Hetrocyclic Compound: by Dr. Moona Mehboob Khan Associate Professor Chairperson: Pharmaceutical Chemistry Dcop, Duhs
Hetrocyclic Compound: by Dr. Moona Mehboob Khan Associate Professor Chairperson: Pharmaceutical Chemistry Dcop, Duhs
Hetrocyclic Compound: by Dr. Moona Mehboob Khan Associate Professor Chairperson: Pharmaceutical Chemistry Dcop, Duhs
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
⚫ 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
47
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.
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
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)
On Leucocytes
LTB4 & 5 or 12 HETE----increase
leukocyte chemoyaxis &
aggregation
57
On GIT
On hypothalmus
On carpus Leutium
PGs
58
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
61
APPROACHES
62
Prostaglandin Receptors
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
Inhibit
Platellet Pain
IP PGI2 aggregation sensation
Arterial Inc
dilation GFR
65
Prostaglandin Receptors
Contractile (EP1, FP,
TP)
Receptor Ligand Uterus EYE Blood Lung Kidney
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
72
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.
74