Heterocyclic compounds as drugs: nature and medicine

Heterocyclics in Nature and Medicine

Heterocyclic compounds
as drugs

Aromatic Heterocyclic Compounds

4
5
3
5
2
Positions of
reactivity
6
2
S
O
1
pyridine
pyrrole
thiophene
1
furan
4
3
quinoline
5
2
N
N
N
1
H
isoquinoline
pyrimidine
indole
N
. .
Hückel Rule, (4n+2) ¡ electrons needed for aromaticity - lone pair involved
in aromaticity and therefore not available to make heteroatom basic
N
..
N
N
H

Aliphatic Heterocyclic Compounds

4
3Aliphatic Heterocyclic Compounds
pyrrolidine
..
. .
N
O
THE
H
IZ:
..
H
H
H
piperazine
HN
H
H
NH
H
H
H
H
HN
N
HN
NH
/>..
N
H
H
tetrahydrofuran,Join: vevox.app ID: 196-463-849
POLL OPEN
Which is heterocycle is present in the
molecule shown?

1. Pyrrole
   10.71%
2. Piperazine
   0%
3. Pyrrolidine
   HN
   64.29%
4. Thiophene
   7.14%
5. Indole
   17.86%

Examples of Heterocyclics in Nature

HO
O
Tetrahydrocannabinol (THC). A
psychoactive substance found in
cannabis.
Chlorophyll A. green
plant pigment,
catalyst for
photosynthesis.
N
N
2+
Mg
N
N
O
CH2OO
20 39
O
O
O
N
-
N
Nicotine. A tobacco alkaloid.
You are not
expected to
memorise these
structures!

Examples of Medicinal Heterocyclics

Bioactivity often directly related to chemistry of the heterocycle
I
O
N
N
N
N
O
Caffeine. A stimulant of the
central nervous system, heart,
and respiration. It is also a
diuretic.
H
S
N
N
O
O
O
HO
Penicillin G. An antibiotic
You are not
expected to
memorise these
structures !

Further Medicinal Heterocyclic Examples

HS
N
O
CO2H
Captopril®. Antihypertension
agent. Angiotensin converting
enzyme (ACE) inhibitor.
N
HN
O
S
N
H
NO
2
Ranitidine. Zantac®. Anti-ulcer remedy.
Histamine receptor antagonist.
HO2C
O
N
Cetirizine®. For treatment of seasonal allergic
rhinitis. A histamine-1 receptor blocker.
N
Cl
You are not
expected to
memorise these
structures !Join: vevox.app ID: 196-463-849
POLL OPEN
Which is heterocycle is present in ranitidine?
1
-N
HN
O
S
N
H
NO
2

1. Pyrrole
   4%
2. THF
   4%
3. Furan
   92%
4. Thiophene
   0%
5. Indole
   0%

Additional Medicinal Heterocyclic Examples

N
N
N
H
F
CO2H
O
Norfloxacin®. An antibacterial
compound.
O
NH
H
NEN
N
O
N
O
OH
Zidovudine®, Retrovir®, Retrovis®.
(Azidothymidine, AZT). An anti-retroviral drug,
the first treatment to be approved for use
against HIV.
O
N
NH
O
N
N
N
N
O
O S
5
Viagra®. (Sildenafil citrate [citrate group not
shown]). Used to treat male impotence.
You are not
expected to
memorise these
structures !

More Medicinal Heterocyclic Examples

N
H
O
O
Ritalin®. (Methylphenidate, MPH). An
amphetamine-like prescription stimulant
commonly used to treat Attention Deficit
Hyperactivity Disorder (ADHD) in children and
adults.
N
HN
Cl
N
Chloroquine®. An anti-malarial agent.
O
N
Cl
N
Diazepam®. An anxiolytic (treatment
of anxiety) agent.
You are not
expected to
memorise these
structures !

Lead Compounds and Analogues

Heterocyclic compounds
as drugs

Drugs from Nature

Digitoxin (cardiac
stimultant) from
Foxglove
O
O
O
O
O
OH
HO
O
O
O
OH
OH
OH
https://commons.wikimedia.org/wiki/File:Foxglove - Digitalis purpurea.jpg

Morphine from Opium Poppy

1
N
Morphine from Opium
Poppy
Ol.Papaveraceae.
2
5
3
WM.
1
4
259. Papaver somniferum L. Stylof over Satmoly.
*
H
HO
O
OH
https://commons.wikimedia.org/wiki/File:Opium poppy.jpg
https://commons.wikimedia.org/wiki/File:Illustration Papaver somniferum0.jpg

Quinine from Cinchona Bark

Rubiaceae.
3
6
2
Quinine (malaria relief)
from Cinchona bark
A
OH
7
4
1
O
N
N
https://commons.wikimedia.org/wiki/File:Cinchona officinalis -
K%C3%B6hler%E2%80%93s Medizinal-Pflanzen-180.jpg
https://commons.wikimedia.org/wiki/File:Cinchona officinalis 001.JPG

Cocaine from Coca Leaves

Cocaine (pain relief) from
Coca leaves (Erythroxylum
coca; South America)
O
O
N
O
O
https://commons.wikimedia.org/wiki/File:Three coca leaves.jpeg
https://commons.wikimedia.org/wiki/File:Coca (Erythroxylum coca) en Meta (Colombia)
1.jpg

Lead Compounds and Analogues Overview

175
NE
Scientists still search the natural world for
compounds that might yield new drug
molecules.
Once naturally occurring drug found and
structure determined, it serves as a prototype -
'the lead compound' - for other biologically
active compounds.
Lead compound - a compound that plays a
leading role in the search.
Analogues of the lead compound are synthesised
to:
· improve therapeutic properties, or
· produce fewer side effects.
https://commons.wikimedia.org/wiki/File:Cinchona officinalis 001.JPG
https://commons.wikimedia.org/wiki/File:VariousPills.jpg

Lead Compounds & Analogues: Examples

Analogues may have different substituents, a branch or different ring system to the lead
compound. Changing the structure is called 'molecular modification'.
Example: Cocaine
· From Coca leaves (South American Andes).
. Highly effective local anesthetic, but dangerous to central
nervous system (CNS) / severe depression.
· Removal of methoxycarbonyl group & 7-membered ring,
produces an improved lead compound with local anesthetic
properties but no damaging CNS effects.
O
O
N
O
N
O
O
cocaine
Improved lead compound
https://commons.wikimedia.org/wiki/File:Coca (Erythroxylum coca) en Meta (Colombia)
1.jpg

Analogues: Benzocaine, Procaine, Lidocaine

NH2
O
O
Benzocaine
®
NH2
O
N
O
A topical anesthetic
NPN 002.0561
HURRY CAINE
Topical Anesthetic Spray
Pulvérisation anesthésique troca
Benzocaine Topical Aerosol 20% wy
For ral Mucosal Application
Mármol pique à la benzocaine 20% pb
À appliquer sur le muqueuses bucca'es
original Wild Cherry
Guit original cerise doute
CAUTIONZATTENTION
CONTAINER MAY EXODE IF HATE
LERECIMENT PEUT EXPLORS'IL EST CHUP
Nat West
Poids Met
99,7 g 12 ad
00120 Mn M5655
Procaine (local anesthetic used for injection) has a
short half-life since the ester group is hydrolysed
relatively rapidly by enzymes.
Procaine / Novocain
®
H
N
N
O
Lidocaine / Xylocaine
®
Therefore ester replaced by an amide group (less
reactive): Lidocaine is one of the most widely used
injectable anesthetics. Hydrolysis is further reduced by
the 2 ortho-methyl groups, which provide steric
hindrance to the reactive carbonyl group.
https://commons.wikimedia.org/wiki/File:Benzocainespray.JPG

Lead Compounds & Analogues: Triptans

1
NH2
HO
N
H
1
N-
O
N
H
S
O
N
H
N-
-
O
NH
N
O
Zolmitriptan / Zomig
®
N
N
1
N
N
H
Rizatriptan / Maxalt®
N
O
N
-
S
H
O
N
H
Naratriptan / Amerge
®
https://commons.wikimedia.org/wiki/File:Migraine aura.jpg
New, second generation triptans introduced in 1997/98.
Longer half-life, reduced cardiac side effects and improved
CNS penetration compared to Sumatriptan.
N-
H
Serotonin
implicated
in
generation of migraine attacks
Sumatriptan (Imitrex®, 1991) binds to serotonin
receptor, relieving pain and other symptoms of
migraine, e.g., nausea and sensitivity to light
and sound.Join: vevox.app ID: 196-463-849
POLL OPEN
Which statement is incorrect?

1. Benzocaine is an analogue of cocaine
   4%
2. Lidocaine is an analogue
   0%
3. Cocaine is a lead compound
   8%
4. Seratonin is an analogue of sumatriptan
   76%
5. Rizatriptan is an analogue of seratonin
   12%

1,3-Dipolar Cycloaddition Reaction

Theory and Examples of 1,3-Dipolar Cycloaddition

-
X
X
X
+
Y
Y
1
z
1,3-dipole
Alkene (or alkyne)
Heterocyclic compound
X, Y, Z can be any element that supports the charges;
e.g.,
–
–
S
O
+
+
+
N
Bu-N
N
Compare to this
reaction to the Diels-
Alder Reaction (1,4-
Dipolar Cycloaddition)
Et
-
O
+
Y
z

1,3-Dipolar Cycloaddition Mechanism

H
O
CH3
N.
C-
11
C-C-H
/
1
H
H
H
H
H
CH3
3
O
C
+
II
N
N
C
H
H
C
C
Alkene
Heterocyclic compound
1,3-dipole
O
N
CH3
3
–

Fill in the Blanks: 1,3-Dipolar Cycloaddition

–
O
CH3
+
H3C-N
+
H2C
CH3
H3C
–
S
/
S
+
+
HC
CH3
HN
HN
CH2
O
N

More Fill in the Blanks: 1,3-Dipolar Cycloaddition

-
Et
S
+
Me-N
II
+
O
S
N
OJoin: vevox.app ID: 101-101-715
POLL OPEN
Which product will be formed in the
following reaction?
1. A
0%
V2. B
N.
-O
A
Ph
N-O
92.86%
Ph
B
N-O
Ph
C
Ph
Ph
Ph
N-O
Ph
Ph
Ph
Ph
3. C
0%
4. D
0%
5. E
7.14%
N +
+
?
Ph
Ph
N-
-O
D
E

Synthesis of 3,5-Diphenylisoxazoline

O
N
+
HO
N
/
N
Alkene
(styrene)
1,3-dipole
(i) NaOCl, Et3N, CH2Cl2
O
i