Medicinal Chemistry-I
By
Dr. Mehnaz Kamal
Assistant Professor
Pharmaceutical Chemistry
Prince Sattam Bin Abdulaziz University
DRUG
METABOLISM
The Fate of a Drug
DOSE
Pharmaceutics
ABSORPTION
MOST TISSUES
PROTEIN
BOUND
NONSPECIFIC
BINDING
PLASMA
FREE
DISTRIBUTION
BIOPHASE
ELIMINATION
METABOLISM
RECEPTOR
BINDING
RENAL
EXCRETION
EFFECT
Pharmacokinetics
Pharmacodynamics
Drug at site
of administration
1. Absorption
Drug in plasma
2. Distribution
Drug/metabolites
3. Metabolism
in tissues
Drug/metabolites
in urine, feces, bile
4. Elimination
BIOTRANSFORMATION/METABOLISM OF
DRUGS
 Chemical modification of drugs
compounds (xenobiotics) in the body.
or
foreign
The apparent function of drugs or xenobiotics
metabolism is their transformation into watersoluble derivative which can be easily eliminated via
renal route.
Effect of drug metabolism
Active drug
Inactive prodrug
Inactive Drug
Metabolic activation
Active drug
Inactive metabolite
 Lipid Solubility
R-H
R-OH
Chemical hook
 Drug metabolism reactions traditionally have
been regarded as detoxification processes.
However, it is incorrect to assume that drug
metabolism reactions are always detoxifying.
 It is becoming increasingly clear that not
all metabolites are nontoxic. Many toxic side
effects
of
drugs
and
environmental
contaminants can be attributed directly to
the
formation
of
chemically
active
metabolites that are highly detrimental to
the body.
Implications For Drug Metabolism
1.
Termination of drug action
2.
Activation of prodrug
3.
Bioactivation and toxication
4.
Carcinogenesis
 The objective of studying drug metabolism is to
make medicinal chemists aware of the chemical
processes involved in the biotransformation of
drugs and to encourage them to further study so
as to be able to use the acquired knowledge in the
design of new more safe drugs.
 Two categories of xenobiotics are not or are
hardly subject to metabolic transformations :
1- Hydrophilic compounds (e.g. saccharine, strong
acids or bases)
O O
S
NH
O
2- Highly lipophilic polyhalogenated xenobiotics
such as some insecticides e.g. DDT.
 Innumerable examples exist of metabolic
reactions not leading to inactivation and
detoxication.
 Some metabolite will possess its own activity
which will be similar to or different from that of
the parent drug.
 Other metabolites may be highly reactive entities
able to bind covalently to soluble or membrane
proteins, enzymes, or even DNA (mutagenic and
carcinogenic compounds).
 Lethal synthesis: a classic example of lethal
synthesis is provided by the metabolic conversion
of the nontoxic insecticide parathion into its
oxygenated
isostere
paraoxon,
a
potent
acetylcholinesterase inhibitor
OEt
O2N
O-P-OEt
OEt
O2N
O-P-OEt
S
Parathion
O
Paraoxon
Fig.2. Metabolic conversion of the nontoxic insecticide parathion to paraoxon
 Major Sites of Metabolism
 Drug metabolism can occur in every tissue (e.g. gut, lung,
kidney). However, the major drug metabolizing enzymes
(DMEs) are expressed at the highest levels in the liver,
which serves as the major organ of metabolic clearance
High
liver
Medium
lung, kidney, intestine
Low
skin, testes, placenta, adrenals
Very low
nervous system
Extrahepatic microsomal enzymes
(oxidation, conjugation)
Hepatic microsomal enzymes
(oxidation, conjugation)
Hepatic non-microsomal enzymes
(acetylase, sulfate transferase,
GSH S-transferase,
alcohol/aldehyde dehydrogenase,
hydrolase, oxidase/reductase)
 The LIVER is the chief organ for drug metabolism
because:
– The blood flow through the liver is high
– Hepatocytes contain numerous metabolic enzymes
 Biotransformation broadly classified into two
types of reactions:
– PHASE I: Functionalization reaction, new polar groups
such as CO2H, OH or NH2 are introduced or
unveiled/unmasked from pre-existing functions through
oxidative, reductive or hydrolytic reactions.
– PHASE II: known as conjugation reactions, link an
endogenous solubilizing moiety either to the original drug (if
polar functions are already present) or to the phase I
metabolite.
Phase I
H
Phase II
OH
O.SO3H
Fig. 1. A phenyl ring in a xenobiotic first undergoes a functionalization reaction (phase I) and is then conjugated (phase II)
 Phase I or Functionalization Reactions
1- Oxidation
electron removal, dehydrogenation and hydroxylation.
2- Reduction
electron addition, hydrogenation and removal of
oxygen
3- Hydrolytic reactions/Hydrolysis
Oxidation
Reduction
• hydroxylations
aromatic, aliphatic, nitrogen
• dealkylations(N-, S-, P)
• deaminations
• N-, S-, P- oxidations
oxidoreductases
• S-replacements
oxidases
monoamine oxidases
• epoxidations
mixed function oxidases
• others
•
•
•
•
azo reduction
nitro reduction
disulfide reduction
others
oxidoreductases
reductases
esterases
Hydrolysis
• esters
• amides
amidases
peptidases
lipases
1. Oxidation reactions
The great majority of these oxidations are
carried out by the haemoprotein cytochrome P450 which is embedded within the phospholipid
environment of the microsomes derived from the
endoplasmic reticulum of living cells.
Cytochrome P450 (CYPs)
• Cytochrome P450 is a family of enzymes located
in the endoplasmic reticulum of liver.
•When liver is homogenized and biochemically fractionated
these enzymes are found in the microsomal fraction (small
closed ER membrane fragments). Thus these enzymes are
called microsomal enzymes.
 Cytochrome P450 enzymes perform many of the most
important biotransformation reactions.
 These enzymes oxidize a wide variety of compounds
foreign to the body.
There are at least 18 different forms of cytochrome
P450 identified in humans, produced by different genes.
 60% of drugs are metabolized primarily by
CYPs.
• Important cytochrome P450 enzymes:
1. CYP3A4.
2. CYP1A2.
3. CYP2C.
3. CYP2D6.
• Individual enzymes differ in their substrate specificity
and regulatory properties.
The reaction sequence illustrated by CyP Redox Cycle :
CYP450 Reaction
Sequence
OH
DRUG
DRUG
CYP450
Fe3+
CYP450
Fe3+
CYP450
Fe3+
DRUG
DRUG
NADPH +
OH
CYP450
Fe3+
H+
e-
CYP450
reductase
CYP450
Fe2+
NADPH + H+
DRUG
:
O
..
DRUG
H+
eH2O
CYP450
Fe2+
O2
CYP450
Fe2+
DRUG
DRUG
O21-
R-H + O2 + 2e- + 2H+
O2
R-OH + H2O
oxidation
C
• hydroxylations
aromatic, aliphatic, nitrogen
• dealkylations (N-, S-, P-)
• deaminations
• N-, S-, P- oxidations
• S-replacements
• epoxidations
• others
C
H
OH
N
N
N
N
H
O
OH
O
CONH2
O
C
C
C
CONHOH
C
P
P
O
C
S
C
O
O
O
S
S
O
O
C
S
C
S
Si
H
Si
OH
Fig. 4. Major reactions of oxygenation catalyzed by cytochrome P450.
1.1. Carbon oxidation reactions/ C-oxidation
reactions
The reactions of C-oxidation represent the
common metabolic attacks on xenobiotics.
a) Hydroxylation of saturated aliphatic carbon atoms
– In practice a non-activated alkyl group
undergoes mainly  and -1 oxidation
 Oxidation occurs at the terminal methyl group
-1 oxidation occurs at the carbon atom next to the
last one (penultimate carbon atom)
n C3H7
H2
C
HO H2C
H3C
COOH
5-Hydroxyvalproic acid
n C3H7
H2
C
CH
C
H2
Oxidation
CH
C
H2
COOH
Oxidation
Valproic acid
n C3H7
OH
CH
H3C
CH
C
H2
COOH
4-Hydroxyvalproic acid
Fig. 5: and 1Oxidation
nC3H7
H2
C
HOOC
CH
C
H2
COOH
2-n-Propylglutaric acid
 Cyclic aliphatic systems are usually hydroxylated on
the least-hindered or most-activated carbon atoms
O
HN
O
O
SO2
HN
N
H
O
SO2
N
H
Fig. 6: Hydroxylation on cyclic aliphatic system
OH
b) Hydroxylation at activated SP3 carbon atoms
OH
R
R
OH
OH
OH
R
X
O
R
R
XH
+
X
X = O, N-R, S
Fig. 7: Hydroxylation at activated SP3 carbon atoms
N
CH3
Br
N
HCHO
CHCH2CH2N
H
Br
CHCH2CH2N
CH3
N
HCHO
H
Br
CHCH2CH2N
CH3
Desmethyl bromopheniramine
Bromopheniramine
H
Bisdesmethyl bromopheniramine
NH3
N
N
Br
CHCH2COOH
3-(p-Bromophenyl)-3-pyridylpropionic
Br
CHCH2CH2OH
3-(p-Bromophenyl)-3-pyridylpropanol
Fig. 8: Oxidation of carbon atoms to heteroatom
The final result is dealkylation when a secondary
or tertiary amine loses an alkyl substituent, and
deamination when the substrate loses an amino
group
 Aromatic ethers undergo a similar hydroxylation, followed by hydrolysis of the
hemiacetal to a phenol and aldehyde
O
H
N
O
O
H
H
N
N
+ CH3CHO
O
OH
O
OH
Fig. 9: Oxidative O-dealkylation of phenacetin yields paracetamol
Dealkylation reactions can also result from direct oxidation
of the heteroatom (N,S) as opposed to that of the -carbon.
 Dehalogenated carbonyl compounds are formed
which may lead to toxic reactions.
c) Oxidation attack on unsaturated aliphatic systems
 Carbon-carbon double bonds undergo metabolic epoxidation
to the corresponding epoxide, an alkylating metabolite which
can, for example, alkylate nucleic acids
H
C
O
CH2
GSH
Styrene
Mercapturic acid
derivative
Styrene Oxide
Covalent binding to
proteins and nucleic acid
OH
OH
O
HO
HO
Fig. 11: Epoxidation of Styrene and diethylstilbesterol
 Carbon-Carbon
insertion yields
heterolytic C-O
highly reactive
covalently to the
triple
bonds,
oxygen
an oxirene which opens by
bond cleavage to form a
intermediate which binds
enzyme.
d) Hydroxylation of aromatic rings
R
OH
R
Arenols
H2O
R
R
OH Trans-Dihydrodiols
OH
R
Arene
o
GSH
Arene Oxide
OH Glutathione Adducts
GS
R
M
Macromolecular Adducts
OH
M
Fig. 13: Possible reaction pathways for arene oxides
 As a rule, hydroxylation occurs on the lesshindered site, usually the para- position. Electronic
factors are also operative. This can be seen in the
following representative examples:
O
NH-CO-CH3
7
S
OH
3
N
Cl
N
Acetanilide
Chlorpromazine
7
O
O
Warfarin
1.2. N-oxidation reactions
–Tertiary aliphatic amines are usually oxidized to
the corresponding N-oxides, but the reaction is
strongly affected by steric hindrance.
O
CH 3
M
CH 2
CH
N
M
CH 2
CH
CH 3
R
N
CH 3
CH 3
R
–Secondary and primary amines are N-oxygenated to
hydroxylamines, the intermediate is believed to be an
N-oxide.
H
N
R
R
H
O
O
N
N
R
R
H
R
R
 Methaemoglobinaemia toxicity caused by
several aromatic amines, e.g. Dapsone, is
attributed to their bioconversion to the
corresponding N-hydroxy derivative
RHN
SO2
NH2
Dapson R = H
N-Acetyldapson R=CH3CO
RHN
SO2
NHOH
N-Hydroxy derivatives
Amides can be N-oxygenated to hydroxylamides.
The
overdose
toxicity
of
Acetaminophen/Paracetamol has been attributed to
NAPQI (N-acetyl-p-benzoquinone imine).
1.3. S-oxidation reactions
 S-Oxidation constitutes an important pathway in
metabolism of the H2-histamine antagonist,
Cimetidine. The corresponding sulfoxide derivative
is the major metabolite.
S
HN
N
H
N
H
N
N
S
HN
C N
N
O
H
N
H
N
N
C N
 Sulfoxide drugs and metabolites (e.g. those of
phenothiazines) may be further oxidized to
sulfones (-SO2-).
2. Reduction reactions
 It is a major route of metabolism for aromatic
nitro and azo compound as well as for a wide
variety of aliphatic and aromatic N-oxides which
are reduced to tertiary amines.
 From a quantitative point of view,
reduction reactions are less important than
oxidations since the human organism is
mostly an aerobic one.
2.1. Reductions at carbon atoms
The major reactions of reduction at carbon
atoms can be illustrated by the following
scheme
R1
C
R1
C
R2
R1 OH
O
C
R2
R2
R3
R1
C
H
R3
CH CH
C
R4
O
R2
C
R4
O
2.2. Reductions at other atoms
Various reactions of N-oxidation are reversible, Cyt
P450 and other reductases being able to
deoxygenate N-oxides back to amine.
CH3
R N
R N O
CH3
CH3
Ar
Ar
NO2
Ar
NO
O
Ar
N N Ar
Ar = Aryl
Ar
CH3
N N Ar
Ar
NHOH
H H
N N Ar
Ar
2
Ar
NH2
NH2
Other reductions involve sulfur and a few other
atoms. Thus, disulfides are reduced to thiols, and
there are numerous examples of the reduction of
sulfoxides to sulphides e.g. sulindac to sulindac
sulfide.
R1
S
S
R2
R1
SH
+ HS
R1
S
R2
R2
R1
S
O
R2
CH2CO2H
F
CH2CO2H
F
CH3
CH3
H
H
H3C
S
O
H3C
S
3. Hydrolytic reactions/
Hydrolysis
The vast majority of esters and amides may be
hydrolyzed in the animal body, the extent and
rate of hydrolysis being dependent upon the
chemical reactivity of the functional group.
 Hydrolysis or hydrolytic cleavage are catalyzed by
esterases, peptidases or other enzymes, but nonenzymatic hydrolysis is also known to occur for
sufficiently labile compounds under biological
conditions of pH and temperature.
R1
R2
R1
CO2H
ONO2
R
OH
CONH R2
R1
CO2
R
R1
+
R2
OH
R2
NH2
+ HNO 3
CO2H
+
Esterase Reactions: e.g. aspirin (others include procaine, clofibrate)
CO 2 H
OCOCH 3
CO 2 H
OH
Esterase
Amidase Reactions: e.g. lidocaine (others include peptides)
O
N
N
H
Amidase
OH
N
O
+
NH2