Hetrocyclic Compound

By
Dr. Moona Mehboob Khan
Associate Professor
Chairperson: Pharmaceutical Chemistry
DCOP,DUHS
Lecture 1
 Learning Objectives
⚫ At the end of the lecture students will be able to
understand
⚫ Heterocyclic compounds, their chemistry, behavior,
method of synthesis
⚫ Major class of it as pyrrol, furan and thiophene with
their examples
 Heterocyclic Compound
⚫ These are organic cyclic compounds having at least
one or more than one atom other than carbon as
oxygen, nitrogen, or sulfur.
⚫ These hetero atoms gives heterocyclic compounds
distinct physical and chemical properties.
⚫ These heterocyclic rings may have single, double, or
triple bonds or be aromatic and the compound may
contain one or more single rings or have fused rings.
 General aspects of heterocyclic
compounds
⚫ The most common heterocycles are those having five-
or six-membered rings and containing heteroatoms
⚫ of nitrogen (N) pyridine, pyrrole, oxygen (O) furan ,
or sulfur (S) thiophene.
Basic structure of heterocyclic
compounds
 Classification of hetrocyclic
compound
⚫ Heterocycles too may be classified as
⚫ Saturated (pyrrolidine)
⚫ Unsaturated (4,5-dihyrofuran)
⚫ Aromatic (pyridine).
 Hetro-aromatic compounds
⚫ These are hetrocylic organic compounds having
aromaticity.
⚫ Aromaticity is due to the presence of conjugated
system—in which six π electrons generally participate.
⚫ Aromaticity provides stabilization to the system.
 Nature of hetroatom in aromatic
system
⚫ A fundamental distinction is usually made between
⚫ 1 Those heteroatoms that participate in a cyclic
conjugated system by means of a lone, or unshared,
pair of electrons that are in an orbital perpendicular
to the plane of the ring.
Nature of hetroatom in aromatic
system
⚫ 2 Those heteroatoms that do so because they are
connected to another atom by means of a double
bond.
Behaviour of Hetroatoms
⚫ If hetero atom’s electrons are participating in
aromatic system they may be referred to as pyrrole
like
⚫ or
⚫ If hetero atom’s electrons are not participating in
aromatic system they may be referred to as pyridine-
like.
Nitrogen
⚫ A nitrogen atom in a ring can carry a positive or a
negative charge, or it can be in the neutral form.
⚫ Oxygen or sulfur atom in a ring can either be in the
neutral form or carry a positive charge
Classification of hetroatom
⚫ First class:
⚫ The pyrrole like hetero atoms −NR− (R being
hydrogen or a hydrocarbon group), −N−−, −O−, and
−S− tend to donate electrons into the π-electron
system.
⚫ Second class:
⚫ The pyridine-like heteroatoms −N=, −N+R=, −O+=,
and −S+= tend to attract the π electrons of a double
bond.
Classification of hetroatom

First class: pyrol like Second class: pyridine like

Explanation First class
⚫ Nitrogen has an outermost shell of five electrons, three of
which can enter into three covalent bonds with other
atoms.
⚫ After the bonds are formed, as in the case of pyrrole,
there remains an unshared electron pair that can engage
in cyclic conjugation.
⚫ The aromatic sextet in pyrrole is made up of two
electrons from each of the two carbon-carbon double
bonds and the two electrons that compose the unshared
electron pair of the nitrogen atom.
⚫ As a consequence, there tends to be a net flow of electron
density from the nitrogen atom to the carbon atoms as
the nitrogen's electrons are drawn into the aromatic sextet.
 Explanation of Second Class
⚫ Pyridine also has a π-electron sextet,but the nitrogen
atom contributes only one electron to it, one
additional electron being contributed by each of the
five carbon atoms in the ring.
⚫ In particular, the unshared electron pair of the
nitrogen atom is not involved. Moreover, because
nitrogen's attraction for electrons
(its electronegativity) is greater than that of carbon,
electrons tend to move toward the nitrogen atom
rather than away from it, as in pyrrole.
Refrences
⚫ The chemistry of hetrocyclic compounds:thiophene &
its derivative, Pharmacologically active compounds &
other thiophene derivative pg 354 Salo Gronowitz,
Jeffery B press
⚫ Wilson gisvold
Hetrocyclic Compound
By
Dr.Moona Mehboob Khan
Assistant Professor
DCOP,DUHS
Lecture 2
16.3.2016
Learning Outcomes
⚫ At the end of the lecture students will be able to
understand
⚫ Major classes of hetrocyclic compounds
⚫ Pyrol
⚫ Furan
⚫ Thiophene
 Major classes of heterocyclic
compounds
⚫ 3 or 4 membered rings
⚫ Three- and four-membered rings, because of their
small size, are geometrically strained and thus readily
opened; they are also readily formed.
⚫ Such heterocycles are well-known reactive
intermediates.
⚫ E.g nitrogen mustard (formed 3 membered
aziridinium ion) and penicillins (four membered beta-
lactum ring system)
⚫ 5 or 6 membered rings
⚫ Five- and six-membered rings are readily formed and
are very stable; their sizes also allow the development
of aromatic character.
⚫ 7 membered rings
⚫ Seven-membered rings and larger are stable but less
readily formed and relatively less well investigated
 Five-membered rings with one
heteroatom
⚫ The parent aromatic compounds of this
family— pyrrole, furan, and thiophene
⚫ The saturated derivatives are called pyrrolidine,
tetrahydrofuran, and thiophane, respectively.
Pyrrole
⚫ The nitrogen atom in molecule of pyrrole are sp2
hybridized
⚫ Four pi electrons are contributed by the carbon atom
of ring
⚫ The nitrogen contribute two electrons to give
aromatic sixtet
In medicinal chemistry
⚫ Statins are used to treat hypercholestremia.
⚫ It reduces mortality rate due to CVD in
hyperchlolesteremic patients.
⚫ Atorvastatin or Simvastatin are more effective as
compared to that of Lovastatin
What is the difference b/w them
⚫ Lovastatin

⚫ Atorvastatin
⚫
⚫ serotonin
 Importance
⚫ Pyrrole rings are found in the amino acids,
proline and hydroxyproline, which are components of
many proteins and which are present in particularly
high concentrations in collagen, the structural protein
of bones, tendons, ligaments, and skin.
⚫ Pyrrole compounds are found among the alkaloids, a
large class of alkaline organic nitrogen compounds
produced primarily by plants.
⚫ The heme group of the oxygen-carrying
protein hemoglobin
Furan
⚫ Furan are structurally similar to pyrrole
⚫ Oxygen atom in furan are sp2 hybridized
⚫ The p orbital of the hetero atom donates electron to
pi system
Thiophene
⚫ It is five membered heterocycle
⚫ Sulphur atom is present as heteroatom
⚫ All atom are are sp2 hybridized
Furan and thiophene containg
drugs
⚫ Furosemide (furan contain ring) & azosemide
(thiophene contain ring ) are diuretics.
⚫ Pharmacokinetic properties changes by replacing
furan to thiophene.
Why thiophene, pyrol & furan derivatives
are intersting to pharmaceutical chemist
⚫ Thiophene with its six pi electron aromaticity is
electronically & sterically similar to benzene, furan
and pyrol
⚫ Thus thiophene analogues of biologically active
benzene derivatives may well exhibit similar activities
⚫ Presence of hetro-atom or lower resonance energy of
thiophene also affect drug metabolism & generally
their metabolite are less toxic than benzene
derivative or heaving better therapeutic profile
Why thiophene, pyrol & furan derivatives are
interesting to pharmaceutical chemist
⚫ Second reason of thiophene selection lies in its SAR
(structure activity relationship)
⚫ In many drugs having benzene ring, substitution of
electron withdrawing or donating group maximize
the therapeutic activity of drug. As thiophene act as
biososters & electron rich aromatic system, it may be
superior to subs benzene in certain conditions
⚫ Thiophene selection provides novelty to chemical
structure which is beneficial to pharmaceutical
industry. (
Electron Densities ↔ Reactivities: pyrrole,
furan & thiophene compare with benzene
⚫ Pyrrole, furan & thiophene have 6-electrons
distributed over 5 atoms so the carbon frameworks
are ALL inherently ELECTRON RICH (relative to
benzene with 6 -electrons over 6 atoms) – all react
quicker than benzene with E+
⚫ Additionally, the distribution of pi-electron density
between the heteroatom and the carbons varies
considerably between the 3 ring-systems due to
differences in electronegativity.
Refrences
⚫ The chemistry of hetrocyclic compounds:thiophene &
its derivative, Pharmacologically active compounds &
other thiophene derivative pg 354 Salo Gronowitz,
Jeffery B press
⚫ Wilson gisvold
Heterocyclic Compound
fused with Benzene ring
By
Dr.Moona Mehboob Khan
Assistant Professor
DCOP,DUHS
Lecture 3
22.03.2016
Learning Objectives
⚫ At the end of the lecture students will be able to
understand
⚫ Thiophene & its chemistry
⚫ Heterocyclic (five & six membered) compounds fused
with benzene-ring indole, quinoline and
isoquionoline
⚫ Their chemistry, behavior, pharmacological responses
with their examples
Indole
⚫ Indole is an aromatic heterocyclic organic compound
having benzene ring fused to a five-
membered nitrogen-containing pyrrole ring
serotonin
Refrences
⚫ Wilson Gisvold, 11th edition,chapter 9, antimalarial,
page # 282-286.
⚫ Foye, 6th edition, chapter 36Non steroidal anti-
inflammatory agents, page # 954
⚫ Wilson Gisvold, 11th edition,chapter # 24, analgesics,
page # 792.
⚫ The chemistry of hetrocyclic compounds:thiophene &
its derivative, Pharmacologically active compounds &
other thiophene derivative pg 354 Salo Gronowitz,
Jeffery B press
38
Heterocyclic Compound
fused with Benzene ring
By
Dr.Moona Mehboob Khan
Assistant Professor
DCOP,DUHS
Lecture 4
26.03.2016
 Quinoline and Isoquinoline
⚫ Quinoline and Isoquinoline
⚫ Isoquinoline is a structural isomer of quinoline.
⚫ They are benzopyridines, which are composed of a
benzene ring fused to a pyridine ring.
4- aminoquinoline & 8-
aminoquinoline derivative
⚫ Both are anti-malarial.
⚫ d/f in position of modification.

41
Where d/f exists
⚫ In arrangement of functional group
⚫ So also in MOA
⚫ Net conclusion
⚫ SAR as a result of which drug may bind to different
receptor (some additional receptor) or bind with the
same receptor in different way
Refrences
⚫ Wilson Gisvold, 11th edition,chapter 9, antimalarial,
page # 282-286.
⚫ Foye, 6th edition, chapter 36Non steroidal anti-
inflammatory agents, page # 954
⚫ Wilson Gisvold, 11th edition,chapter # 24, analgesics,
page # 792.
⚫ The chemistry of hetrocyclic compounds:thiophene &
its derivative, Pharmacologically active compounds &
other thiophene derivative pg 354 Salo Gronowitz,
Jeffery B press
43
 Dr. Moona Mehboob Khan
DATE Ph.D. (Pharm. Chem.)
Assistant Professor
29 & 30/03/2016 DCOP, DUHS

615
MEDICINAL CHEMISTRY I
Lecture
5-6th
4 year, 7 th
semester
OBJECTIVES
• At the end of lecture student will be
able to
⚫ Define
⚫ Prostaglandins,
⚫ Leukotrienes,
⚫ Biosynthesis
⚫ Metabolism
EICOSANOIDS

46
EICOSANOIDS
⚫ Eicosanoids are lipids, derived from Arachidonic acid
(5,8,11,14 eicosatetraenioc acid): 20-carbon,
unsaturated fatty acid produced from membrane
phospholipids.

8 5

10

11 14
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EICOSANOIDS
The eicosanoids are considered "local hormones."
⬥ They have specific effects on target cells close to their
site of formation.
⬥ They are rapidly degraded, so they are not transported
to distal sites within the body.

⚫ These are present in all body cell except RBCs

where they act as paracrine & autocrine in
response to chemical & mechanical stimuli.

48
EICOSANOIDS
⚫ Principal pathways:
⚫ Cyclo-oxygenase (COX) or PGH2 synthase pathway
or Cyclic pathway: Oxidative metabolism of
arachidonic acid produces prostaglandin H2 (PGH2)
which leads to further production of different PGs,
thromboxanes & prostacyclins
⚫ 5-lipoxygenase: Produces a collection of leukotrienes
(LT)

49
POSTAGLANDINS
⚫ POSTAGLANDINS (PGA through PGJ)
⚫ Group of naturally occurring 20 –carbon fatty acid
derivatives produce by the oxidative metabolism of
5,8,11,14-eicosatetraenoic acid (arachidonic acids)

50
Two major pathways of eicosanoid
metabolism.

51
Cyclooxygenase (COX) or PGH2 synthase or
Cyclic pathway

⚫ Prostaglandin H2 Synthase (COX) catalyzes the

committed step in the “cyclic pathway” that
leads to production of prostaglandins,
prostacyclins, & thromboxanes
⚫ Three isoforms of COX
⚫ COX-1 regulates normal PGs function
⚫ COX-2 regulates inflammatory
⚫ COX-3 A novel COX-1 splice variant termed COX-3,
sensitive to acetaminophen,

52
Cyclooxygenase Pathway
 5, 8, 11, 14

Lipoxygenase
pathway

11 9 7
10 8 5 5

14

54
Prostaglandin Functions
⚫ In general, they modify response to hormone
⚫ Involve in inflammation
⚫ Prevent stomach ulcers
⚫ Dilate air ways
⚫ Regulate body temperature
⚫ Involve in blood clotting etc.

55
Prostaglandin Functions (action vice)
Action on platelet aggregation
Inhibitor Inducer
PGD2 TXA2 (dec cAMP in platelet & stimulate release of
ADP & serotonin in brain)

PGI2 (inc cAMP in platelet)

5 or 12 HPETE
On vessels
Dilator Constriction
PGE1 , PGE2 (renal vasodilator), TXA2
PGI2 (potent)
5 OR 12 HPETE
On Respiratory system
Dilator Constriction
PGE1 LTC/D4 in human & guinea pig lung Parenchymal
strips
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 On Smooth muscle
Contractor Relaxation
PGE1---GIT PGE2, PGF2, TXA 2
PGE2----UTERUS
PGF2----UTERUS
LTC/D4---GUNIA PIG
On Lipid metabolism
PGE1------ inhibit lipolysis

On Leucocytes
LTB4 & 5 or 12 HETE----increase
leukocyte chemoyaxis &
aggregation

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 On GIT

PGE2---dec acid secretion

On hypothalmus

PGE2----elevates thermoregulatory setup in anterior hypothalmus

On carpus Leutium

PGF2----increase luteolysis in animals

PGs

PGJ2---increase osteogenesis, inhibit cell proliferation

LTC/D4---slow reacting substances of anaphylaxis (SRASA),
increase vascular permeability

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DRUG ACTION MEDIATED BY EICOSANOIDS

⬥ NSAIDs
⬥ Metabolism of arachidonic acid
⬥ Salicylic acid, phenylbutazone, naproxen, sulindac, ibuprofen
(inhibition of arachidonic acid oxygenation)
⬥ Aspirin & halogenated such as indomethacin, flurbiprofen,
meclomen (inhibit PGH-synthase)
⬥ Prolongation of bleeding time

59
EICOSANOID DRUGS

⬥ Factors
⬥ Chemical complexity
⬥ Relative instability
⬥ Rapid degradation in vivo
⬥ Caution prostaglandin analogs

60
APPROACHES

⬥ STRUCTURAL ANALOGS
⬥ Alter eicosanoids

⬥ Reduce rapid metabolism

⬥ Increase biological half-life
⬥ Methylation at the 15, 16 position ----eliminate oxidation
of essential 15-(S)-alcohol moiety
⬥ Esterification of carboxylic acid function ----absorption
characteristics

61
APPROACHES

⬥ DELIVERING DESIRED AGENTS

⬥ Lungs, stomach, uterus in form of aerosols, gel,
suppository
⬥ PGF-type derivatives --- use in eyes to lower intraocular
pressure (IOP) in glaucoma

62
Prostaglandin Receptors

⬥ Most affect other cells by interacting with plasma

membrane G-protein coupled receptors.
Depending on the cell type, the activated G-protein
may stimulate or inhibit formation of cAMP, or may
activate a phosphatidylinositol signal pathway leading
to intracellular Ca++ release.
⬥ Another prostaglandin receptor, designated PPARγ, is
related to a family of nuclear receptors with
transcription factor activity.

63
Prostaglandin Receptors
⚫ Classes of prostanoid receptor
⚫ Relaxant
⚫ Promote smooth muscle relaxation by raising intracellular
cyclic adenosine monophosphate (cAMP) levels
⚫ Contractile
⚫ Promote smooth muscle contraction with calcium ion
mobilization
⚫ Inhibitory
⚫ Prevents smooth muscle contraction by lowering
intracellular cAMP levels

64
 Prostaglandin Receptors
Relaxant (DP, EP2, EP4,
& IP)
Receptors Ligand Uterus GIT Blood Brain Lung Kidney Heart

Relax sleep
DP PGD 2 illum induction

PGE 2, Broncho-
EP 2 PGE 1 Implantation dilation

PGE 2, Mucosa Inc Ductus

EP 4 PGE 1 endometrum secretion GFR arteriosis

Inhibit
Platellet Pain
IP PGI2 aggregation sensation

Arterial Inc
dilation GFR
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 Prostaglandin Receptors
Contractile (EP1, FP,
TP)
Receptor Ligand Uterus EYE Blood Lung Kidney

EP1 PGE2 contraction constriction

dec
Intra
PGF 2 Occular
FP Alpha luteolysis pressure constriction
TXA2
(alpha-dec
cAMP Platelet
Beta-inc aggregator, dec
TP cAMP) vasoconstriction GFR

66
Prostaglandin Receptors
⚫ Inhibitory Receptors
⚫ These receptors include EP 3 .
⚫ EP3 receptors are further classified as EP 3 a, EP3 b, EP3 c &
EP3d
⚫ EP3a decreases cAMP levels.
⚫ EP3b & EP3c increases cAMP levels.
⚫ EP3d increases inositol tri phosphate level.
⚫ Their ligands are PGE1 & PGE2.
⚫ They are gastric anti-secretory, cytoprotective,
Uterine contraction & in brain induces fever
response

67
 CLINICAL USE
⚫ Prostaglandin E2 (PGE2)
⚫ Potentiate effects of oxytocin
⚫ Carbopros-tromethamine
⚫ PG derivative
⚫ Prevent metabolic oxidation at 15 position alcohol
⚫ IM injection to induce abortion
⚫ To ameliorate severe postpartum hemorrhage

68
CLINICAL USE
⚫ Prostaglandin E1 (PGE1)
⚫ Maintaining a patent (opened) ductus arteriosus in
infants with congenital defects that restrict pulmonary
or systemic blood flow
⚫ Prostaglandin E1 cyclodoxtrin
⚫ Cyclic polysaccharide complex
⚫ Orphan drug for Tx of severe peripheral arterial occlusive
disease (graft & angioplasty not indicated)
⚫ Enhance water solubility & reduce rapid metabolic
inactivation

69
CLINICAL USE
⚫ Misolrostol
⚫ Potent gastric anti-secretory & gastro-protective effect
⚫ Use to prevent gastric ulceration with NSAIDs
⚫ Safe for long term anti-arthritic therapy
⚫ Induce abortion
⚫ Combine use of IM methotrexate & intravaginal
misoprostol to termination of early pregnancy

70
CLINICAL USE
⚫ Lubiprostone
⚫ Chronic idiopathic constipation in adult
⚫ Prostacyclin
⚫ Tx of primary pulmonary hypertension (PPH)
⚫ Potent vasodilatory, platelet anti-aggregatory effect
⚫ To prevent symptoms of rebound pulmonary
hypertension

71
OPHTHALMIC USE
⚫ Iloprost
• Tx of pulmonary arterial hypertension (PAH)
⚫ Tx of open-angle glaucoma or ocular hypertension
⚫ Lower intraocular pressure (IOP) .
⚫ Side effects
⚫ Conjunctival hypertension
⚫ Increased pigmentation & growth of eyelashes
⚫ Ocular pruritus
⚫ Increased pigmentation of the iris & eyelid

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 OPHTHALMIC USE
⚫ Bimatoprost
⚫ Latanoprost
⚫ Combination with ophthalmic product as beta-
adrenergic blocking agent
⚫ Travoprost
⚫ Unoprostone
⚫ 15 position alcohol is oxidize to ketone

73
Refrences
⚫ Wilson Gisvold, 12th edition,chapter 26,
prostaglandins, leukotrines, and other eicosanoids,
page # 868-879.

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