Role of chirality in stereoselective and specific theraputic agent

1. PRESENTED BY
KARANVIR SINGH
M PHARM
(PHARMACEUTICAL CHEMISTRY)
ROLE OF CHIRALITY IN SELECTIVE AND SPECIFIC THERAPUTIC AGENTS
ISF COLLEGE OF PHARMACY
MOGA

2. 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.

3. TYPES OF ISOMERS

4. 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.

5. 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

6. OPTICAL ISOMERISM
Enantiomers: A pair of stereoisomers that are non- superimposable mirror
images of each other.
• presence of a chiral centre.
• Physiochemical properties ( solubility, melting and boiling point ionization
constant) are identical.
• Four different groups/atoms are attached at 4 corner of regular tetrahedron,
than the molecule is asymmetric and exist in 2 new forms

7. example

8. Diastereomers
• Stereoisomers that are not mirror images of each other and are not
enantiomeric.
• Physiochemical properties are different.
• Separation is easy

9. GEOMETRIC ISOMERS
Geometric Isomer - is as a result of free rotation impossibility of molecule parts around double-bonded
C=C.
1. Cis Isomers
2. Trans Isomers

10. DISCOVERY OF OPTICALACTIVITY
• In 1850, French Physicist Jean-Baptise Biot observed that solutions of some organic
compounds like sugar and camphor have the ability to rotate plane polarized light
• Up till then the basis of this phenomenon was not yet known

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 – 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 rotatespolarized light is said to be optically active

14. Racemic mixture:
• It is an equimolar mixture of both Enantiomers and is thus optically inactive.
• Most chiral drugs are administered as racemicmixtures
Optical isomers of Sulindac

15. 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 +,-

16. 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 , for
example, Receptors, enzymes, antibodies, and hormones.
• The enantiomers of a chiral drug may display different biological and pharmacological behaviors in
chiral living systems.
• 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 correctfit.

17. This can be easily understood with the example of a drug-receptor model depicted in. In
possession of different spatial configurations, one active isomer may bind precisely to the
target sites (α, β, γ), while an inactive isomer may have an unfavorable binding or bind to
other unintended targets. Pharmacological effects of enantiomeric drugs may be
categorized as follows

18. Easson and Stedman model
L.H Easson and E. Steadman(1993)
hypothised that stereospecificity of optical
isomers in biological action is due to one
isomer being able to achieve a three point
attachment with its receptor molecule

19. • The point illustrated by adrenaline (with its nitrogen quaternised),the(-)isomer of
which is more active (with three Sites in contact with the receptor) than the (+)-
isomer which has only two point attachment with the same receptor due to change
in configuration at the β-carbon. It has been shown that deoxy-adrenaline which
lacks the alcoholic hydroxy group has about the same pressor effect as (+)-
adrenaline

20. Importanceofchiralityindrugs
• 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.

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

22. PHOCOMELIA

23. BIOLOGICAL
AND
PHARMACOLOGICAL ACTIVITES
OF CHIRAL DRUGS

24. carvedilol sotalol
1. Both enantiomers act on the same biological target(s), but one isomer has
higher binding affinity than the other.
• For example, carvedilol is marketed as a racemate for the treatment of hypertension
and congestive heart failure. It is a nonselective β- and α-adrenergic receptor
blocking agent. Nonselective β blocking activity resides mainly in the (S )-carvedilol,
and the α-blocking effect is shared by both (R)- and (S )-enantiomers.
• Sotalol is a racemic β-adrenergic blocker. The (R)-enantiomer possesses the
majority of the β-blocking activity, and the (R)- and (S )- enantiomers of sotalol share
an equivalent degree of class III antiarrhythmic potency.

25. 2. Both enantiomers act on the same biological target, but exert opposed
pharmacological activities:
• For example, (–)-dobutamine demonstrated an agonistic activities against α-
adrenoceptors, whereas its antipode (+)- dobutamine is an antagonist against the
same receptors. The latter also acts as an β1-adrenoceptor agonist with a tenfold
higher potency than the (–) isomer and is used to treat cardiogenic shock.
• The individual enantiomers of the 1,4-dihydropyridine analog Bayk8644 have
opposing effects on L-type calcium channels, with the (S )-enantiomer being an
activator and the (R)-enantiomer an antagonist
(-)-dobutamine Bayk8644

26. 3. Both enantiomers may act similarly, but they do not have a synergistic effect:
• Two enantiomers of ∆-3-tetrahydrocannabinol (S)or(R) were assayed in humans for
psychoactivity. The 1S enantiomer had definite psychic actions, qualitatively similar to
those of ∆-1-tetrahydrocannabinol,but quantitatively less potent (1:3 to 1:6).
• Adding two enantiomers together did not increase the effect, confirming that activity was
solely in one enantiomer and that there was no synergistic effect between the two
isomers
∆-3-tetrahydrocannabinol (S) and (R)

27. 4. Both enantiomers have independent therapeutic effects through action on
different targets:
• The classical example of this behavior is quinine and quinidine. Quinine, which
was originally obtained from the bark of cinchona trees, has been used for the
treatment of malaria for centuries.
• Quinidine, on the other hand, is used as a class 1A antiarrhythmic agent and
acts by increasing action potential duration.
quinine and quinidine

28. 5. One or both enantiomers have the desired effect; at the same time, only
one enantiomer can cause unwanted side effects:
Racemic dropropizine has long been used in human therapy as an antitussive
agent. Recent studies have revealed that (S )-dropropizine possesses the same
antitussive activity as the racemic mixture, but has much lower selective activity on
the CNS. Therefore, particular clinical significance is attached to drugs of which
one enantiomer may contribute side or toxic effects
dropropizine

29. 6. The inactive enantiomer might antagonize the side effects of the active
antipode:
• In such cases, taking into account both efficacy and safety aspects, the racemate
seems to be superior to either enantiomer alone. For example, the opioid analgesic
tramadol is a used as a racemate and is not associated with the classical side
effects of opiate drugs, such as respiratory depression, constipation, or sedation.
• The (+)-enantiomer is a selective agonist for μ receptors with preferential inhibition
of serotonin reuptake and enhances serotonin efflux in the brain, whereas the (–)-
enantiomer mainly inhibits noradrenaline reuptake. The incidence of side effects,
particularly opioid-mediated effects, was higher with the (+)-enantiomer than with ±
tramadol or the (–)-enantiomer. Therefore, the racemate of tramadol is superior to
the enantiomers for the treatment of severe postoperative pain.

30. Structure of tramadol

31. 7. One isomer is active and the other isomer is responsible for toxicity
• D-penicillamine(S) is an antiarthritic drug while enantiomer L-penicillamine (R) is
extremely toxic
• (S,S)-Ethambutol is an antitubercular while (R,R)-ethambutol has ocular toxicity

32. 8.The two isomer of the same molecule differ not only with respect to
pharmacological or biological activities but may differ in taste or colour
• (R)-Carvone has caraway odour while (S)-carvone has spearmint odour.
• D- and L-asparagine where the former has sweet taste while the latter has
tasteless.

33. Examples of Chiral Drugs from Various
Antiarrhythmics Propafenone, tocainide
Antibiotics Ofloxacin, moxalactam
Anticoagulants Warfarin, Acenocoumarol
Antiemetics Ondansetron
Antihistamine Loratadine. Terfenadine
Antihyperlipidemic Atorvastatin
Antineoplastic Cyclophosphamide, iphosphamide
Antimalarials Chloroquine, halofantrine, mefloquine
Muscle relaxants Methocarbamol, baclofen
NSAIDS Ibuprofen, ketorolac
β -blockers Propranolol, metoprolol
β -adrenergic Salbutamol, terbutaline
Calcium channel blockers Verapamil, nimodipine
Opiate analgesics Methadone, pentazocine
Proton pump inhibitors Omeprazole, pantoprazole, Iansoprazole

34. THANK YOU

35. 1.Etomidate
• Etomidate is a intravenous anaesthetic drug.
• Administered as a single isomer: R-isomer.
• Site of action: GABAa receptor.
• R-isomer is 15 times more potent than the S-isomer.
• S-isomer lacks hypnotic activity.

36. 2.
Ketamine

37. • S-ketamine is 2-4 times more potent than R-ketamine
• as an anaesthetic and analgesic agent.
R-ketamine: Emergence reactions like hallucinations, vivid dreams and agitation
• Ketamine is highly lipid soluble and acts rapidly
• The primary site of action of ketamine is in the cortex and subcortical areas
Ketamine acts mainly by inhibiting the NMDA type of excitatory amino acid
receptors in brain and not interacting with GABA A receptor
• Metabolism of S-ketamine by liver microsomes is 20% greater than R-ketamine
and 10% greater than the racemate - faster clearance of the drug.

38. 3.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
The s(-) enantiomer of bupivacaine is equally potent but
less cardiotoxic and less prone to cause seizures than racemic bupivacaine.
It is being used as single enantiomer in some countries

39.  Ropivacaine
• it act as local analgesic agent.
• r(+) and s(-) enantiomers of local anesthetics have been demonstrated to have
different affinity for different ion channels of sodium, potassium, and calcium.
• the s(-)enantiomer have low central nervous system (CNS) and cardiac toxicity
(cardiotoxicity) as compared with the r(+)enantiomer.
• ropivacaine causes reversible inhibition of sodium ion influx, and thereby blocks
impulse conduction in nerve fibers. this action is potentiated by dose-
dependent inhibition of potassium channels. ropivacaine is less lipophilic than
bupivacaine and is less likely to penetrate large myelinated motor fibers;
therefore, it has selective action on the pain-transmitting a β and c nerves
rather than aβ fibers, which are involved in motor function

40. 4. 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.
• Isoflurane likely binds to GABA, glutamate and glycine receptors, but
has different effects on each receptor

42. 5.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.

43. Cis-atracurium
• 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

44. CETIRIZINE
• Cetirizine, an effective H1‐receptor antagonist, is a racemate mixture of two enantiomers:
levocetirizine (R enantiomer) and dextrocetirizine (S enantiomer)
• antihistaminic effects were not seen with dextrocetirizine
• Levocetirizine have less sedative effect than dextrocetirizine

45. WARFARINE
• Warfarin is administered as racemate.
• Warfarin (WAR) is widely used as an oral anticoagulant and functions as a vitamin K antagonist by
inhibiting the synthesis of vitamin K reductase and vitamin K epoxide reductase, thus decreasing
the ability of blood to form clot
• The (S)-WAR is 2–5 times more potent anticoagulant, and is metabolized much quicker (~1.5 times
faster) than the (R)-WAR

46. PENICILLIN
• The penicillin molecule contain three chiral carbon atoms at C-3, C-5 and C-6
• All natural and synthetic penicillin's have the same absolute configuration about these
three centres
• The 6th carbon atom bearing the acetyl amino group has the L-configuration, where as
the carbon to which the carboxyl group was attached has the D-configuration.
• Thus the acetyl amino group and carboxyl group are trans to each other, with the former
α and latter in the β orientation relative to penam ring.
• The absolute stereochemistry of the penicillin was designated as 3S:5R:6R.
• The atoms composing the 6- amino penicillanic acid are biosynthetically derived from
two amino acid , L-cysteine and D- valine

47. Isomer of ampicillin
D- isomer of ampicillin is 2-8 times more potent than l-isomer
• penicillin-v ampicillin
•