chirality in drugs and their siginificance

2. GUIDED BY
Mr. R. C. Bag
Mr, M. D. Patra
Dr. D.L. Singh
Miss. Snehil Padhan
Mr. S,R, Pradhani
PRESENTED BY
Manas Ranjan Gadtia
Harekrushna Bhoi

3. CONTENTS
ISOMERISM
CHIRALITY
EXAMPLES OF CHIRAL MOLECULES
OPTICAL ACTIVITY
CHIRAL DRUGS
EXAMPLES OF CHIRAL DRUGS
SIGNIFICANCE OF CHIRAL DRUGS

4. ISOMERISM
Isomers by definition are the molecules of identical
atomic compositions (molecular formulas), but with
different bonding arrangements of atoms or orientation
of their atoms in space.The phenomenon is known as
Isomerism.

5. TYPES OF ISOMERS

6. 1.CONSTITUTIONAL ISOMERISM
These are also called structural or positional isomers are
molecules with the same atomic composition but different
bonding arrangements between atoms.
Simple example of constitutional isomerism is given examples
of catechol, resorcinol, and hydroquinone all of these
compounds having the same atomic composition (C6H602), but
different bonding arrangements of atoms. These are thus
distinct chemical entities with different chemical and physical
properties.

8. STEREOISOMERISM
Same molecular formula and chemical structure but a different
configuration (i.e. different three dimensional spatial
arrangement of their atoms)
Two types:
1. Optical isomers
2. Geometrical isomers

9. OPTICAL ISOMERISM
Enantiomers: A pair of stereoisomers that are non-
superimposable mirror images of each other.
Cause of Enantiomerism:
• presence of a chiral centre.
• Physiochemical properties ( solubility, melting and
boiling point ionization constant) are identical.
• Separation is difficult.
asparagine 2-butanol
C
C
OHO
CH2
H NH2
C
O NH2
C
C
O OH
CH2
HH2N
C
OH2N

10. Diastereomers:
 Stereoisomers that are not mirror images of each other and
are not enantiomeric.
 Physiochemical properties are different.
 Separation is easy

11. CHIRALITY
 “Chirality” is the property possessed by a molecule with such spatial arrangement
of atoms that it cannot superimpose on its mirror image. The object and mirror
image pair of molecules has the same constituents and structural formula.
 Chiral centre / asymmetric carbon / stereogenic centre – A carbon atom
attached to four different substituents.

13. Optical activity
With chiral compounds, the plane of the polarized light is
rotated through an angle . A compound that rotates polarized
light is said to be optically active

14. With achiral compounds, the light that passes through
the compound remains unchanged. A compound that
does not change the plane of polarized light is said to be
optically inactive

15. Racemic mixture:
 It is an equimolar mixture of the two right and left handed
 Enantiomers and is thus optically inactive.
 Most chiral drugs are administered as racemic mixtures
Optical isomers of Sulindac

16. Naming convention
Based on optical activity
 Compounds that rotate the plane of polarized light to the
right (clockwise) are called dextrorotary d(+)IUPAC
convention
 Compounds that rotate the plane of polarized light to
the left (counterclockwise) are called levorotary. l(-)IUPAC
convention
 Racemic mixture: d,l or +,-

17. R and S configuration
Cahn-Ingold-Prelog Convention
This is the preferred International Union of Pure and Applied
Chemistry (IUPAC)-endorsed method of naming and identifying
stereoisomers

18. RULES FOR NAMING R S
SYSTEM

20. Why is Stereochemistry and Chirality Important?
We’ve now learned the basics of stereochemistry - chirality, isomers, enantiomers, and
optical activity. Which leaves the question – why is this so important? And how does it
relate to human health?
The simple answer was alluded to earlier in this report, which is - humans are chiral
beings. From the top or our heads to the tip of our toes practically every molecule in the
human body is chiral. Thereby creating a chiral environment in which all the body’s
biochemical interactions take place. This is important because the biochemical response
to a particular molecule often depends on how that molecule fits a particular site on a
receptor molecule. As only the left-handed glove will fit the left hand, so too will a left-
handed receptor require a particular enantiomer (left-handed) for a correct fit.

21. 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, as proposed by Easson and Stedman.

22. Importance of the chirality in drugs
 This stereoisomerism results in different physical and
chemical properties of the compound. If this compound
happens to be drug then it results in different pharmacokinetic
and pharmacodynamic properties
 .
The importance of chiral drugs in the drug development
space cannot be understated. In pharmaceutical industries,
56% of the drugs currently in use are chiral molecules and
88% of the last ones are marketed as racemates (or racemic
mixtures), consisting of an equimolar mixture of two
enantiomers.

23.  Biomolecules (sugars, amino acids, DNA, proteins, steroids)
are chiral.
 Proteins are built from L-amino acids, which implies that
enzymes – the catalysts of nature - are chiral.
 Also, receptors (drug, taste, biopharmaceuticals,
agrochemicals) are chiral and the natural ligand to a receptor
is often only one specific enantiomer
Stereoisomerism in biological system

24.  In 1960 in Europe, racemic thalidomide was given to
pregnant females to cure morning sickness.
 This led to deformations in babies and neurotoxic effects.
 These were due to S-thalidomide.
 R-thalidomide contained the desired therapeutic activity
Thalidomide-disastrous biological
activity of the wrong enantiomer

26. EXAMPLES OF CHIRAL DRUGS
 INTRAVENOUS ANAESTHETICS
 LOCAL ANAESTHETICS
 INHALATIONAL AGENTS
 NUEROMUSCULAR BLOCKING AGENTS
 SOME OTHER DRUGS

27. SOME CHIRAL DRUGS USED IN
ANAESTHTIC PRACTICE

28.  Intravenous anaesthetics
Etomidate
 Ketamine
Thiopentone

29. 1.Etomidate
 Administered as a single isomer: R-isomer.
 Site of action: GABAA receptor.
 R-isomer is 15 times more potent than the Sisomer.
 S-isomer lacks hypnotic activity.

30. 2. Ketamine

31.  S-ketamine is 2-4 times more potent than R
ketamine
as an anaesthetic and analgesic agent. R-
ketamine: Emergernce reactions like
hallucinations, vivid dreams and agitation
Metabolism of S-ketamine by liver
microsomes is 20% greater than R-ketamine
and 10% greater than the racemate - faster
clearance of the drug.


32.  LOCAL ANAESTEHTICS
 Prilocaine
 Mepivacaine
 Bupivacaine

33. 1.BUPIVACAINE
Long acting local anaesthetic marketed as 50:50 racemic mixture.
Reports of death due to
 Bupivacaine induced CNS toxicity and cardiotoxicity on accidental
intravenous injection and
 difficult resuscitation following cardiotoxicity.
Safer alternatives:
 Levobupivacaine
 Ropivacaine
These are S-enantiomers of bupivacaine.
 Ropivacaine is the first ‘pure’ enantiomer containing >99% of the S-form.

34.  INHALATIONAL AGENTS
Isoflurane
•Some studies have found S(+)-isoflurane to be 50%
more potent than R(-)- isoflurane while other studies have
found no significant difference.
•Both enantiomers are equally soluble in the lipid bilayers.
•S-isoflurane induced about 50% longer sleep times
than R-isoflurane.

36.  Majority of the inhalational agents
currently used are chiral except, Sevoflurane

37.  NEUROMUSCULAR BLOCKING AGENTS
 Pancuronium
 Vecuronium
 Rocuronium
 Atracurium
 Mivacurium

38. 1. Atracurium
 Intermediate duration non-depolarizing neuromuscular
blocker.
 Causes histamine release, transient hypotension,
tachycardia, facial or truncal flushing.
 Continuous infusion in critical patients can lead to
laudanosine accumulation, which is epileptogenic.
 Its structure contains 4 chiral centres and is a mixture of 10
optical and geometric isomers.

39. Cisatracurium
• It is R-R’ optical isomer representing 15% of the
mixture
• It is more safe
• Causes less histamine release
• Not been reported to cause bronchospasm

40.  OTHER DRUGS
 Levosimendan
 Dexmedetomidine
 L-cysteine
 Tramadol
 NSAIDs
 Esomeprazole

41. Potential advantages of single
enantiomer products
 Less complex, more selective pharmacodynamic profile
 Potential for an improved therapeutic index
 Less complex pharmacokinetic profile
 Reduced potential for complex drug interactions
 Less complex relationship between plasma concentration
and effect

42. THANK YOU