Stereochemistry is the ‘chemistry of space’ , that is stereochemistry deals with the spatial arrangements of atoms and groups in a molecule.
Stereochemistry can trace its roots to the year 1842 when the French chemist Louis Pasteur made an observation that the salts of tartaric acid collected from a wine production vessel have the ability to rotate plane-polarized light, whereas the same salts from different sources did not have this ability.
Isomers are compounds that contain exactly the same number of atoms, i.e., they have exactly the same empirical formula, but differ from each other by the way in which the atoms are arranged.
Constitutional isomers, also known as structural isomers, are specific types of isomers that share the same molecular formula but have different bonding atomic organization and bonding patterns.
Stereoisomers are molecules having the same molecular formula and the atomic arrangement, but differ in their spatial arrangement.
Geometric isomers are two or more coordination compounds which contain the same number and types of atoms, and bonds (i.e., the connectivity between atoms is the same), but which have different spatial arrangements of the atoms.
There are 2 types of geometric isomers, ‘cis’ and ‘trans’.-cis isomers: when similar groups are present on the same side of the double bonds, then they are termed as cis.- trans isomers: when similar groups are present on the opposite sides of the double bonds then they are called trans isomers.
cis-diethylstilbestrol has only 7% of the estrogenic activity of trans-diethylstilbesterol.
Cisplatin have anticancer activity where ae trans platin is an inactive compound.
In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes.
Chirality is the property of being non identical to ones mirror image.
Chiral center is defined as the atom bearing 4 different atoms or group of atoms.
Molecules that form nonsuperimposable mirror images, and thus exist as enantiomers, are said to be chiral molecules.
For a molecule to be chiral, it cannot contain a plane of symmetry.
The term enantioselectivity refers to the efficiency with which the reaction produces one enantiomer.
Enantiomers are stereoisomers that are non-superimposable mirror images.
Have identical properties.
Similar shapes
Diastereomers are stereoisomers that are non superimposable and are not mirror images.
Have distinct physical properties.
Have different molecular shapes.
Enantiomers consist of a pair of molecules that are mirror images of each other and are not superimposable.
When a molecule contains only one chiral centre , the two stereoisomers are known as enantiomers.
These may be referred to or labelled using the configurational descriptors as either:
R(rectus meaning right handed) or S(sinister meaning left handed),
D(dextrorotatory)or L (laevorotatory)
E-Entgegen or Z- Zusamen
Penicillin, one of the first and still one of the most widely used antibiotic agents, is derived from the penicillium mold. In 1928 Scottish bacteriologist alexander fleming in a contaminated green mold penicillium notatum. He isolated the mold, grew it in a fluid medium, and found that it produced a substance capable of killing many of the common bacteria that infect humans. Australian pathologist howard florey and British biochemist ernst Boris chain isolated and purified penicillin in the late 1930s, and by 1941 an injectable form of the drug was available for therapeutic use.
Penicillin's are beta lactam antibiotics and characterized by three fundamental structural requirements
The fused beta-lactam and thiazolidine ring structure.
free carboxylic acid group.
And one or more substituted acylamino side chain.
Penam nucleus: 7-oxo-l-thia-4-azabicyclo [3.2.0] heptane
Absolute configuration: 3-S, 5-R, 6-R.
Instrumental methods of characterization:
FTIR
MASS
C13-NMR
1H-NMR
FTIR: -
Penicillin G molecule and its IR spectra in D2 O and in DMSO. Spectra are characterized by the presence of three intense bands.
β- lactam CO stretching observe at 1761 cm-1 in D2O and 1762 cm-1 in DMSO solution.
Amide group is observe at 1640 cm-1 in D2O and 1674 cm-1 in DMSO solution.
Asymmetric stretching of carboxylate group is observe at 1601 cm-1 in D20 and 1615 cm-1 in DMSO solution.
A large red shift of amide , out of the frequency window, is observed upon proton exchange in DMSO.
Collision-Induced Dissociation (CID) technique
MASS:-
A high-resolution, hybrid tandem mass spectrometer was used to obtain CID spectra. The CID spectra were acquired by:
Mass selecting the precursor ions using the first mass spectrometer.
Injecting the ions into the first quadrupole (collision cell) where they undergo CID.
Mass-analyzing the fragment ions produced using the second quadrupole.
Argon was used as the collision gas, and the pressure in the collision cell was adjusted to attenuate the precursor ion intensity to 20-50% of the original intensity. The collision energy of the ions ranged from 160 to 180 eV. The mass spectra shown abundant fragmentations at m/z 160 and m/z 176 that were reported to arise from cleavage of the β-lactam ring.
protonated benzyl penicillin exhibits abundant fragment ions at m/z 160, m/z 176, m/z 217, m/z 128, and m/z 289. The most abundant CID fragment at m/z 160 and the molecular ion peak was observed at m/z 334.
C13-NMR: -
The four sp3 ring carbons give rise to resonances in the decreasing chemical shift order C-3, C-5, C-2 and C-6.
Chemical shift for C-2 is 64.9 ppm and the substituents attached with it are α-methyl 27.0 ppm and β-methyl 31.4 ppm. Chemical shift for C-3 is 73.6 ppm and 174.5 ppm for carboxylate functions (reflecting the smaller de-shielding influence of COOH over that of COO-). The chemic shift for C-5 is 67.2 ppm. The chemic shift for C-6 is 58.4 ppm.
The lactam group shows its chemical shift at 175.0 ppm
Amino group
Penicillin, one of the first and still one of the most widely used antibiotic agents, is derived from the penicillium mold. In 1928 Scottish bacteriologist alexander fleming in a contaminated green mold penicillium notatum. He isolated the mold, grew it in a fluid medium, and found that it produced a substance capable of killing many of the common bacteria that infect humans. Australian pathologist howard florey and British biochemist ernst Boris chain isolated and purified penicillin in the late 1930s, and by 1941 an injectable form of the drug was available for therapeutic use.
Penicillin's are beta lactam antibiotics and characterized by three fundamental structural requirements
The fused beta-lactam and thiazolidine ring structure.
free carboxylic acid group.
And one or more substituted acylamino side chain.
Penam nucleus: 7-oxo-l-thia-4-azabicyclo [3.2.0] heptane
Absolute configuration: 3-S, 5-R, 6-R.
Instrumental methods of characterization:
FTIR
MASS
C13-NMR
1H-NMR
FTIR: -
Penicillin G molecule and its IR spectra in D2 O and in DMSO. Spectra are characterized by the presence of three intense bands.
β- lactam CO stretching observe at 1761 cm-1 in D2O and 1762 cm-1 in DMSO solution.
Amide group is observe at 1640 cm-1 in D2O and 1674 cm-1 in DMSO solution.
Asymmetric stretching of carboxylate group is observe at 1601 cm-1 in D20 and 1615 cm-1 in DMSO solution.
A large red shift of amide , out of the frequency window, is observed upon proton exchange in DMSO.
Collision-Induced Dissociation (CID) technique
MASS:-
A high-resolution, hybrid tandem mass spectrometer was used to obtain CID spectra. The CID spectra were acquired by:
Mass selecting the precursor ions using the first mass spectrometer.
Injecting the ions into the first quadrupole (collision cell) where they undergo CID.
Mass-analyzing the fragment ions produced using the second quadrupole.
Argon was used as the collision gas, and the pressure in the collision cell was adjusted to attenuate the precursor ion intensity to 20-50% of the original intensity. The collision energy of the ions ranged from 160 to 180 eV. The mass spectra shown abundant fragmentations at m/z 160 and m/z 176 that were reported to arise from cleavage of the β-lactam ring.
protonated benzyl penicillin exhibits abundant fragment ions at m/z 160, m/z 176, m/z 217, m/z 128, and m/z 289. The most abundant CID fragment at m/z 160 and the molecular ion peak was observed at m/z 334.
C13-NMR: -
The four sp3 ring carbons give rise to resonances in the decreasing chemical shift order C-3, C-5, C-2 and C-6.
Chemical shift for C-2 is 64.9 ppm and the substituents attached with it are α-methyl 27.0 ppm and β-methyl 31.4 ppm. Chemical shift for C-3 is 73.6 ppm and 174.5 ppm for carboxylate functions (reflecting the smaller de-shielding influence of COOH over that of COO-). The chemic shift for C-5 is 67.2 ppm. The chemic shift for C-6 is 58.4 ppm.
The lactam group shows its chemical shift at 175.0 ppm
Amino group
There are many ways that drug-resistant infections can be prevented: immunization, safe food preparation, handwashing, and using antibiotics as directed and only when necessary. In addition, preventing infections also prevents the spread of resistant bacteria.The main cause of antibiotic resistance is antibiotic use. When we use antibiotics, some bacteria die but resistant bacteria can survive and even multiply. The overuse of antibiotics makes resistant bacteria more common. The more we use antibiotics, the more chances bacteria have to become resistant to them.
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
Contents includes at least three strategies of synthesis for each of three, four, five and six membered heterocylic ring with one or two heteroatoms. One mechanism described out of the three strategies. Few name reactions are described and the other are simple synthetic methods. This presentation was prepared for the partial fulfillment of Master of Pharmacy. The content was taken from the various books, mentioned in slide with the title of references.
Active constituent of drugs used in diabetic therapyAkshay Kank
In this slide the active constituents which is isolated from herbal sources used for to treat the type 1 and type 2 diabetes is covered. 'Gymnema' and 'swerita chirata' herbal plant is also covered in the slide.This work help in to focus the herbal emphasis on diabetes.
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
ENZYME INHIBITION THE MOST IMPORTANT TOPIC FOR BIOLOGY AS WELL AS CHEMISTRY PEOPLES. WE HAVE HERE COVERED FOR THE PHARMA STUDENTS THIS WILL MAKE THEM EASY AS WE ARE COLLECTED ALL THE DATA A SINGLE PLACE WICH COVERS ALL THE COTENTS.
Presented by Shikha Popali and Harshpal singh Wahi students from Gurunanak college of pharmacy, Nagpur in Department of pharmaceutical Chemistry. The explained topic is seful for every chemistry student and for others too
Sythesis of heterocyclic drugs ketoconazole and metronidazoleandhra university
A Heterocyclic compounds are those which has atoms of at least two different elements as members of its ring.
Heterocyclic chemistry is a branch of organic chemistry dealing with the synthesis, properties, and applications of these heterocycles.
e-content of Stereochemistry for Pharmacy and Chemistry students.
contents includes Isomerism, Chirality, Stereoisomers, Enantiomer, Diastereomer, Cis And Trans Configuration ,L And D Configuration ,R And S Configuration and Importance of the chirality in drugs ,Intravenous anaesthetics , etc.
There are many ways that drug-resistant infections can be prevented: immunization, safe food preparation, handwashing, and using antibiotics as directed and only when necessary. In addition, preventing infections also prevents the spread of resistant bacteria.The main cause of antibiotic resistance is antibiotic use. When we use antibiotics, some bacteria die but resistant bacteria can survive and even multiply. The overuse of antibiotics makes resistant bacteria more common. The more we use antibiotics, the more chances bacteria have to become resistant to them.
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
Contents includes at least three strategies of synthesis for each of three, four, five and six membered heterocylic ring with one or two heteroatoms. One mechanism described out of the three strategies. Few name reactions are described and the other are simple synthetic methods. This presentation was prepared for the partial fulfillment of Master of Pharmacy. The content was taken from the various books, mentioned in slide with the title of references.
Active constituent of drugs used in diabetic therapyAkshay Kank
In this slide the active constituents which is isolated from herbal sources used for to treat the type 1 and type 2 diabetes is covered. 'Gymnema' and 'swerita chirata' herbal plant is also covered in the slide.This work help in to focus the herbal emphasis on diabetes.
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
ENZYME INHIBITION THE MOST IMPORTANT TOPIC FOR BIOLOGY AS WELL AS CHEMISTRY PEOPLES. WE HAVE HERE COVERED FOR THE PHARMA STUDENTS THIS WILL MAKE THEM EASY AS WE ARE COLLECTED ALL THE DATA A SINGLE PLACE WICH COVERS ALL THE COTENTS.
Presented by Shikha Popali and Harshpal singh Wahi students from Gurunanak college of pharmacy, Nagpur in Department of pharmaceutical Chemistry. The explained topic is seful for every chemistry student and for others too
Sythesis of heterocyclic drugs ketoconazole and metronidazoleandhra university
A Heterocyclic compounds are those which has atoms of at least two different elements as members of its ring.
Heterocyclic chemistry is a branch of organic chemistry dealing with the synthesis, properties, and applications of these heterocycles.
e-content of Stereochemistry for Pharmacy and Chemistry students.
contents includes Isomerism, Chirality, Stereoisomers, Enantiomer, Diastereomer, Cis And Trans Configuration ,L And D Configuration ,R And S Configuration and Importance of the chirality in drugs ,Intravenous anaesthetics , etc.
this presentation describes ways to enantiomeric product synthesis, hence introducing to chiral catalysts. the temperature effects are discussed with relation to soai autocatalysis. it shows introduction to stereocartography.
Enzymes - A complete introduction and applicationsIndhra Yogaesh
Enzymes are macromolecular biological catalysts. Enzymes accelerate, or catalyze, chemical reactions. The molecules at the beginning of the process are called substrates and the enzyme converts these into different molecules, called products.
This section has been prepared by Worthington Biochemical Corporation as a practical
introduction to enzymology. Because of its close involvement over the years in the theoretical
as well as the practical aspects of enzymology, Worthington's knowledge covers a broad
spectrum of the subject. Some of this information has been assembled here for the benefit of
laboratory personnel.
Sanjo College of Pharmaceutical Studies, Physical Pharmaceutics I , 3rd semester B.Pharm, Complexation & protein binding, Classification in detail, determination methods, application of complexes in pharmacy.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
Nutraceutical market, scope and growth: Herbal drug technology
STEREOCHEMISTRY AND DRUG ACTION.pptx
1. PRESENTED BY:
ACHAL YAWALKAR
M.PHARM I YEAR
PHARMACEUTICAL CHEMISTRY
GUIDED BY:
Dr. B.R. PRASHANTHA KUMAR
ASSOCIATE PROFESSOR
DEPT OF PHARMACEUTICAL CHEMISTRY
2. Elements
1. WHAT ARE ISOMERS ?
2. WHAT ARE STEREOISOMERS ?
3. WHAT IS CHIRALITY ?
4. WHAT DO YOU UNDERSTAND BY
THE TERM ENATIOSELECTIVITY &
HOW IS IT RELATED TO VARIOUS
PHARMACOKINETIC PARAMETERS
?
3. STEREOCHEMISTRY
Stereochemistry is the branch of chemistry that involves “the study of the different spatial arrangements of
atoms in molecules”.
Stereochemistry is the ‘chemistry of space’ , that is
stereochemistry deals with the spatial arrangements of atoms
and groups in a molecule.
Stereochemistry can trace its roots to the year 1842 when
the French chemist Louis Pasteur made an observation that
the salts of tartaric acid collected from a wine production vessel
have the ability to rotate plane-polarized light, whereas the
same salts from different sources did not have this ability.
4. ISOMERS:
Stereoisomers are molecules having the
same molecular formula and the atomic
arrangement, but differ in their spatial
arrangement.
Isomers are compounds that contain exactly the
same number of atoms, i.e., they have exactly
the same empirical formula, but differ from each
other by the way in which the atoms are
arranged.
STEREOISOMERS:
Constitutional isomers, also known as
structural isomers, are specific types of
isomers that share the same molecular
formula but have different bonding atomic
organization and bonding patterns.
CONSTITUTIONAL
ISOMERS:
5. GEOMETRIC ISOMERS:
Geometric isomers are two or more coordination compounds which contain
the same number and types of atoms, and bonds (i.e., the connectivity
between atoms is the same), but which have different spatial arrangements
of the atoms.
There are 2 types of geometric isomers, ‘cis’ and ‘trans’.
-cis isomers: when similar groups are present on the same side of the
double bonds, then they are termed as cis.
- trans isomers: when similar groups are present on the opposite sides
of the double bonds then they are called trans isomers.
cis-diethylstilbestrol has only 7% of the estrogenic activity of trans-
diethylstilbesterol.
Cisplatin have anticancer activity where ae trans platin is an inactive
compound.
6. In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any
combination of rotations, translations, and some conformational changes.
Chirality is the property of being non identical to ones mirror image.
CHIRALITY:
Chiral center is defined as the atom bearing 4 different atoms or group of atoms.
Molecules that form nonsuperimposable mirror images, and thus exist
as enantiomers, are said to be chiral molecules.
For a molecule to be chiral, it cannot contain a plane of symmetry.
A plane of symmetry is a plane that bisects an
object (a molecule, in this case) in such a way
that the two halves are identical mirror images.
7. ENATIOSELECTIVITY:
The term enantioselectivity refers to the efficiency with which the reaction produces one
enantiomer.
ENANTIOMERS DIASTEREOMERS
Enantiomers are stereoisomers
that are non-superimposable
mirror images.
Have identical properties.
Similar shapes
Diastereomers are stereoisomers that
are non superimposable and are not
mirror images.
Have distinct physical properties.
Have different molecular shapes.
8.
9. ENANTIOMERS
Enantiomers consist of a pair of molecules that are mirror images of each
other and are not superimposable.
When a molecule contains only one chiral centre , the two stereoisomers are
known as enantiomers.
These may be referred to or labelled using the configurational descriptors as
either:
R(rectus meaning right handed) or S(sinister meaning left handed),
D(dextrorotatory)or L (laevorotatory)
E-Entgegen (high priority groups on opposite side of double bond) or Z-
Zusamen (high priority groups on
same side of double bond)
10. The most famous example of a chiral drug is Thalidomide.
Thalidomide has a tragic history :
It was introduced in Germany in 1957 as a sedative and hypnotic and was marketed over the
counter largely as a drug for treating morning sickness in pregnant women.
In the following few years, about 10,000 infants worldwide were born with phocomelia, or limb
malformation. Only half of the infants survived, and some of those who did had other defects in
addition to limb deficiencies.
Thalidomide exists in two mirror-image forms: it is a racemic mixture of (R)- and (S)-enantiomers. The (R)-
enantiomer, shown in the figure, has sedative effects, whereas the (S)-isomer is teratogenic. Under
biological conditions, the isomers interconvert, so separating the isomers before use is ineffective.
The thalidomide disaster caused many
countries to tighten drug approval regulations.
11. Vigabatrin, one of the most widely used
antiepileptic drugs, is marketed and administered
as a racemic mixture in which only S-enantiomer is
therapeutically effective.
R- Vigabatrin
S-Vigabatrin
Tramadol is marketed as a racemic mixture of both R- and S-
stereoisomers, because the two isomers complement each other's
analgesic activities .
The (+)-isomer is predominantly active as an opiate with a higher
affinity for the µ-opiate receptor (20 times higher affinity than the (-)-
isomer).
12. PHARMACOKINETIC PARAMETERS:
1.Absorption
Passive intestinal absorption
Carrier transporter stereoselectivity
Oral bioavailability
Local blood flow
2. Distribution
Protein binding
Tissue distribution
Storage mechanism
Tissue uptake transporter
Efflux process
3.Metabolism
First pass metabolism
Phase 1 and Phase 2 metabolism
4. Elimination
Glomerular Filtration
Active secretion
Passive & active reabsorption.
13. The process of movement of drug from its site of administration to systemic circulation is
called as absorption.
Most important mechanism of drug absorption is passive diffusion through biological
membranes, a process that is dependent upon the physicochemical properties of the
molecule:
i. Lipid solubility
ii. pKa
iii. Molecular size
iv. Dissloution time
v. Drug stability …..etc
If a chiral drug is absorbed by a passive process then differences between enantiomers
would not be expected.
In contrast , diastereoisomers may show differences in absorption as a result of the
differences in their solubility i.e
Enantiomeric
Do not show any differences in the absorption rate
Diastereomeric
May show differences in absorption as a result of the
differences in their solubility.
14. The aqueous solubility of ampicillin with 2R stereochemistry in
the acylated side chain (corresponding to D- configuration) is
greater than that of 2S epimer (L-configuration in side chain).
Many of the b-lactam antibiotics are substrates for the gut dipeptide
transport system and as such their absorption would be expected to be
stereoselective.
The influence of the stereochemistry of the 7-acyl side chain on the
absorption of the diastereoisomers of cefalexin has been
investigated in the rat.
Both diastereoisomers are substrates for the carrier-mediated
transport system with the L-epimer showing a higher affinity than,
and acting as a competitive inhibitor for, D-cefalexin transport.
However, the L-epimer is also more susceptible to the intestinal
wall peptidases and cannot be detected in serum, whereas the D-
isomer is well absorbed. The drug is marketed as the single D-
epimer
15. i)There was 15% difference in bioavailability of
the enantiomers of Atenolol. It was postulated
that this was a result of an enantioselective
active absorption.
ii)Esomeprazole( Nexium) is more bioavailable than racemic omeprazole( Prilosec).
iii)Greater bioavailability of (-)R-terbutaline compared
to the less active (+)S- enantiomer is due to the result
of
stereoselectivity in first pass metabolism and due to (-
) enantiomer posses increasing membrane
permeability in absorption.
16. Difference in the absorption of enantiomers may also due to
difference in their effect on local blood flow.
(-) Bupivacaine has a longer duration of action than (+) Bupivacaine
following intradermal
injection. This difference in activity is due to vasoconstrictor effects
of the (-) enantiomer reducing
blood flow locally.
The majority of the drugs undergo reversible binding to plasma
proteins.
• In case of chiral drugs, the drug enantiomer- protein complexes
are diastereoisomeric
and individual enantiomers would be expected to exhibit
differences in binding affinity
to the circulating proteins.
• The differences in the binding affinity result in differences between
enantiomers in free
or unbound fraction that is able to distribute into the tissue.
17. The two most important plasma proteins with respect to drug binding are human
serum albumin (HSA) and alpha1-acid glycoprotein (AGP).
a) Generally acidic drugs bind to HSA and basic drugs bind to AGP.
b) Differences between enantiomers in the plasma protein binding may be relatively
small and in some cases less than1%.
Stereoselectivity in plasma protein binding also influences clearance for drugs, total
clearance being proportional to fraction bound.
Differences between enantiomers for plasma protein-binding sites may also result in
pharmacokinetic complications.
Most of the drug undergo reversible binding to plasma proteins.
Types of plasma proteins are-
-Human serum albumin -Weak acid to weak base drugs
-Alpha-1 acid glycoproteins-Basic drugs
-Lipoproteins- Basic lipophilic drugs
-Alpha-1 globulin-Steroids
-Alpha-2 globulin-Vitamins
-Hemoglobin -Phenytoin, pentobarbital, etc
18. Enantiomers display different magnitudes of stereoselectivity between various proteins found in
plasma.
1. R- Propranolol binding to albumin is greater than S- propranolol and S enantiomer binding to
alpha 1 glycoprotein is greater than R- albumin.
2. S- warfarin extensively binds to albumin than R – warfarin thus posses lower volume of
distribution.
3.Levo cetrizin has lesser volume of distribution than its dextro isomer.
R-Propranolol S- Warfarin Levo -cetrizin
19. Enantioselectivity in binding may also vary between HSA and AGP.
R- Propranolol
Highly albumin bound
Less potent
Highly metabolized
Low plasma concentration
S- Propranolol
Highly bound to AGP available as unbound
40 to 100 time more potent
Less metabolized
High plasma concentration
20. (S)-oxazepam hemi succinate binds to HSA with an affinity 40
times than that of R-enantiomer.
Enantioselective protein binding interaction was
reported between warfarin and lorazepam acetate.
Where, R, S- warfarin allosterically increased the
binding of S – Lorazepam acetate, but there was no
effect of them on R enantiomer.
Similarly, S- lorazepam acetate increased the
binding of R,S – Warfarin.
21. Storage mechanisms: The S
enantiomer of adreno receptor
antagonists propranolol and atenolol
undergo selective storage and
secretion.
The uptake of (-)- atenolol in to the
storage granules has been reported to
be 5 fold that of (+)- enantiomer.
Stereoselective distribution may also occur as a result of
interactions with: Tissue uptake transporter:
E.g.: the BBB clearance of the R-enantiomer is four fold
greater than that of
either (S)-or racemic baclofen (Muscle relaxant).
22. Stereoselectivity in metabolism may be associated with the
binding of the substrate to the enzyme, and therefore associated
with the chirality of the enzyme-binding site.
Alternatively, selectivity may be associated with catalysis due to
differential reactivity and/or orientation of potential target groups
with respect to the enzyme catalytic site.
The individual enantiomers of a racemic drug may be
metabolized by different routes to yield different products and
they are metabolized at different rates.
23. The stereoselectivity of the reactions of drug
metabolism may be associated with:
• 1. Substrate stereoselectivity, i.e. the selective
metabolism of one enantiomer compared to the
other in either rate and/or route of metabolism
• 2. Product stereoselectivity, i.e. the preferential
formation of a particular stereoisomer rather than
other possible stereoisomers
• 3. Substrate product specificity, i.e. the selective
metabolism of one enantiomer resulting in the
preferential formation of one of a number of possible
diastereoisomeric products.
Prochiral to chiral
transformations
Chiral to chiral
transformations
Chiral to
diastereo
isomer
transformations
Chiral to achiral
transformations
Chiral
inversions
24. PROCHIRAL TO CHIRAL TRANSFORMATION:
The molecule acquires chirality by metabolism, which
may take place at either a prochiral centre or on an
enantiotopic group bonded to it.
Examples: The antiepileptic drug phenytoin has a
prochiral center at carbon -5 of the hydantoin ring
system and the two phenyl rings are enantiotopic as
indicated by pro-S and pro-R. The major route of
metabolism of phenytoin in both animals and humans
involves aromatic oxidation which in human shows
product stereoselectivity for formation of (S)-4-
hydroxyphenytoin.
CHIRAL TO CHIRAL TRANSFORMATION:
In this type of transformations metabolism take place at a site in the
molecule that does not alter the chirality of the metabolite relative to
that of the drug.
Example: Esmolol is an ultrashort acting relatively cardioselective B-
adrenoreceptor antagonist, is used as a racemate but the
pharmacological activity resides in the enantiomer of the S-
configuration; the R-enantiomer is pharmacologically inactive.
The ester functionality of esmolol is hydrolysed by the enzyme in
blood esterases . The hydrolysis of S-esmolol is faster than that of
the R-enantiomer in the animals whereas in human beings the
hydrolysis of both enantiomers occur at similar rates.
25. CHIRAL TO DIASTEREOISOMER
TRANSFORMATION:
This type of transformation involves the introduction of
an additional stereogenic centre into a chiral molecule .
Such centres may arise by a phase 1 or
functionalization, metabolic reaction at a prochiral
centre or by a phase 2, or conjugation, process by
reaction with a chiral conjugating agent.
Example: Reaction of a first type include reduction of
the prochiral ketone group in warfarin to yield a pair of
diastereoisomeric warfarin alcohols. In both rat and
human, the reduction is substrate selective for (R)-
warfarin and the predominantly formed isomer of the
alcohol has S-configuration at the new centre.
CHIRAL TO ACHIRAL
TRANSFORMATIONS:
In reactions of this type the biotransformation
results in a loss of chirality, the reaction taking place
at the stereogenic centre.
Example: 1,4-dihydropyridine calcium channel
blockers nitrendipine and nilvadipine .
26. CHIRAL INVERSION:
Chiral inversion is a relatively rare metabolic transformation
and involves the conversion of a stereoisomer to its
enantiomer with no other chemical change to the molecule.
Example: The reaction was initially observed in 2-arylpropionic
acid NSAID’s e.g. ibuprofen and since then it has been found to
occur with the chemically related 2-aryloxypropionates, which
are used as herbicides e.g. haloxyfop
27. Renal excretion is the net result of glomerular filteration, active secretion and passive &
active reabsorption.
Since glomerular filteration is a passive process differences between enantiomers
would not be expected.
However, apparent stereoselectivity in renal clearance may arise as a consequence of
stereoselectivity in protein binding.
Active renal tubular secretion is thought to be responsible for the
differential clearance of the enantiomers of number of basic drugs with
stereoselectivities in the range of 1.1 to 3.0
28. Eg : The renal clearance of quinidine is four
times greater than its diastereoisomer quinine.
For those agents that undergo active tubular secretions,
the interactions between the enantiomers may occur in
such a way that their excretions differs as single
enantiomer or as a racemates.
Ex- S- Ofloxacin administration with more of its R –
enantiomer resulted in reduction of renal clearance of S-
enantiomer. Mechanism followed was by competitive
inhibitor of active transport system
29. BIBLOGRAPHY:
a) Smith and William’s introduction to principles of drug
design, second edition, published by John wright,
Pg.no.140-149
b) Burger’s Medicinal Chemistry And Drug Discovery, 6th
edition, pg.no.782-787
c) Thomas L.L and David A Williams, Foye’s Principle of
Medicinal Chemistry, 6th edition, Wolters Kluwer, Chapter
2 pg.24-36