Isomerism

Compounds with the same molecular formula but different structures are isomers.
1-butene and 2-butene have the same molecular formula, C4H8, but structurally they are different
because of the different positions of the double bond.
two types of isomer: constitutional isomers and stereoisomers.

Constitutional isomers
 Two different compounds have the same molecular formula but differ in the nature or sequence of
bonding.
 Ethanol and dimethylether: same molecular formula,C2H6O, but they differ in the sequence of
bonding. Butane and Isobutane are two constitutional isomers.
 Have different physical and chemical properties.

Stereoisomer
 Stereoisomer is compounds where the atoms are connected in the same order but with
different geometries, i.e. they differ in the three-dimensional arrangements of groups or
atoms in space.
 α-glucose and β-glucose, the atoms are connected in the same order, but the three dimensional
orientation of the hydroxyl group at C–1 is different in each case.
 cis- and trans-cinnamic acid only differ in the three dimensional orientation of the atoms or
groups.
 Two major types of stereoisomer: conformational isomers and configurational isomers.
 Configurational isomers include optical isomers, geometrical isomers, enantiomers and
diastereomers.

Conformational isomers
 Atoms within a molecule move relative to one another by rotation around single bonds, rotation of
covalent bonds gives rise to different conformations of a compound.
 Conformers rapidly interconvert at room temperature.
 Staggered and eclipsed conformers : In the staggered conformation, the H atoms are as far apart as
possible. This reduces repulsive forces between them. This is why staggered conformers are
stable. In the eclipsed conformation, H atoms are closest together. This gives higher repulsive
forces between them. As a result, eclipsed conformers are unstable. At any moment, more
molecules will be in staggered form than any other conformation..
 Torsional energy : Torsional energy is the energy required for rotating about the C–C s bond.
Torsional strain is the strain observed when a conformer rotates away from the most stable
conformation (i.e. the staggered form). Torsional strain is due to the slight repulsion between
electron clouds in the C–H bonds as they pass close by each other in the eclipsed conformer.

Configurational isomers
Differ from each other only in the arrangement of their atoms in space, and cannot be converted
from one into another by rotations about single bonds within the molecules

Chirality : mirror images of each other, and not superimposable on each other.
The most common feature in chiral molecules is a tetrahedral (i.e. sp3-hybridized) carbon atom with
four different atoms or groups attached known as chiral carbon or an asymmetric carbon. Chiral
molecules do not have a plane of symmetry.

two or more atoms/groups that are the same, the carbon is achiral - have a plane of symmetry.

 If a molecule can be divided by a plane into two equal halves that are mirror images of each other,
the plane is a plane of symmetry, and the molecule is achiral.
 With achiral molecules, the compound and its mirror image are the same, i.e. they can be
superimposed. If you rotate the mirror image through 180°, it is identical to the original structure.

Enantiomers : enantio means ‘opposite’. A chiral molecule and its mirror image are called
enantiomers or an enantiomeric pair.They are nonsuperimposable. The actual arrangement or
orientation (in space) of atoms/groups attached to the chiral carbon (stereogenic centre or
stereocentre) is called the configuration of a compound.
Have same physical and chemical properties,e.g. melting points, boiling points and solubilities.
differ in their activities with plane polarized light, which gives rise to optical isomerism, and also in
pharmacological actions.
Light oscillates in all directions. When a beam of ordinary light is passed through a polarizer, the
polarizer interacts with the electrical vector in such a way that the light emerging from it oscillates in
one direction or plane. This is called plane polarized light

When plane-polarized light passes through a solution of an enantiomer, the plane of light rotates. Any
compounds that rotate plane-polarized light are called optically active. If the rotation is in a clockwise
direction, the enantiomer is said to be dextrorotatory and is given the (+) sign in front of its name.
Anticlockwise rotation gives an enantiomer which is known as levorotatory and is given the sign (-) in
front of its name. The amount of rotation can be measured with an instrument called a polarimeter.
Enantiomers are optically active, and are called optical isomers, with one being (+) and the other (-)
When we have a pair of enantiomers, each rotates the plane-polarized light by the same amount, but in
the opposite direction. A mixture of enantiomers with the same amount of each is called a racemic
mixture. Racemic mixtures are optically inactive (i.e. they cancel each other out) and are denoted by
(±).

Specific rotations

The specific rotation of a compound, designated as [a]D, is defined as the observed rotation, a, when
the sample path length l is 1 dm, the sample concentration C is 1g/mL and light of 599.6 nm
wavelength (the D line of a sodium lamp, which is the yellow light emitted from common sodium
lamps) is used.

As the specific rotation also depends on temperature, the temperature at which the rotation is measured
is often shown in the equation. A specific rotation measured at 25 _C is denoted more precisely as
 where 25 is temperature and 132 degree anticlockwise

The optical activity does not tell us the actual configuration of an enantiomer. It only gives us the
information whether an enantiomer rotates the plane-polarized light clockwise or anti-clockwise.
There are two systems to designate configuration of enantiomers:
The D and L system, and the (R) and (S) system
D dextro Right, L Levo Left
R Rectus Right and S Sinister Left
The following rules or steps are applied for designating any enantiomer as R or S.
(a) Each of the four groups attached to the chiral carbon is assigned 1–4 (or a–d) in terms of order of
priority or preference, 1 being the highest and 4 being the lowest priority. Priority is first assigned on
the basis of the atomic number of the atom that is directly attached to the chiral carbon. Higher atomic
number gets higher priority.

(b) When a priority cannot be assigned on the basis of the atomic numbers of the atoms that are
directly attached to the chiral carbon, the next set of atoms in the unassigned groups is examined. This
process is continued to the first point of difference. In 2-hexanol, there are two carbon atoms directly
attached to the chiral carbon; one is of the methyl group, and the other is of the propyl group. In this
case, on the basis of the atomic number of the carbon atom alone, one cannot assign the priority of
these two carbon atoms, and must consider the next set of atoms attached to these carbon atoms.
When we examine the methyl group of the enantiomer, we find that the next set of atoms consists of
three H atoms. On the other hand, in the propyl group, the next set of atoms consists of one C and two
H atoms. Carbon has a higher atomic number than H, so the CH3CH2CH2– group receives priority
over CH3.
(c) Groups containing double or triple bonds (p bonds) are assigned priorities as if both atoms were
duplicated or triplicated

(d) Having decided on the priority of the four groups, one has to arrange (rotate) the molecule in such
a way that group 4, i.e. the lowest priority, is pointing away from the viewer.

Then an arrow from group 1! 2! 3 is to be drawn. If the direction is clockwise, it is called an (R)-
isomer. If it is anti-clockwise, it is called an (S)-isomer. With enantiomers, one will be the (R)-isomer
and the other the (S)-isomer. Again, there is no correlation between (R) and (S), and (+) and (-).
Stereoisomerism in compounds with two stereo centres: diastereomers and meso structure In
compounds whose stereoisomerism is due to tetrahedral stereocentres, the total number of
stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocentres

If we look at structures A and C or B and D, we have stereoisomers, but not enantiomers. These are
called diastereomers. Diastereomers have different physical properties (e.g. melting point).
In tartaric acid, four isomeric forms are theoretically expected (22¼4). However, because one half of
the tartaric acid molecule is a mirror image of the other half, we get a meso structure. This means this
compound and its mirror image are superimposable, i.e. they are the same compound. Thus, instead of
four, we obtain only three stereoisomers for tartaric acid. Structures 1 and 2 are enantiomers, and both
are optically active. In structures 3 and 4, there is a plane of symmetry, i.e., there is a mirror
image within a single molecule. Such a structure is called a meso structure. Structures 3 and 4 are
superimposable, and essentially are the same compound. Hence, we have a meso-tartaric acid and it is
achiral (since it has a plane of symmetry, and it is superimposable on its mirror image). Meso-tartaric
acid is optically inactive. Therefore, for tartaric acid, we have (+), (-) and meso-tartaric acid.

Geometrical isomers
Geometrical isomerism is found in alkenes and cyclic compounds. In alkenes, there is restricted
rotation about the double bond. When there are substituent groups attached to the double bond, they
can bond in different ways, resulting in trans (opposite side) and cis (same side) isomers. These
are called geometrical isomers. They have different chemical and physical properties. Each isomer can
be converted to another when enough energy is supplied, e.g. by absorption of UV radiation or being
heated to temperatures around 300 _C. The conversion occurs because the p bond breaks when
energy is absorbed, and the two halves of the molecule can then rotate with respect to each other
before the p bond forms again. When there is the same substituent attached to the double bonded
carbons, as in the above example, it is quite straightforward to designate trans or cis.
However, if there are more than one different groups or atoms present, as in the following
examples, the situation becomes a bit more complicated for assigning cis and trans.

To simplify this situation, the E/Z system is used for naming geometrical isomers. Z stands for
German zusammen, which means the same side, and E for German entgegen, meaning on the opposite
side.In the E and Z system, the following rules or steps are followed.
(a) On each C atom of the double bond, we have to assign the priority of the atoms bonded. The
priority should be on the same basis as the (R)/(S) system (i.e. on the basis of atomic number).
(b) If the two higher priority groups of the two C atoms are on the same side of the double bond, it is
called the (Z)-isomer.
(c) If the two higher priority groups of the two C atoms are on opposite sides of the double bond, it is
called the (E)-isomer.
Let us take a look at 1-bromo-1,2-dichloroethene as an example. In this molecule, atoms attached are
Cl and Br on C-1, and Cl and H on C-2. Atomic numbers of these substituents are in the order of
Br>Cl>H. So,once the priorities are assigned, we can easily draw the (E)- and (Z)-isomers
of 1-bromo-1,2-dichloroethene in the following way.

Now, let us have a look at the cyclic compounds. We can use this (E) and (Z) system for a cyclic
compound when two or more groups are attached to a ring. For example, if in the following substituted
cyclopentane A and B are different groups, each C atom attached to A and B is a chiral carbon or
stereocentre.
Ibuprofen is a popular analgesic and anti-inflammatory drug. There are two stereoisomeric forms of
ibuprofen. This drug can exist as (S)- and (R)-stereoisomers (enantiomers). Only the (S)-form is
active. The (R)-form is completely inactive,

When four different groups are situated around the central atom in silicon, germanium
and nitrogen compounds, the molecules are chiral. Sulphoxides, where one of the four groups is a
nonbonding electron pair, are also chiral.A molecule is chiral if it is not superimposable on its mirror
image. A tetrahedral atom with four different groups is just one of the factors that confer chirality on a
molecule. There are a number of molecules where a tetrahedral atom with four different groups is not
present, yet they are not superimposable, i.e. chiral. For example, 1,3-dichloroallene is a chiral
molecule, but it does not have a tetrahedral atom with four different groups.

An allene is a hydrocarbon in which one atom of carbon is connected by double bonds with two other
atoms of carbon. Allene is also the common name for the parent compound of this series, 1,2-
propadiene. The planes of the p bonds of allenes are perpendicular to each other. This geometry of the
p bonds causes the groups attached to the end carbon atoms to lie in perpendicular planes. Because of
this geometry, allenes with different substitutents on the end carbon atoms are chiral. However, allenes
do not show cis–trans isomerism.

(-)hyoscyamine, which exhibits 15 to 20 times more mydriatic activity than (+)hyoscyamine.

(-)ephedrine. which shows 3 times more pressor activity than ( + )ephedrine. 5 times more pressor
activity than (+ )-pseudoephedrine. and 36 times more pressor activity than (-)pseudoephedrinc.
All of ascorbic acid's antiscorbutic properties reside in the (+) isomer.
(-) epinephrine shows l2to 15 times more vasoconstrictor activity than( + ) epinephrine

The dextrorotatory isomers in the morphine series are cough suppressants with less risk of substance
abuse, whereas the levorotatory isomers contain the analgesic activity and significant
risk of substance abuse. While the direction of optical rotation is opposite to that of the morphine
series. Dextropropoxyphene contains the analgesic activity, and the L isomer contains antitussive
activity.

Levobupivacaine. Which is the S isomer of Buivacaine. Both the R and S isomers

have good local anesthetic activity. but the R isomer may cause depression of the myocardium leading
to decreased cardiac output. heart block hypotension. bradycardia. And ventricular ari-hythmias. In
contrast, the S isomer shows less cardiotoxic responses but still good local anesthetic
activity.Escialopram is the S isomer of the antidepressant citalopram. There is some evidence that the
R isomer, which contains little of the desired selective serotonin reuptake inhibition. contributes more
to the adverse reactions than tines the S isomer.

Ibuprofen: The S enantiomer contains the anti-inflammatory activity by inhibiting cyclooxygenase.

The R isomer does have centrally acting analgesic activity, but it is converted to the S form in viva

Calcium channel antagonist verapamil, which illustrates why it is diflicult to conclude that one isomer
is superior to the other. S-Verapamil is a more active pharmacological stereoisomer
than R-verapamil, but the former is more rapidly metabolized by the first-pass effect.

Lipinski Rule of Five

A candidate molecule is more likely to have poor absorption or permeability if
I. The molecular weight exceeds 500
2. The calculated octanol/water partition coefficient exceeds 5
3. There are more than 5 H-bond donors expressed as the sum of 0—H and N—H groups
4. There are more than 10 H. bond acceptors expressed us the sum of N and 0 atoms

isoters: compounds or groups of atoms having the same number and arrangement of electrons
isoelectric : same total charge as well as the Same number of electrons

Metabolism Pathways

Drug metabolism reactions have been divided into two categories:

Phase1 (functionalization) and phaseII (conjugationon) reacttons.
Phase I, or functionalization reactions, include oxidative. reductive, and hydrolytic
biotransformations The purpose of these reactions is to introduce a functional polar group(s) (e.g..
OH. COOH, NH2, SH) into the xenobiotic molecule to produce a more water soluble compound. This
can be achieved by direct introduction of the functional group (e.g.. aromatic and aliphatic
hydroxylation) or by modifying or "unmasking" existing functionalities (e.g.. reduction of ketones and
aldehydes to alcohols; oxidation of alcohols to acids: hydrolysis of ester and amides to yield COOH,
NH2. and OH groups; reduction of azo and nitro compounds to give NH2 moieties; oxidative N-, 0-.
And S-dealkylation to give NH2. OH. and SH groups). Although phase I reactions may not produce
sufficiently hydrophilic or inactive metabolites, they generally tend to provide a functional group or
'handle" on the molecule that can undergo subsequent phase II reaclions.

Phaes II attach small, polar and ionizable endogenous compounds such as glucuronic
acid, sulfate. glycine. and other amino acids to the functional "handles" of phase I metabolites or
parent compounds that already have suitable existing functional groups to form water-soluble
conjugated products. Conjugated metabolites are readily excreted in the urine and are generally devoid
of pharmacological activity and toxicity in humans. Other phase II pathways, such as methylation and
acetylation. Terminate or attenuate biological activity, whereas glutathione (GSH) conjugation
protects the body against chemically reactive compounds or metabolites.
Cytochrome P450 Monooxygenses
Mixed Function oxidase or monooxygenase: introduce oxygen molecule to compound
RH + NADPH + O2 + H+ →ROH + NADP + +H2O

The reaction requires both molecular oxygen and the reducing agent NADPH (reduced form of
nicotinamide adenosine dinucleotide phosphate). During this oxidative process. one atom of molecular
oxygen (02) is introduced into the substrate R-H to form R-OH and the other oxygen atom is
incorporated into water.

NADPH-dependent cytochrome P-450 reductase and the NADH-Iinked cytochrome b5. The latter two
components, along with the cofactors NADPH and NADH. supply the reducing equivalents (electrons)
needed in the overall metabolic oxidation of foreign compounds are the part of mixed function oxidase
system
cytochronte P-450 enzymes are heme proteins. The heme portion is an iron-containing porphyrin
called protoporphyrin IX. and the protein portion is called the apaprotein. cylochrome P450
monooxygenazex are located in the endoplasmic reticulum
Aromatic hydroxylation (mostly at Para position) is a major route of metabolism for many drugs
containing phenyl groups. Most phenolic metabolites formed from aromatic oxidation undergo further
conversion to polar and water-soluble glucuronide or sulfate conjugates

Aromatic hydroxylation reactions appear to proceed most readily in activated (electron-rich) rings,
whereas deactivated aromatic rings (e.g.. those containing electron. withdrawing groups Cl, -N +R3.
COOH. SO2NHR) are generally slow or resistant to hydroxylation. The deactivating groups (Cl. -N H
= C) present in the antihypertensive clonidine may explain why this drug undergoes little
aromatic hydroxylation in humans.The uricosuric agent probenecid (Benemid), with its electron-
withdrawing carboxy and sulfamido groups, has not been reported to undergo any aromatic
hydroxylation.. compounds with two aromatic rings. hydroxylation occurs preferentially in the
more electron-rich ring.
Olfeins: first undergoes epoxidation and than introduces two –OH moiety at double bond

Intermediate Oxide is highly reactive and forms covalent bond with DNA and RNA

Oxidation at Benzylic Carbon Atom:

Carbon directly attached to aromatic ring converts to alcohol and eventually acid or ketone.
Primary alcohol→ Aldehyde→ acid (Oxidation)
Secondary alcohol→ketone (oxidation)

Oxidation at Allylic Carbon Atoms

Oxidation at Carbon Atoms α to Carbonyls and Imines

The mixed.function oxidase system also oxidizes carbon atoms adjacent (i.e.. a) to carhonyl and imino
(C = N) ftinctionalities. An important class of drugs undergoing this type of oxidation is the
benzodiazepines

Oxidation at Aliphatic and Alicyclic Carbon Atoms

Alkyl or aliphatic carbon centers are subject to mixed-function oxidation. Metabolic oxidation at the
terminal methyl group often is referred to as w oxidation, and oxidation of the penultimate carbon
atom (i.e., next-to-the-last carbon) is called w— I oxidation)'4' '5The initial alcohol metabolites
formed from these enzymatic w and w — I oxidations are susceptible to further oxidation to yield
aldehyde. kelones. or carboxylic acids. Alternatively, the alcohol metabolites may undergo
glucuronide conjugation.

Oxidation Involving Carbon-Heteroatom Systems

Metabolic oxidation of carbon-nitrogen, carbon-oxygen, and carbon-sulfur systems principally
involves two basic types of biotransformation processes:
I. Hydroxylation of the α-carbon atom attached directly to the heteroatom (N. O. S). 'The resulting
intermediate is often unstable and decomposes with the cleavage of the carbon-heteroatom
bond: Oxidative N-. 0-. and S-dealkylation as well as oxidative deamination reactions fall under this
mechanistic pathway.
2. Hydroxylation or oxidation of the heteroatom (N. S only, e.g.. N-hydroxylation. N-oxide formation.
sulfoxide. and sulfone formation).
OXIDATION INVOLVING CARBON-NITROGEN SYSTEMS

Through either α-carbon hydroxylation or N-oxidation

Tertiary aliphatic and alicyclic amine : removal of alkyl group (Oxidative de alkylation)
The initial step involves a-carbon hydroxylation In form a carbinolamine intermediate, which is
unstable and undergoes spontaneous heterolytic cleavage of the C—N bond to give a secondary amine
and a carbonyl moiety (aIdehyde or ketone)
Delakyaltion is for methyl, ethyl, isopropyl but N dealkylation of the t-butyl group is not possible by
the carbinolamine pathway because α-carbon hydroxylation cannot occur.

Secondary and Primary Amines.: oxidative N-dealkylation. oxidative deamination. and N-oxidation
Reactions. Delakylation of secondary amine yields primary amine which further goes to deamination

N-oxidation of secondary aliphatic and alicyclic amines leads to several N-oxygenated products

secondary alicyclic amines. like their tertiary amine analogues, are metabolized to their corresponding
lactam derivatives.

Primary amine: N oxidation is major route

Aromatic Amines and Heterocydhc Nitrogen Compounds,

Tertiary amine: . oxidative N-dealkylation as well as N-oxide formation
Secondary amine:amines may undergo N-dealkylation or N-hydroxyluion to give the corresponding
N-hydroxylamines. Further oxidation of the N-hydroxylamine leads to nitrone products.
which in turn may be hydrolyzed to primary hydroxyl amines.

Primary aromatic amines:N oxidation gives N Hydroxylamie further oxidation to Nitroso (minor)
N-acetylation and aromatic hydroxylation (major)route

Amides:
Carbon-nitrogen bond cleavage (via α-carbon hydroxylation) and N-hydroxylation reactions.
Oxidative dealkylation of many N-substituted amide

Oxidation involving carbon-oxygen system (Ether)

α-carbon hydroxylation to form either a hemiacetal or a heiniketal. which undergoes spontaneous
carbon—oxygen bond cleavage to yield the dealkylated oxygen species
(phenol or alcohol) and a carbon moiety (aldehyde or ketone). Small alkyl groups (e.g., methyl or
ethyl) attached to oxygen are o-dealkylaced rapidly

OXIDATION INVOLVING CARBON-SULFUR SYSTEMS

S-dealkylation. desulfuration. and S-oxidation reactions.
The first two processes involve oxidative carbon-sulfur bond cleavage. S-dealkylation is analogous to
O- and N-dealkylation mechanistically (i.e.. it involves α carbon hydroxylation)
Oxidative conversion of carbon—sulfur double bonds
(C = S) to the corresponding carbon—oxygen double bond (C=O) is called desulfurasion
Oxidation of Alcohols and Aldehydes
Primary alcohol----Aldehyde----Carboxylic acid
Secondary alcohol----Ketone

Oxidative dehydrogenation, Oxidative dehalogenation, and oxidative aromatization

Reduction:

Nitro (NO2)---Nitroso (NO)-----Hydorylamie(NHOH)------Amine(NH2)

Azo (N=N)---hydrazine intermediate (NH-NH-)-Aromatic amine
Aldehyde----primary alcohol
Ketone---secondary alcohol
N oxide---tertiary amine

The hydroxyl and amino moieties of the metabolites arc much more susceptible to conjugalion
Reduction of N-oxides to their corresponding tertiary amines and reduction of sulfoxides
to sulfides. Reductive cleavage of disultide linkages and reduction of carbon—carbon double bonds
also occur, but constitute only minor pathways in drug metabolism

Reduction of α,β unsaturated ketones results in reduction not only of the ketone group but of the
carbon—carbon double bond as well

Hydrolysis of Esters and amides

Ester—hydrolysis---carboxylic acid+ alcohol
Amide—hydrolysis—carboxylic acid+ Amine

PHASE II OR CONJUGATION REACTIONS

Convert Phase I metabolites to more polar and water-soluble products by attaching small, polar and
ionizable endogenous molecules, such as glucuronic acid, sulfate. glycinc. and glutamine. to
the phase I metabolite
methylation and acetylation (Phase II) do not generally increase water solubility but mainly serve to
terminate or attenuate pharmacological activity

Glucuronic acid conjugation

Glucuronidation is the most common conjugative pathway in drug metabolism for several reasons: (a)
a readily available supply of D-glucuronic acid (derived from D-glucose). (b) numerous functional
groups that can combine enzymatically with glucuronic acid, and (c) the glucuronyl moiety (with
its ionized carboxylate pKa 3.21 and polar hydroxyl groups). which, when attached to xenobiotic
substrates, greatly increases the water solubility of the conjugated

Hydroxy and carboxy groups form O- glucuronic conjugation

Hydroxy and phenolic are major group undergoing glucuronidation
Sulfate Conjugation
Conjugation of xenobiotics with sulfate occurs primarily with phenols and, occasionally, with
alcohols, aromatic amines. and N-hydroxy compounds.

Conjugation with Glycin, Glutamin and Other Amino Acids

Aromatic acids and arylalkyl acids are the major substrates undergoing glycine conjugation
Glutamine conjugation occurs mainly with arylacetic acids, including endogenous phenylacctic and 3-
indolylaecetic acid

GSH or Mercapturic Add Conjugates

GSH (tripeptide (y-glutanxyl-cysteinylglycine) conjugation is an important pathway for detoxifying
chemically reactive electrophilic compounds. GSH protects vital cellular constituents against
chemically reactive species by virtue of its nucleophilic sulfhydryl (SH)) group. The SH group reacts
with electron-deficient compounds to form S-substituted GSH adducts. Metabolites conjugated with
GSH usually are not excreted as such but undergo further biotransformation to give S-substituted N-
acetylcysteine products called mercapturic acids.
Conjugation is catalyzed by a family of cytoplasmic enzymes known as glutathione S-transferases.
Degradation of GSH conjugates to mercapturic acids is carried out principally
by renal and hepatic microsomal enzymes
Compounds that react with GSH do so by two general mechanisms:
(a) nuclcophilic displacement at an electron-deficient carbon or heteroatom or (b) nucleophilic
addition to an electron- deficient double bond.
Many aliphatic and arylalkyl halides (Cl, Br, I, sulfates, sulfonates (OSO2R). nitrates (NO2). and
organo- phosphates (O-P[0RJ2) possess electron-deficient carbon atoms that react with GSH (by
aliphatic nucleophilic displacement) to form GSH conjugates,

Acetylation
Acetylation constitutes an important metabolic route for drugs containing primary amino groups. This
encompasses primary aromatic amines (ArNH2). Sulfonamides (H2NC6H4SO2NHR). hydrazines (—
NHNH2), hydrazides (—CONHNH2), and primary aliphatic amines. The amide derivatives formed
from acetylation of these amino functionalities are generally inactive and nontoxic.

Methylatlon
Methylation reactions play an important role in the biosynthesis of many endogenous compounds
(e.g.. epinephrince and melatonin) and in the inactivation of numerous physiologically
active biogenic amines (e.g.. norepinephrine, dopamine, serotonin and histamine)