ROLE OF STEREOCHEMISTRY IN

DRUG DESIGN

Presented by
ABHISHEK CHOLLI
MC/01/2018
Department of Medicinal
Chemistry
NIPER-H
 Contents

Introduction Classification of Different Separation of

isomers isomers Conclusion
stereoisomers

1 3 5 7 9

2 4 6 8 10
Case study Chirality Importance of Synthesis References
stereochemistry
 Introduction
STEREOCHEMISTRY

A branch of chemistry that deals with the spatial arrangement(3D) of

atoms and groups in molecules

French chemist louis pasteur (1848) discovered that crystalline optically

inactive sodium ammonium tartarate was a mixture of two types of crystals
which were mirror image of each other

Louis Pasteur

Sodium Ammonium Tartarate Sodium Ammonium Tartarate

Left Hand Crystals Right Hand Crystals
TARTARIC ACID

LACTIC ACID
WHY IT CAME INTO PICTURE ?
 Thalidomide Disaster
The thalidomide disaster is one of the darkest episodes in pharmaceutical research
history.

Thalidomide was first marketed in 1957 as Contergan.

Thalidomide was marketed to a world hooked on tranquilizers and sleeping pills.

Afterword, used against nausea and to ease morning sickness in pregnant women.

Tragically the drug proved to be human teratogen that caused major birth defects in
an estimated 10,000 childrens.
Phocomelia.

(R)(+)-Thalidomide (S)(-)-Thalidomide
Sedative and hypnotic Teratogenic
Classification of Isomers
 Enantiomers
Diastereomers
180°

I II III IV
Meso form
 Chirality
Chiral comes from the Greek word “cheir” meaning “HAND”

Hands are non-superimposable mirror images — they are chiral

 Enantiomers

Enantiomers are pair of stereoisomers that are nonsuperimposable mirror images

Enantiomers arise from different substituents on a tetrahedral carbon

Identical in most properties, differ in interaction with polarized light

R-2-Bromobutane S-2-Bromobutane R-Lactic acid S-Lactic acid

 Diastereomers
Pair of stereoisomers containing more than one chiral center.

They are non-super imposible mirror images.

2-bromo,3-chloro-butane
 Dextrorotatory Levorotatory

When the plane of When the plane of

polarized light is polarized light is
rotated in a clockwise rotated in a counter-
direction, its called clockwise, its called
dextrorotatory levorotatory

It is denoted by (+) or It is denoted by (-) or

(d) (l)

D-propranolol L-propranolol
Not have adrenoceptor Adrenoreceptor antagonist
antagonist
Stereospecific binding of Drug with binding site

Easson and Stedman model Recognition of chiral drugs by specific drug receptors is
explained by a three-point interaction of the drug with the receptor site
Stereospecific binding of Drug with Protein
 Geometric isomers
Same molecular formula, same functional groups, same positions, but different orientation around a
double bond or on a ring

An important criteria to exhibit geometric isomerism is that the isomers cannot be interconverted through
mere rotation around a single bond

Diethylstilbestrol

Trans Diethylstilbestrol Cis Diethylstilbestrol

Estrogenic activity Estrogenic activity
10 Times more Active Less Active
 Conformational Isomers
Conformation: 3D arrangement of atoms in a molecule that results from rotation about a single bond.

Molecules constantly rotate through all the possible conformations.

Acetylcholine

Fully Eclipsed Staggered

Nicotinic activity Muscarinic activity
Importance of stereochemistry in drug design and
development

Organoleptic

Therapeutic Toxicity
Stereochemistry
activity

Potency
DRUGS WITH DIFFERENT POTENCY
Carvedilol

(S)-(–)- Carvedilol (R)-(+)- Carvedilol

β adrenoreceptor blocker β adrenoreceptor blocker
100 times greater potency Less potency
Drugs with different potency
Ibuprofen

S(+)-Ibuprofen
Anti-inflammatory R(-)-Ibuprofen
100 time More Potent Anti-inflammatory
Less Potent
Drugs with different therapeutic activity
Methorphan

L-isomer of methorphan D-isomer of methorphan

Potent opioid analgesic Cough suppressant
Drugs with different therapeutic activity
Cinchona Alkaloid

(-) Cinchona alkaloid (-) Cinchona alkaloid

(Quinine) (Quinidine)
Anti-malarial activity Anti-arrhythmic
activity
Drugs with different organoleptic features
Asparagine

R(+) Asparagine S(-) Asparagine

Sweet Bitter
Drugs with different organoleptic features
Carvone

R(+) Carvone S(-) Carvone

Spearmint odour Caraway Odour
Drugs with different toxicity profiles
Ethambutol

(S,S)-Ethambutol (R,R)-Ethambutol
Tuberculostatic Blindness
Drugs with different toxicity profiles
Naproxen

(S)-(+)-Naproxen (R)-(-)-Naproxen
Analgesic Cause liver toxicity
Stereoselective synthesis of tuberculostatic agent (S,S)-Ethambutol

ETHAMBUTOL

Organic Communications 2014, 7 (1), 28

Techniques For Seperation Of Enantiomers

BIOCHEMICAL
METHOD CHEMICAL
MECHANICAL METHOD
Eg. P. gloucum
SEPERATION Lactic acid +
destroy +
tartaric acid drug

KINETIC SELECTIVE
METHOD ADSORPTION
Racemic form drugs
Drugs available in single-enantiomer form
 Conclusions
Earlier stereochemistry was easily overlooked but now scenarios have
changed, scientists have realised the importance

Pharmaceutical companies have started developing single stereoisomer in

most cases

Thus in conclusion, integration of stereochemistry studies at the very early

phase of drug design and development has become major area of research
 References
 Kumar, J. K.; Narsaiah, A. V., Stereoselective synthesis of tuberculostatic agent (S, S)-ethambutol. Organic
Communications 2014, 7 (1), 28.
 Singh, K.; Shakya, P.; Kumar, A.; Alok, S.; Kamal, M.; Praksh, S. In Stereochemistry and its role in drug design,
International: 2014.
 Sekhon, B. S., Exploiting the power of stereochemistry in drugs: an overview of racemic and enantiopure drugs. J.
Mod. Med. Chem 2013, 1, 10-36.
 Williams, K.; Lee, E., Importance of drug enantiomers in clinical pharmacology. Drugs 1985, 30 (4), 333-354.
 Smith, S. W., Chiral toxicology: it's the same thing… only different. Toxicological sciences 2009, 110 (1), 4-30.
 H Brooks, W.; C Guida, W.; G Daniel, K., The significance of chirality in drug design and development. Current
topics in medicinal chemistry 2011, 11 (7), 760-770.
 Carreira, E. M.; Sandmeier, T.; Krautwald, S., Stereoselective Synthesis of Piperidines via Iridium‐Catalyzed
Cyclocondensation. Angewandte Chemie International Edition 2017.
 References
 Mohan, J. C.; Shah, S. N.; Chinchansurkar, S.; Dey, A.; Jain, R., Rediscovering Chirality–Role of S-Metoprolol in
Cardiovascular Disease Management. Journal of The Association of Physicians of India 2017, 65, 74.
 Lötvall, J.; Palmqvist, M.; Ankerst, J.; Persson, G.; Rosenborg, J.; Bengtsson, T.; Rott, Z.; Poczi, M.; Devai, Á.;
Waldeck, B., The effect of formoterol over 24h in patients with asthma: the role of enantiomers. Pulmonary
pharmacology & therapeutics 2005, 18 (2), 109-113.
Thank you