Chirality of Drugs

1. CHIRALITY OF DRUGS….
Dr. Sruthi N.

2. INTRODUCTION
Isomerism
Chirality&Enantiomers
Dextro rotatory & Levo rotatory
Significance of Chirality
Properties of Chiral drugs
Applications of Chirality
Limitations& Future prospects
Cis-Trans isomerism

3. Isomerism
Structural
Isomerism
Stereoisomerism
Geometric
isomerism
Cis trans
isomerism
Optic isomerism/
Enantiomerism

4. CHIRALITY
Greek word “Cheir” meaning Hand

5. Louis Pasture
(Sodium ammonium tartarate)
Term coined by….Lord Kelvin

6.  Mirror images
 Non- super imposable
 Same structural formula
 Different 3D arrangements

7. ENANTIOMERS
 Enantio,“ Opposite ” and merso , “part”
 One pair of mirror images
 Opposite configuration

8. Sinister(S) Left handed Rectus(R)Right handed
Cahn Ingold Prelog rules

9. Rotation of Plane Polarized Light

10. Polarimeter

11. (+) (-)
Dextrorotatory Levorotatory
Racemic mixture

12. SIGNIFICANCE
 Biomolecules are chiral

13. Different smell of carvone
Spearmint oil Caraway oil

14. Receptors are chiral
Binding sites specific for one enantiomer
Biological systems respond differently
Easson & Stedman
Three point interaction

16. In pharmaceutical industry
• 56% of drugs are Chiral
• 88% marketed as racemic mixtures

17. PROPERTIES OF ENANTIOMERS
Same physical and chemical properties
 Melting points
 Molecular weight
 Pka
 Solubility

18. PHARMACOKINETIC DIFFERENCE BETWEEN ENANTIOMERS
Absorption
 Esomeprazole is more bioavailable than racemic Omeprazole
 l-Methotrexate is better absorbed than d-Methotrexate
Distribution
 Vd of Levocetrizine is smaller than its dextro form
 S-Warfarin is more extensively bound to albumin than R-Warfarin

19.  d-Propranolol is more bound to proteins than l-Propranolol.
Metabolism
 S-Warfarin is metabolized by ring oxidation while R-Warfarin by side chain
reduction.
Excretion
 Clearance of R- Fluoxetin is 4 times greater than S-Fluoxetin

20. PHARMACODYNAMIC DIFFERENCES
Group 1 Racemic drugs with
one major bioactive
enantiomer
Beta blockers
ACE Inhibitors
CCB
Beta 2 agonists
Group 2 Racemic drugs with
equally bioactive
enantiomers
Fluoxetine
Cyclophosphamide
Group 3 Racemic drugs with
chiral inversion
Ibuprofen
Thalidomide

22. Isomer potency Examples
l -isomer>d-isomer Beta blockers
CCB
Thiopental
Beta 2 agonists
d- isomer >l-isomer Anaesthetics
NSAIDs

23. • Quinidine has an Antiarrythmic property.
Quinine has Antimalarial activity
• d-Sotalol is antiarrythmic
l-Sotalol is beta-blocker.
• Dextromethorphan is a cough suppressant
Levomethorphan is potent opioid analgesic.
• S-isomer has no beta-2-agonistic activity.
Salbutamol is available as a single isomeric preparation of R-isomer
DIFFERENT THERAPEUTIC USES AND ADVERSE DRUG REACTION

24. • S-Thalidomide: teratogenic effects
R-Thalidomide : sedative
• S-Naproxen is teratogenic
R-Naproxen is used for arthralgic pain
• l- Ethambutol : blindness
d-Ethambutol : antiTB drug
• d-DOPA: Agranulocytosis.
l-DOPA : Parkinson's disease

25. Frances Oldham Kelsey receiving award

26. APPLICATIONS OF CHIRALITY
Single Enantiomers vs. Racemic Mixtures
Single enatiomers have less complex and more selective
pharmacodyanamic profile as compared to racemic mixture.
1. Lesser adverse drug reactions.
2. Improved therapeutic profile.
3. Less chances of drug interactions.

27. IN DRUG DEVELOPMENT
• Both enantiomers should undergo separate trials before approval.
• Some drugs whose enantiomers are toxic are avoided & drug
manufactured as single enantiomers.
Eg- Levodopa , D Pencillamine

28. FDA now requires information about the structure and
activity of each isomer present in a racemic mixture of a new
medication

29. Better and safer drugs

30. CHIRAL SWITCHING
• The development of single enantiomer from chiral
drugs
• Can improve potential health benefits -improved
safety margin and cost effectiveness

31. CHIRAL INVERSION
• Conversion of one enantiomer into its mirror image
• Levofloxacin,Levosalbutamol
CHIRAL METASHIFT
• A chiral metabolite of the parent drug is developed

32. Chiral separation
• Diasteromeric salt
formation
• Enzymatic/kinetic
resolution
• HPLC
• Simulated moving bed
(SMB) chromatography
Chiral catalysts

33. Limitations & Future prospects
• Difficult to separate
• Cost
• New separation techniques
• Long clinical assessments

34. •In molecules with limited rotation
•Cis-functional groups are on same side of carbon chain
Trans-on opposing sides
•Non superimposable,not mirror images.
•Differ in physical and chemical properties
•Eg: cis-platin,cis form of thioxanthenes,9-cis retinoic acid
CIS-TRANS ISOMERISM

35. SUMMARY
• What is Chirality?
• Significance ?
• Pharmacokinetic &Pharmacodynamic differences?
• Applications of Chirality?