) of the
d-isomer, only levorotatory form called l-Dopa is actually used in
therapeutics.
• Secobarbital: Enantiomers are equipotent as anticonvulsants,
but the S-(-)-isomer is more toxic than the R-(+)-isomer

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 THALIDOMIDE: DISASTROUS BIOLOGICAL ACTIVITY OF THE
“WRONG” ENANTIOMER
O O H H O O
N N
N O O N
*
*
H H
O O

(R)-isomer (S)-isomer

In the 1960’s thalidomide was given as racemic mixture

(RS) to pregnant women to reduce the effects of
morning sickness.
This led to many disabilities in babies and early deaths in
many cases.
Later found that only the R-isomer can be used safely.
In 1998, thalidomide has been approved by USFDA to
reduce the immune system’s inflammatory response in
a host of illnesses, including arthritis, lupus, cancer,
leprosy, and AIDs.
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 Group 4. Racemic Drugs with Chiral Switch
• This type of chiral inversion/switch is classified as:
A) Unidirectional inversion,
B) Bi-directional inversion.
A) Unidirectional Chiral Inversion: Only one isomer will be converted to
another one, not vice versa. Example: NSAIDs like ibuprofen,
ketoprofen, fenprofen, benoxaprophen, etc. For this class of drug, only
the S-enantiomer is active possessing analgesic and anti-inflammatory
effect.
• In the body, only inactive R-enantiomer can undergo chiral inversion by
hepatic enzymes into the active S-enantiomer and not vice-versa.
• For example, S-ibuprofen is over 100-fold more potent as an inhibitor of
the Cyclooxygenase-1 enzyme than (R)-ibuprofen.

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 Group 4. Racemic Drugs with Chiral Switch

B) Bi-directional Chiral Inversion: Both the enantiomers can

covert to other and form racemic mixture.

Example: 3-Hydroxy-benzodiazepines (oxazepam,

lorazepam, temazepam) and thalidomide R and S
enantiomers can racemize in vitro in aqueous medium.

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 Group 5. Racemic Drugs with Equally Bioactive
Enantiomers

B oth of the enantiom ers are biologically active to one target.

Exam ples: Cyclophospham ide, Flecainide, Fluoxetine.

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 Group 6.
Enantiomers with Different Therapeutic Action

QUININE QUINIDINE

Antimalarial Antiarrythmic

Cough supressant Opioid analgesic

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Group 7. Differential Protein Binding

Propafenone

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 Diastereomeric Drugs
• Diastereomers are non-superimposable non-mirror images having
different spatial arrangement of atoms.
• Diastereomers can be easily separated by chromatography or
recrystalization and they can be tested for biological activity.
• Anti-histaminic activity of E-triprolidine is 1000-fold greater than it’s Z-
isomer.
• Neuroleptic potency of Z-chlorprothixene is 12 times greater than that
of the E-isomer.

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 STERODIFFERENTIATION OF
PHARMACOKINETIC PROCESS
Stereodifferentiation of Pharmacokinetic Process
• The absorption of chiral drug appears to be stereoselective.
• Their distribution, metabolism, and renal excretion usually
favour one enantiomer versus the other.
• In terms of distribution, plasma protein binding is
stereoselective for most of these drugs, resulting in up to two-
fold differences between the enantiomers in their unbound
fractions in plasma and volume of distribution.
• Methadone, a central-acting analgesic (opiod), is a racemate
with predominantly active R-(+)-isomer. In humans, the ratios
of R/S methadone levels varied from 0.6 to 2.0 in serum and
1.2- 2.0 in urine.
• Hepatic metabolism of one enantiomer also differs from
another due to the enzyme selectivity of enantiomers.
Eur. J. Clin. Pharmacol. 1996, 50, 385-389. 58
 Pharmacokinetic Aspects of Drug Action
• S-(-)-Warfarin (anticoagulant) is oxidised by cytochrome
CYP2C9 and then excreted into bile whereas R-(+)-warfarin is
metabolised by CYP1A2 to an inactive alcohol that is excreted
into urine.
• R-(+)-Warfarin is in itself a competitive inhibitor of CYP2C9.
• S-(-)-Warfarin is 3 to 5 times more potent than R-(+)-warfarin
whereas the clearance of R-(+)-warfarin is 70% that of S-(-)-
warfarin.
• The half-life of R-(+)-warfarin is longer than that of S-(-)-
warfarin (43 versus 32 h).
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 STERODIFFERENTIATION OF
PHARMACOKINETIC PROCESS

A. ABSORPTION
Frel D-Methotrexate/L-Methotrexate = 0.025
(anti-cancer and immuno-suppressant)

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 STERODIFFERENTIATION OF
PHARMACOKINETIC PROCESS

B. DISTRIBUTION
Drug Free Fraction Ratio (+/-)
+ -
disopyramide 0.27 0.39 0.7
ibuprofen 0.006 0.0039 1.5
mexilitine 0.283 0.198 1.4
methadone 0.092 0.124 0.7
propoxyphene 0.018 0.018 1.0
propranolol 0.203 0.176 1.2
tocainide 0.17 0.14 1.2
verapamil 0.064 0.11 0.6
warfarin 0.012 0.009 1.3

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C. METABOLISM
Drug Clearance Form (+) (-) Ratio
disopyramide Clu,nr.iv isomer 0.23 0.18 1.28

propranolol CLivracemate 1.21 1.03 1.17

CLu,iv racemate ~6.0 ~5.9 1.02
CLo racemate 2.78 1.96 1.42
CLu,o racemate 13.7 11.1 1.23

verapamil CLivisomer 0.80 1.40 1.75

CLu,iv isomer 5.96 5.85 1.02
CLo racemate 1.72 7.46 4.33

warfarin CLo racemate 0.234 0.333 1.42

CLu,o racemate ~21.9 ~37.0 1.69

Data from: Tucker GT ,Lennard MS. Pharmacol Ther 45:309-329, 1990.

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 Differntial Metabolism

Primaquine Omeprazole Ketorolac

• (-)-Isomer is metabolized to • R-(+)- Enantiomer • S (−) Enantiomer was
greater extent by liver metabolized more 4 times that of the
microsomal enzymes so it is rapidly by CYP2C19 R (+) enantiomer
less toxic then (+)-isomer than S-(-)

63
From: Olbe et al, Nat Rev Drug Discovery 2:132, 2003 64
 CYP Isoforms Different Between Enantiomers
O O
O O O
P O P
CYP2B6 P
NHCH2CH2Cl H2N N
NH NHCH2CH2Cl
N
ClH2CH2C
S-3-Dechloroethylifosfamide CYP3A4 CH2CH2Cl
R-Ifosfamide S-2-Dechloroethylifosfamide
O
O CYP2B6
P O
O
NH2 O P
N O
P CYP3A4 ClH2CH2CHN
CH2CH2Cl HN
ClH2CH2CHN N
R-2-Dechloroethylifosfamide R-3-Dechloroethylifosfamide
ClH2CH2C
+ +
S-Ifosfamide
ClCH2CHO ClCH2CHO
Chloroacetaldehyde Chloroacetaldehyde
(Neurotoxic) (Neurotoxic)

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D. EXCRETION
Drug Clearance Form (+) (-) Ratio
chloroquine CLR,u racemate 824 519 1.6

Disopyramide CLR,u isomer 338 182 1.8

Mexilitine CLR racemate 0.5 0.5 1.0

pindolol CLR,u racemate 453 534 1.2

terbutaline CLR isomer 2.7 1.5 1.8

tocainide CLR isomer 55 55 1.0

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Omeprazole Esomeprazole
• Heal the erosion in the esophagus caused
by gastroesophageal reflux disease, thus
providing a clinical advantage

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 Chiral Switch:
Racemic to Pure Enantiomeric Form

68
• The chiral switch process provides a strategy to extend
the profitable life of a pharmaceutical “bestseller“, and
may result in extended patent protection and provide an
advantage against generic competition

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