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OUR LADY OF FATIMA UNIVERSITY

College of Pharmacy UNIT OUTCOMES
At the end of this module, the students are expected to:
PHARMACEUTICAL AND 1. Relate the concepts of metabolism to organic medicinal
chemistry and drug design
MEDICINAL ORGANIC 2. Trace the biosynthetic pathways involved in the metabolism of
CHEMISTRY 3.
drugs
Classify and differentiate metabolic reactions and enumerate
PMOC 311 drugs that undergo these reactions
4. Predict metabolites and metabolic reactions
Phase 1 Metabolism 5. Apply principles of organic medicinal chemistry and
pharmaceutical chemistry in the synthesis and characterization
WEEK 4
of organic medicinal

UNIT OUTLINE REQUIRED READINGS and VIDEOS

1. Define Metabolism Please watch the following videos thru the given link.
2. Differentiate Phase 1 and Phase 2  https://www.youtube.com/watch?v=rUSOtkvZx_k
3. Identify metabolic reactions under oxidation  https://www.youtube.com/watch?v=oCPRi5JFMdg
4. Identify metabolic reactions under reduction
5. Identify metabolic reactions under hydrolysis

 NOTE: This has been assigned to you by your instructor

during the previous meeting.

CHECKLIST
 Read course outcomes

 Read course guide prior to class attendance

 Proactively participate in discussions

METABOLISM
 Watch videos related to the topic PMOC 311
 Participate in discussion board (Canvas)

 Answer and submit course unit tasks

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METABOLISM
BIOTRANSFORMATION
Inactive
 plays a central role in the elimination of drugs and
other foreign compounds (xenobiotics) from the
body. Active
Parent
 an essential tool for pharmacists in their role of drug
selecting and monitoring appropriate drug therapy
Non toxic
for their patients.
Toxic

Phase I Reactions
 Functionalization phase
METABOLIC PATHWAYS
 polar functional groups are introduced into the
molecule or unmasked by:
oxidation
reduction
Hydrolysis

Achieved by:
 functional polar group(s):  by direct introduction of the functional group
Example: aromatic and aliphatic hydroxylation
OH
COOH  by modifying or "unmasking" existing functionalities
NH2 Examples:
 reduction of ketones and aldehydes to alcohols
SH  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).

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Reactions under Phase I

Liver is principal site of drug metabolism:
 Other sites include the gut, lungs, skin and kidneys
 For orally administered compounds, there is the
“First Pass Effect”
 Intestinal metabolism
 Liver metabolism
 Enterohepatic recycling
 Gut microorganisms - glucuronidases
1. Oxidation
 Most are mediated by microsomes.
 Although oxidation would seem to imply the
addition of oxygen, that is not always the case.
Oxidation refers to the change in oxidation
state of the substrate.

Reactions under Phase I

Two types of oxidation reactions:
 Oxygen is incorporated into the drug molecule (e.g.
hydroxylation)
 Oxidation causes the loss of part of the drug molecule
(e.g. oxidative deamination, dealkylation)
Microsomal Mixed Function Oxidases (MFOs)
 “Microsomes”
form in vitro after cell homogenization and
fractionation of ER
 Rough microsomes are primarily associated with
protein synthesis
 Smooth microsomes contain a class of oxidative
enzymes called

 “Mixed Function Oxidases” or “Monooxygenases”

 These enzymes require a reducing agent (NADPH)
and molecular oxygen
(one oxygen atom appearing in the product
and the other in the form of water)

• MFO consists of two enzymes:

– Flavoprotein, NADPH-cytochrome reductase

• One mole of this enzyme contains one mole each of
flavin mononucleotide (FMN) and flavin adenine
dinucleotide (FAD)
• Enzyme is also called NADPH-cytochrome P450
reductase

– Cytochrome P450
• named based on its light absorption at 450 nm when
complexed with carbon monoxide
• is a hemoprotein containing an iron atom which can
alternate between the ferrous (Fe++) and ferric
(Fe+++) states
• Electron acceptor
• Serves as terminal oxidase

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OH
R- C6H5 ------------------- R- C6H5 OH
OXIDATIVE REACTIONS
Oxidation of Aromatic Moieties
 Aromatic hydroxylation ROS
 refers to the mixed-function oxidation of aromatic compounds
(arenes) to their corresponding phenolic metabolites (arenols).
 proceed initially through an epoxide intermediate called an
"arene oxide.” which rearranges rapidly and spontaneously to the
arenol

 NIH Shift leading to the formation

of arenols
 May also acted upon by epoxide
hydrases leading to the formation of
trans-dihydrodiols
 Or be acted upon by sulfhydryl
group in GSH to yield GSH adduct
then finally mercapturic acid
derivative.
3 ways to stabilize the arene oxide
 1. spontaneous rearrangement (NIH shift)
 -ARENOL
 2. hydration (epoxide hydrase)
 -trans-1,2-dihydrodiol
 3. glutathione conjugation
 -glutathione metabolite

 It is important to prevent the

formation of ROS by arene oxides

 Aromatic hydroxylation Drugs resistant to aromatic hydroxylation

 major route of metabolism  Clonidine (Catapres)
for many drugs containing  The deactivating groups (Cl. -N H = C)
phenyl groups.
 Probenecid (Benemid)
 electron-withdrawing grps: carboxy and sulfamido grp

 Hydroxylation occurs at the

para position

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Compound with two aromatic rings:

Oxidation of OIefins
 The metabolic oxidation of olefinic carbon—carbon double
bonds leads to the corresponding epoxide (or oxirane).

 Epoxides
 more stable than the arene oxides formed from aromatic
compounds
 susceptible to enzymatic hydration by epoxide
hydrase to form trans-l,2-dihydrodiols (also called
If there are two or more phenyl rings, hydroxylation proceeds in the 1,2-diols or 1,2-dihydroxy compounds
electron rich ring

Olefinic Epoxidation Olefinic epoxidation

 The epoxide is cleaved by epoxide hydrases to form trans-  Eg. Carbamazepine (Tegretol)
diols  The epoxide is reasonably stable and can be measured
quantitatively in the plasma of patients receiving the
 There are inhibitors such as cyclohexene oxide and
parent drug
trichloropropene

urinary metabolite

Olefinic epoxidation
 Toxicity of olefinic compounds may result from their
 Protriptyline Cyproheptadine metabolic conversion to chemically reactive epoxides….
(Vivactil) (Periactin)

 AFLATOXIN
 Other compounds DES, stilbene and vinyl chloride

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Oxidation at Benzylic Carbon Atoms

Oxidation at Benzylic Carbon Atoms
Primary alcohol  Eg. TOLBUTAMIDE (Orinase)
 Forms CARBINOL
metabolite -
OH carbinol
R- C6H5 –CH3 -------- R- C6H5 CH2 OH
O2
-------- R- C6H5 COOH + H2O

Oxidation at Benzylic Carbon Atoms Oxidation at Benzylic Carbon Atoms

 tolmetin (Tolectin)

(Lopressor)

Oxidation at Allylic Carbon Atoms Oxidation at Allylic Carbon Atoms

 ALLYL structural formula : H2C=CH-CH2R

C7

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other examples see hexobarbital and Oxidation at Carbon Atoms alpha to

pentazocine carbonyls and imines
 Allylic hydroxylation generally does not lead  Common to benzodiazepines
to the generation of reactive  Oxidized to 3-hydroxy metabolites
intermediates

 Diazepam(Valium)
 3.hydroxydiazepam (also called N-methyloxazepam)
 flurazepam (Dalmane)
 and nimetazepam are

benzodiazepines

Take note that the carbon

involved is an alpha carbon. --in
forming the 3-hydroxy
metabolite

Oxidation at Aliphatic and AlicycIic

Carbon Atoms
 Metabolic oxidation at the terminal or the penultimate methyl
group often is referred to as ω oxidation, and oxidation of the
penultimate carbon atom (i.e., next-to-the-last carbon) is called
ω— I oxidation)

(Doriden)
Hypnotic

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Oxidation at Aliphatic Carbon Atoms Oxidation at Aliphatic Carbon Atoms

Oxidation at Aliphatic Carbon Atoms Oxidation at Aliphatic Carbon Atoms

Oxidation at AlicycIic Carbon Atoms

Alicyclic hydroxylation
Enzymatic introduction of a hydroxyl group into a
monosubstituted cyclohexane ring gen. occurs at C-3 and C-4 Major metabolite
which leads to cis and trans isomers

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Oxidation Involving Carbon-Heteroatom Systems Oxidation Involving CARBON-NITROGEN SYSTEMS

 Drugs containing nitrogen
 Hydroxylation of the alpha-carbon atom attached directly
 natural products
to the heteroatom (N, O, S).
(e.g.. morphine, cocaine, nicotine)
 important drugs
 Hydroxylation or oxidation of the heteroatom (e.g., phenothiazines. Antihistamines,
(N, S only, e.g.. N-hydroxylation. N-oxide formation. sulfoxide. tricyclic antidepressants. beta-adrenergic agents,
and sulfone formation). phenylethylamines, benzodiazepincs)

H Oxidative N- dealkylation
Oxidation Involving CARBON-NITROGEN SYSTEMS |
 three basic classes of nitrogen-containing compounds
R N C
1. Aliphatic (primary, secondary, and tertiary) and alicyclic (secondary |
and tertiary) amines CH3
2. Aromatic and heterocyclic nitrogen compounds
3. Amides

 Susceptible to either a-carbon hydroxylation or N-oxidation

Oxidative N- dealkylation Oxidative N- dealkylation

 N-demethylation  N-demethylation

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Alicyclic amines
 Often generate lactam metabolites by alpha
carbon hydroxylation reactions. N
|
 Nicotine CH3
 Cyproheptadine
 diphenidol

Secondary and Primary Amines  Dealkylation of secondary amines gives rise to the corresponding
 susceptible to: primary amine metabolite
 oxidative N-dealkylation  N-deisopropylation

 oxidative deamination
 and N-oxidation reactions

Secondary aliphatic Amine

Oxidative N- dealkylation

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Secondary alicyclic amines

they are metabolized to their lactam  Primary aliphatic amines are biotransformed by oxidative
deamination (through the carbinolamine pathway) or by N-
derivatives. oxidation.
 Enzyme: MFO

Examples: phenmetrazines (anorexic)

 Endogenous primary amines
methylphenidate (e.g.. Dopamine,norepinephrine. tryptamine, and serotonin)
Enzyme: MAO

 In primary aliphatic amines, such as phentermine,

N-demethylation and Oxidative deamination chlorphentermine and amantadine, N-oxidation appears to be

a major biotransformation pathway because a-carbon
hydroxylation cannot occur.

N- hydroxylation
Secondary amine N-hydroxylation
 N- hydroxylation of secondary amines generates the
corresponding N-hydroxylamine metabolites  Other examples n-benzylamphetamines

 phenmetrazine

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Primary amine
OXIDATION INVOLVING CARBON-
OXYGEN SYSTEMS
•

Primary aromatic amines are oxidized to hydroxylamines then

further oxidized to nitroso (Chlorphentermine, Aniline)

OXIDATION INVOLVING CARBON-OXYGEN

SYSTEMS O-dealkylation
Oxidative O-dealkylation
It involves the oxidation of the alpha carbon

GLUCURONIDATION

OH

O-dealkylation O-dealkylation
 Codeine Morphine  Mescaline

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OXIDATION INVOLVING CARBON-

SULFUR SYSTEMS S-dealkylation
 S-dealkylation  It also involves the alpha carbon hydroxylation
 desulfuration
 and S-oxidation reactions

OH

S-dealkylation Desulfuration [thiono to carbonyl]

C=S  C=O
Eg. Methiural Thiopenthal ------------------- Pentobarbital

Sulfoxidation (s- to sulfoxides to

Desulfuration sulfone)
P=S  P=O S-oxidation
Parathion-------------------Paraoxon

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Oxidation of Alcohols and Aldehydes

oxidative aromatization
Primary alcohol ------------Aldehyde [dehydrogenation of the A ring]
 Norgestrel ---------- 17-a-Ethinyl-18-homoestradiol

Secondary alcohol ------------Ketone

oxidative dehalogenation [hydroxylation

of the alpha carbon] oxidative dehalogenation

 Trifluoroacetylchloride
 it can acylate tissue nucleophiles which covalently
binds to liver microsomal proteins.

oxidative dehalogenation

REDUCTION

can lead to the formation of toxic and reactive acyl halide

intermediates.

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2. Reduction
– addition of hydrogen or gain of electrons 2. Reduction

 play an important role in the metabolism of many

 Carbonyl reduction --- alcohol
compounds containing carbonyl, nitro, and azo group
 nitro, and azo reduction ------- amino deriv.

 Hydroxyl and amino groups are susceptible to conjugation

 N-oxides ----- tertiary amine
 Sulfoxides----- sulfides
 Disulfide --- -SH + -SH

aldehyde
Reduction of Aldehyde and ketone Carbonyls Chloral hydrate reduction
 Ketones are resistant to oxidation are reduced to secondary
alcohol

 Aldehydes are reduced to form primary alcohol

 Enzyme : aldo-keto reductases

aldehyde ketone
Acetophenone
Chlorpheniramine

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Acetohexamide
Warfarin
 The (R)( + ) enantiomer of the oral anticoagulant warfarin
undergoes extensive reduction of its side chain keto group to
generate the (R,S)( +) alcohol as the major plasma metabolite

Nitro compounds Nitro compounds

Reduction of Nitro and Azo Compounds
 Leads to primary amine metabolites
 7-nitro benzodiazepine derivatives
clonazepam and nitrazepam
 are metabolized to 7-amino metabolites

 Ex
 Clonazepam
 Nirazepam
 Dantrolene (dantrium)
 metronidazole

Nitro compounds Nitro compounds

dantrolene (Dantrium) Metronidazole

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Nitro compounds
Chloramphenicol  Azo reduction will proceed via a hydrazo intermediate (-NH-
NH-) that is cleaved reductively to yield the corresponding
aromatic amines:

Prontosil Tartrazine

Amaranth

Miscellaneous Reductions
 Reduction of N-oxides to tertiary amine

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 Although sulfoxide functionalities are oxidized mainly to sulfones

Miscellaneous Reductions (-SO2-), they sometimes undergo reduction to sulfides.
 Reduction of sulfur-containing functional groups, such as the disulfide
and sulfoxide
Sulindac Sulindac sulfide

 Disulfiram (Antabuse) yields N,N-diethyldithiocarbamic acid (free or

glucuronidated) as a major metabolite

Reduction of DMSO to dimethyl sulfide 3. Hydrolysis:

 (reaction of water with substrate resulting in breaking scissile
carbon-heteroatom bonds)

 ester or amide

 The reaction is frequently enzyme - mediated although serum pH

may cause reaction.

Hydrolysis
 major biotransformation pathway for drugs containing an
ester functionality.
 ester hydrolysis is mediated by nonspecific esterases found in the :
Liver, kidney, and intestine and Pseudocholinesterases present
in plasma

 Amide hydrolysis appears to be mediated by liver microsomal

amidases. Esterases and deacylases

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Cocaine

Urinary metabolite

Ester derivatives

Carbenicillin Indanyl Ester (Geocillin)  Prednisolone hemisuccinate sodium salt.

 This water-soluble deriv . is metabolized to the parent steroid by
 To improve the poor oral absorption plasma and tissue esterases.

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ASSIGNMENT
 Reminder: Prepare for Online Quiz.
 Assignment 4 : Reduction and Hydrolysis
(see canvas for the assignment)

End of Discussion  Note: Submit this thru CANVAS

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