Unit1 DrRakhiMishra (2) CNP

Noida Institute of Engineering and Technology
(Pharmacy Institute) Greater Noida
STUDY OF NATURAL
PRODUCTS AS LEADS FOR
NEW PHARMACEUTICALS
Unit: I
Chemistry of Natural Products Dr. Rakhi Mishra

(MPC 104T)
Associate Professor
M.PHARM
Ist Semester
Dr.Rakhi Mishra MPC 104T Unit I

1
11/18/2023
Syllabus of Unit 1
Study of Natural products as leads for new pharmaceuticals
for the following class of drugs:
• Drugs affecting the central nervous system: Morphine
alkaloids
• b) Anticancer drugs: Paclitaxel and Docetaxel, Etoposide, and
Teniposide
• c) Cardiovascular drugs: Lovastatin, Teprotide and
Dicoumarol
• d) Neuromuscular blocking drugs: Curare alkaloids
• e) Anti-malarial drugs and analogues
• f) Chemistry of macrolide antibiotics (Erythromycin,
Azithromycin, Roxithromycin,
• and Clarithromycin)
11/18/2023 Dr.Rakhi Mishra MPC 104T Unit I 2

Content
• β - Lactam antibiotics (Cephalosporins and Carbapenem)

Role of natural products in drug development
• Introduction of plant sources
• Drugs affecting the central nervous system: Morphine
alkaloids
• Chemistry and MOA of Paclitaxel and Docetaxel, Etoposide,
and Teniposide
• Chemistry and MOA of Lovastatin, Teprotide and Dicoumarol
• Chemistry and MOA of Neuromuscular blocking drugs:
Curare alkaloids
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Content
• Classification of Anti-malarial drugs and analogues

• Chemistry of macrolide antibiotics and β - Lactam antibiotics
(Cephalosporins and Carbapenem)
• Video link and topic related online lecture
• Summary, Daily quiz,
• Weekly Assignment, MCQs
• Old AKTU question paper,
• Expected Questions for university Exam
• References
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Course Objective
Objectives
• At completion of this course it is expected that students will
be able to understand-
• Different types of natural compounds and their chemistry and
medicinal importance.
• The importance of natural compounds as lead molecules for
new drug discovery.
• The concept of rDNA technology tool for new drug discovery
• General methods of structural elucidation of compounds of
natural origin.
• Isolation, purification and characterization of simple chemical
constituents from natural source.

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Course Outcome
After Completion of Course Students May be Able to
CO1.1 Discuss the role of natural products obtained from

different plants to act as lead for new pharmaceuticals with
their applications in CNS, CVS, malaria diseases.

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Course Outcome with blooms level of
taxonomy
CO No. CO STATEMENT LEVEL OF
TAXONOMY
CO1.1 After Completion of Level II
Course Students May be (Understanding)
Able to:
Discuss the role of natural
products obtained from
different plants to act as lead
for new pharmaceuticals with
their applications in CNS,
CVS, malaria diseases

Programme Outcomes (POs)
POs POs
No.
PO1 An ability to independently carry out research/ investigation
and development work to solve practical problems.
PO2 An ability to write and present a substantial technical

report /document
PO3 Students should be able to demonstrate a degree of master

over the area as per the specialization of the program. The
mastery should be at a level higher than the requirements in
the appropriate bachelor program

CO-PO Mapping
Mapping of Course Outcomes with POs

The notation of 3, 2 and 1 denotes substantially (high),
moderately (medium) and slightly (low).
PO PO1 PO2 PO3

CO1 1 - 2

Topic Objective
Unit Topic Topic Objective
Anticancer By the end of this topic student will
drugs understand :
• The role of lead molecule in cancer
Study of
Natural Anti-malarial • Acquire knowledge about the anti
products drugs malarial drugs
as leads Cardiovascular • Lead molecules for cardiovascular
drugs treatment
Neuromuscula • Neuromuscular blocking drugs with
r blocking their mechanism of action
drugs
βLactam • Chemistry and pharmacological action
antibiotics of beta lactam antibiotics
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Topic Wise Mapping with CO
Mapping of Course Outcomes with Topic
Unit Topic Mapping with CO1.1
Anticancer drugs 3
Anti-malarial drugs 3
Study of
Natural Cardiovascular 3
products as drugs
leads
Neuromuscular 3
blocking drugs
βLactam antibiotics 3
Prerequisite and Topic Wise Recap
This subject illustrates the therapeutic importance of natural
products obtained from plant sources and also their role as
lead compounds. This subject also focus on principle and
applications of recombinant DNA technology with use of
different spectral techniques for structural elucidation of
naturalcompounds

Study of Natural Products (CO1.1)
DRUG DEVELOPMENT
• The process of bringing a new drug to the market, once a lead
compound has been identified through the process of
drug discovery.
NATURAL PRODUCTS
•Natural products are the richest source of biologically active
compounds.
•Many today's medicines are either obtained directly from
natural source or were developed from a lead compound
originally obtained from a natural source.

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ROLE OF NATURAL PRODUCTS IN DRUG

DEVELOPMENT
• The natural products can be classify into
• Following discovery of the penicillins, drug discovery from
microbial sources occurred and diving techniques in the 1970s
opened the seas.

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PLANT SOURCES
Most of biological active natural products are plant secondary
metabolites with complex structures.
Plants are consider as one of the richest source of lead
compounds
Examples:-
• Morphine - Papaver Somniferun
• Cocaine- Erythroxylum Coca
• Digoxin- Digitalis
• Quinine- Cinchona

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• Some relevant examples are khellin, from Ammi visnaga (L) Lamk., which
led to the development of chromolyn (in the form of sodium
chromoglycate) as a bronchodilator;
• galegine, from Galega officinalis L., which was the model for the synthesis
of metformin and other bisguanidine-type antidiabetic drugs [8];
• and papaverine from Papaver somniferum which formed the basis for
verapamil used in the treatment of hypertension (Fig. 1) [8].
• The latter plant is better known as being the source of painkillers such as
morphine and codeine [9],
• but probably the best example of ethnomedicine’s role in guiding drug
discovery and development is that of the antimalarial drugs, particularly
quinine and artemisinin.
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16
Drugs affecting the central nervous system: Morphine

alkaloids
• Morphine was isolated from raw opium in 1805 by a German
pharmacologist, Friedrich Wilhelm Adam Serturner (1783-
1841).
• Morphine is a potent suppressor of pain and is a very useful

drug in painful conditions, especially in severe chest pain
arising due to heart attacks. It also induces sleep in no time

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Morphine obtained from Papaver Somniferum

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• Barely eighteen years after morphine was discovered, it was

used for homicide.
• In fact the name morphine comes from the Greek ‘god of

dreams’, Morpheus. Incidentally Morpheus was the son of
Hypnos, the Greek ‘god of sleep
• Morphine not only brings sleep and dreams but may cause
death when taken in large doses. Morpheus (The God Of
Dreams)

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MECHANISM OF ACTION
• Opioids exert their major effects by interacting with opioid
receptors in the CNS
• Opioids activate 7- transmembrane GPCRs located

presynaptically and postsynaptically along pain transmission
pathways
• High densities of opioid receptors known as mu, delta and

kappa are found in the dorsal horn of the spinal cord and
higherCNS centers

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• Most currently used opioid analgesics act mainly at mu-

opioid receptors
• Morphine acts at kappa receptors in lamina 1 and 11 of the

substantia Granulose of the spinal cord and decreases the
release of substance p, which is modulates pain perception in
the spinal cord

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USES OF MORPHINE
1. It is an analgesic for the relief of severepain
2. Used as pre-anesthetic medication
3. For producing sleep and sedation
4. Used as anti-tussive
5. For the treatment of diarrhea
6. In the treatment of acute left ventricularfailure

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Anticancer drugs: Paclitaxel and Docetaxel, Etoposide, and

Teniposide
• Active ingredients such as alkaloids, flavonoids, terpenoids,
polysaccharide and saponin obtained from natural products
have potent biological properties such as anti-tumor, analgesia,
anti-inflammatory, immunomodulation, anti-viral, etc.
• Most natural anti-neoplastic drugs often do not kill tumor

cells directly, but regulates the human immune function to
achieve this purpose or both..

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• DNA topoisomerase I (Topo I) is an essential enzyme involved

in cell growth.
• The inhibition of Topo I is an important anti-cancer pathway.
• A large number of anti-cancer drugs combat cancers through

cell cycle arrest, induction of apoptosis and differentiation as
well as through inhibition of cell growth and proliferation.

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What is an cancer ?
 Cells are the basic units that make up the human body.
 Cells grow and divide to make new cells as the body needs
them.
 Usually, cells die when they get too old or damaged and new
cells growth take their place.
 Cancer begins when genetic changes occurs.

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 A tumor can be cancerous or benign.
 A cancerous tumor is malignant, it can grow and spread to

other parts of the body.
 A benign tumor means the tumor can grow but will not spread.

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TAXANES
 Taxanes are a class of diterpenes
 The prototype taxane is the natural product paclitaxel ,

originally known as Taxol and first derived from the bark of
the Pacific Yew tree.
 Docetaxel is a semi-synthetic analogue of paclitaxel.
 Taxanes enhance stability of microtubules, preventing the

separation of chromosomes during anaphase.

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• The anticancer activity of taxanes is similar to the action of
vinca alkaloids and is associated with their effect on the
microtubules, which are composed of heterodimers of α-
tubulin and β-tubulin.
• Taxanes, however, constitute the second group of
microtubule-interacting agents—microtubule-stabilising
agents that stimulate the microtubule polymerization .
• The processes of microtubule polymerisation and
depolymerisation are essential for mitotic cell division
Dr.Rakhi Mishra MPC 104T

11/18/2023 28
Unit I
• Taxanes, as opposed to vinca alkaloids, bind with high affinity
to the inside of the microtubules. High concentrations of
taxanes lead to microtubule polymerisation, while the
Catharanthus alkaloids inhibit it.
• Taxanes are one of the most effective drug types used in the
treatment of breast and ovarian cancers; they are also used to
treat squamous cell carcinoma

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Unit I
• Taxanes may be used as single agents or in combination with
the anthracyclines, antimetabolites, and vinca alkaloids or
even in combination with each other to provide benefits in
the treatment of women with HR-negative metastatic breast
cancer (MBC).

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Unit I
• In the treatment of ovarian cancer, dual therapy with
docetaxel and camptothecin, as well as docetaxel in
combination with gemcitabine, has demonstrated promising
results as a second-line therapy.
• Similar results were obtained for triple-therapy treatment
with docetaxel, carboplatin, and anthracycline–epirubicin
• The combination of a taxane, such as paclitaxel or docetaxel,
with cisplatin or carboplatin is a standard therapy for ovarian
cancer.

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Unit I
• The authors suggested that a combination of taxanes with pigment
epithelium-derived factor (PEDF) could serve as a novel strategy for
castration-resistant prostate cancer (CRPC) chemotherapy [50].
• Taxanes are effective drugs that are used to treat many cancers. However,
like other anticancer drugs, they have side effects. The main problem is
the development of cardiotoxicity, especially when they are given together
with doxorubicin. However, this applies not only to the cardiac muscle, but
also to other organs, like the kidneys, liver, and brain.
• It was shown that docetaxel induces oxidative stress in blood plasma in
rats bearing mammary tumours [51,52]. Additionally, paclitaxel and
docetaxel also generate oxidative stress in rat livers and brains [53,54]

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Unit I
However, in this dual therapy, carboplatin is used more often, as it
has relatively fewer side effects with the same level of
effectiveness.
The application of cabazitaxel and its efficacy and safety when
used in combination with prednisone in the treatment of metastatic
castration-resistant prostate cancer (mCRPC) was demonstrated
by Tsao et al. (2014) [49]. Cabazitaxel exhibited a significantly
lower IC50 value than docetaxel.

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Unit I
PACLITAXEL
 A cyclo decane isolated from the bark of the Pacific
yewtree ,Taxus brevifolia
 It stabilizes microtubules in their polymerized form leading to

cell death.
 Abraxane is the latest attempt to improve upon paclitaxel, one

of the leading chemotherapy treatments.

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.
 It’s brand name is Abraxane , Abraxis ,Bioscience, Epitaxol,
Onxol ,Paxceed,Paxene ,Taxol ,Taxol A , Vascular Wrap ,
Xorane. 14
Docetaxel (as generic or under the trade name Taxotere) is a

clinically well- established anti-mitotic chemotherapy
medication (that is, it interferes with cell division).

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Paclitaxel is used in the treatment of breast and ovarian cancers, non-small cell
lung cancer, and Kaposi’s sarcoma [43,44].
A combination of bevacizumab and paclitaxel exhibits synergetic effects, anti-
tumour efficacy, and a satisfactory toxicity profile in tpatients with breast cancer
and in patients with non-small cell lung .
Paclitaxel may be used alone or in combination with other anticancer drugs,
such as cisplatin or carboplatin .

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Unit I
• Paclitaxel (PTX) (6) belongs to the group of drugs obtained
from the European yew (Taxus baccata) and/or the Pacific yew
(Taxus brevifolia) tree needles.
• It belongs to a group of compounds known as taxanes, which
are mitosis inhibitors.
• The natural production of paclitaxel from Taxus is
environmentally unsustainable and economically unfeasible.
Lately, a method of synthesizing the precursor of paclitaxel
10-deacetylbaccatin III has been developed in the
bioengineering sector.
• Paclitaxel and docetaxel are used widely as monotherapies, as
well as in combination with other anticancer drugs that inhibit
mitosis and participate in cell apoptosis. However, both
taxanes demonstrate differences in their toxicity profiles .

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Unit I
MECHANISM OF ACTION OF PACLITAXEL

 The cytotoxic activity of docetaxel is exerted by promoting
and stabilising microtubule assembly.
This leads to a significant decrease in free tubulin, needed for

microtubule formation and results in inhibition of mitotic cell
division.
Because microtubules do not disassemble in the presence of

docetaxel, they accumulate inside the cell and cause initiation
of apoptosis

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USES
• Paclitaxel is approved in the UK for ovarian, breast and lung
cancers and Kaposi's sarcoma.
• For the treatment of advanced breast cancer after the failure of

anthracyclic chemotherapy.
• The main use of docetaxel is the treatment of a variety of

cancers after the failure of anthracycline-based chemotherapy

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ETOPOSIDE
• It is usually prescribed in multiple chemotherapy protocols .
• It is a highly active and widely used antineoplastic agent .
• It is active against many tumour types and used primarily as
part of combination treatment for testicular tumours and
leucopenia.
• This is most active against lung cancer .
• The product is available as an injectable solution to be
administered by infusion or it is administered orally as liquid
capsules

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MECHANISM OFACTION:
 Etoposide forms a tertinary complex with DNA and the
topoisomerase II enzyme (which aids in DNA unwinding),
prevents re-ligation of the DNA strands, and by doing so
causes DNA strands to break.
 Cancer cells rely on this enzyme more than healthy cells, since
they divide more rapidly. Therefore, this causes errors in DNA
synthesis and promotes apoptosis of the cancer cell

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TENIPOSIDE
Teniposide is used for the treatment of lymphomas of acute
refractory leukemia and that of brain and bladder tumors.
 It can be used in single drug therapy for induction of

remission.
It is in a class of drugs known as podophyllotoxin derivatives

and slows the growth of cancer cells in the body

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Lovastatin
• Lovastatin is in a class of medications called HMG CoA
reductase inhibitors (statins).

• It works by slowing the production of cholesterol in the body
to decrease the amount of cholesterol that may build up on

the walls of the arteries and block blood flow to the heart,
brain, and other parts of the body.

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 Higher LDL levels/hypercholesterolemia causes

atherosclerosis,Angina pectoris , coronary artery diseases,
stroke.
 Merck in1979 reported Lovastatin from Aspergillus
terreus-,1987 FDA Approval.
 Statins are competitive inhibitors of HMG-CoA reductase.
 Commercially lovastatin is produced by a variety of
filamentous fungi including Penicillium species, Monascus
ruber and Aspergillus terreus as a secondary metabolite.
 Lovastatin was discovered in Aspergillus terreus and
Monascus ruber in the 1970s and is a natural product
in oyster mushrooms (Pleurotus ostreatus) and red yeast rice
(rice fermented by Monascus).
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 Lovastatin was discovered in Aspergillus terreus and
Monascus ruber in the 1970s and is a natural product
in oyster mushrooms (Pleurotus ostreatus) and red yeast rice
(rice fermented by Monascus).
(Red yeast rice. Red yeast rice is a product of the yeast that
grows on rice. ...
• Psyllium. Psyllium is an herb that's often used to treat
constipation because it contains large amounts of fiber. ...
• Fenugreek. Fenugreek is a plant that grows in parts of Europe
and western Asia. ...
• Fish oil)

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 Lovastatin is a prodrug, an inactive lactone in its native form,
the gamma-lactone closed ring form in which it is
administered, is hydrolysed in vivo to the β-hydroxy acid open
ring form; which is the active form.

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MOA

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• Teprotide, isolated from the venom of the pit viper, Bothrops

jaracaca, led to the design and synthesis of the ACE inhibitors,
captopril and enalapril,12 which are used in the treatment of
cardiovascular disease
• Teprotide was chosen as a lead because of its long-lasting in
vivo activity. This was demonstrated by Bianchi et al.[4] by
administering teprotide to dogs and rats and observing that it
inhibited the vasopressor response induced by angiotensin I.

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• Teprotide was shown to be an effective antihyperension agent

but it had limited use because of its expense and lack of oral
activity. It was found that teprotide inhibits the enzyme that
converts angiotensin I to angiotensin II.
• From this researchers conducted structure-activity studies
which allowed them to identify the active binding site of the
ACE which allowed for the development of antihypertension
drugs to be developed.
• Captopril was the first antihypertension drug developed by
Ondetti and Cushman.[5] Many ACE inhibitors have been
developed since this time but this was the start of them.

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Teprotide, isolated from the venom of the pit viper, Bothrops

jaracaca, led to the design and synthesis of the ACE inhibitors,
captopril and enalapril,12 which are used in the treatment of
cardiovascular disease,Teprotide is a synthetic nonapeptide
(Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) which is identical to
the peptide from the venom of the snake (Bothrops jararaca).
• It inhibits kinase-II and ANGIOTENSIN-I and has been
proposed as an antihypertensive agent.

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MOA of Teprotide:
• It is Angiotensin- converting enzyme(ACE) inhibitor
• A class of drugs whose main indications are the treatment of

hypertension and heart failure. They exert their hemodynamic
effect mainly by inhibiting the renin-angiotensin system.
• They cause mainly vasodilation and mild natriuresis without

affecting heart rate and contractility.

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Dicoumarol
 Dicumarol is a hydroxycoumarin originally isolated from
molding sweet-clover hay. (Melilotus species). Its discovery
led to the development of modern anticoagulant drugs.
 Dicoumarol is a natural chemical substance of combined plant
and fungal origin. It is a derivative of coumarin, a bitter-tasting
but sweet-smelling substance made by plants that does not
itself affect coagulation, but which is (classically) transformed
in mouldy feeds or silages by a number of species of fungi,
into active dicoumarol.
 Dicoumarol does affect coagulation, and was discovered in
mouldy wet sweet-clover hay, as the cause of a naturally
occurring bleeding disease in cattle.
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Dicoumarol
 Dicumarol is a hydroxycoumarin originally isolated from
molding sweet-clover hay. (Melilotus species). Its discovery
led to the development of modern anticoagulant drugs.
 It is used as an oral anticoagulant and acts by inhibiting the
hepatic synthesis of vitamin K-dependent coagulation factors
(prothrombin and factors VII, IX, and X). It is also used in
biochemical experiments as an inhibitor of reductases.

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MOA of Dicoumarol:
•Dicoumarol is a competitive inhibitor of vitamin K epoxide
reductase; thus, it inhibits vitamin K recycling and causes
depletion of active vitamin K in blood.
•This prevents the formation of the active form of prothrombin
and several other coagulant enzymes, and inhibits blood clotting.
• dicoumarol became the prototype of the 4-hydroxycoumarin
anticoagulant drug class. Dicoumarol itself, for a short time,
was employed as a medicinal anticoagulant drug, but since the
mid-1950s has been replaced by its simpler
derivative warfarin, and other 4-hydroxycoumarin drugs.
• It is given orally, and it acts within two days.

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The mechanism of action of Vitamin K along with the toxicity of

dicoumarol are measured with the prothrombin time (PT) blood
test
Dicoumarol was used, along with heparin, for the treatment of
deep venous thrombosis. Unlike heparin, this class of drugs may
be used for months or years.

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Neuromuscular blocking drugs: Curare alkaloids

• The neuromuscular blocking agents are used primarily in
conjunction with general anaesthetic to provide muscle
relaxation for surgery ,while centrally acting muscle relaxants
are used mainly for painful muscle spasms and spastic
neurological conditions.

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Types of Neuromuscular blockers
Neuromuscular blocking agents are of two types
1.Peripherally acting:
A. Non depolarizing agents
i. Long acting : d-Tubocurarine , Pancuronium ,
Pipecuronium , Doxacurium
ii. Intermediate acting : Vecuronium , Atracurium ,
Rapacuronium
iii. Short acting : Mivacurium
B. Direct acting : Dantrolene sodium , Quinine
2. Centrally acting : Metaxalone , Diazepam ,
Baclofen ,Tizanidine , Chlorzoxazone.

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MOA
• . Curare is a nondepolarizing and competitive inhibitor of
acetylcholine (ACh) at neuromuscular junctions preventing the
binding of ACh to their Nicotinic ACh Receptor .
• These postsynaptic nicotinic receptors are responsible for

generating action potentials resulting in muscle contraction .
• Thus, binding of the curare prevents action potentials from

occurring at the postsynaptic membrane and as a result, leads
to paralysis of voluntary muscle group

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Curare alkaloids Source

• Chondrodendron tomentosum , main source plant of 'Tube
Curare' and principal source of D-tubocurarine (DTC), the
alkaloid constituting medicinal curare.
family Menispermaceae.
• Strychnos toxifera, the Strychnos species which is the

principal source of 'Calabash Curare' and its main active
constituent - the alkaloid toxiferine.
family Loganiaceae (sometimes Strychnaceae).

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Chemistry of Curare
• The active ingredient in crude curare is D-tubocurarine.
• Curare is an organic compound classified as either an
isoquinoline or indole alkaloid. In other words, they are
aromatic, nitrogen-containing structures.
• Does not cross blood-brain-barrier (BBB) due to two
quaternary nitrogens = polar molecule

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Uses of curare
o Increased urination, reduce fever, promote menstruation,
reduce fever, and relaxation of skeletal muscle.
o Antibacterial, anti-inflammatory, and antiseptic.
o When used for abdominal pain and treatment of
worms/parasites.
o Used as a muscle relaxant in electric shock therapy to prevent
traumatic complication.
o Curare was used in conjunction with general anaesthetics.

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ANTI-MALARIAL DRUGS AND ANALOGUES

• Drugs used for prophylaxis, treatment and
prevention
• of malaria
Malaria
• Most important parasitic disease of humans, causing
hundreds of millions of illnesses and probably over a million
deaths each year.

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Classification of antimalarial agents

• 4-Aminoquinolines --- Chloroquine, Amodiaquine
•Cinchona alkaloids---- Quinine,
• 8-Aminoquinoline----- Primaquine, Tafenoquine
• Quinoline methanol ----- Mefloquine
•Diaminopyrimidines----Pyrimethamine
•Sulfonamides & sulfone----- Sulfadoxine, Sulfamethopyrazine
Dapsone
• Antibiotics ---- Tetracyclins, Doxycycline, Clindamycin,
Azithromycin

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Malaria parasite life cycle
• Malaria infection begins when an infected
female Anopheles mosquito bites a person,
injecting Plasmodium parasites, in the form of sporozoites,
into the bloodstream.
• The sporozoites pass quickly into the human liver.
• The sporozoites multiply asexually in the liver cells over the
next 7 to 10 days, causing no symptoms.
• In an animal model, the parasites, in the form of merozoites,
are released from the liver cells in vesicles, journey through
the heart, and arrive in the lungs, where they settle within
lung capillaries. The vesicles eventually disintegrate, freeing
the merozoites to enter the blood phase of their
development.*
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1
67
• In the bloodstream, the merozoites invade red blood cells (

erythrocytes) and multiply again until the cells burst. Then
they invade more erythrocytes. This cycle is repeated, causing
fever each time parasites break free and invade blood cells.
• Some of the infected blood cells leave the cycle of asexual
multiplication. Instead of replicating, the merozoites in these
cells develop into sexual forms of the parasite, called
gametocytes, that circulate in the blood stream.
• When a mosquito bites an infected human, it ingests the
gametocytes, which develop further into mature sex cells
called gametes.

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• The fertilized female gametes develop into actively moving

ookinetes that burrow through the mosquito's midgut wall
and form oocysts on the exterior surface.
• Inside the oocyst, thousands of active sporozoites develop.

The oocyst eventually bursts, releasing sporozoites into the
body cavity that travel to the mosquito's salivary glands.
• The cycle of human infection begins again when the mosquito

bites another person.

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Chloroquine
•Chloroquine is used to prevent and treat malaria. It is also used
to treat liver infection caused by protozoa (extraintestinal
amebiasis). Chloroquine may also be used to treat coronavirus
(COVID-19) in certain hospitalized patients
• used to prevent and treat malaria in areas where malaria
remains sensitive to its effects. Certain types of malaria, resistant
strains, and complicated cases typically require different or
additional medication

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History.
In Peru, the indigenous people extracted the bark of the
Cinchona tree (Cinchona officinalis) and used the extract to
fight chills and fever in the seventeenth century. In 1633 this
herbal medicine was introduced in Europe, where it was given
the same use and also began to be used against malaria.

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• Chloroquine has been used in the treatment and prevention

of malaria from Plasmodium vivax, P. ovale, and P. malariae. It
is generally not used for Plasmodium falciparum as there is
widespread resistance to it.[9][10]
• Chloroquine has been extensively used in
mass drug administrations, which may have contributed to
the emergence and spread of resistance. It is recommended
to check if chloroquine is still effective in the region prior to
using it.[11] In areas where resistance is present, other
antimalarials, such as mefloquine or atovaquone, may be
used instead. The Centers for Disease Control and Prevention
recommend against treatment of malaria with chloroquine
alone due to more effective combinations.[
11/18/2023 73
Chloroquine
•Rapidly acting erythrocytic schizontocide against all species of
plasmodia including the sensitive strains of P. falciparum.
•No effect on Pre-erythrocytic and exo-erythrocytic

phases of the parasite does not prevent relapses in vivax and
ovale malaria.

11/18/2023 74
MOA
 It is actively concentrated by sensitive intra-
erythrocytic plasmodia and interferes with degradation of
haemoglobin by parasitic lysosomes.
 Polymerization of toxic haeme to nontoxic parasite
pigment hemozoin is inhibited by formation of
chloroquine-heme complex.
 Haeme itself or its complex with chloroquine then damages
the plasmodial membranes.

11/18/2023 75
 Clumping of pigment and changes in parasite

membranes follow: death.
 Other related anti-malarials like amodiaquine
quinine, mefloquine, lumefantrine act in an analogous
manner

11/18/2023 76

11/18/2023 77
• Hemoglobin is composed of a protein unit (digested by the parasite) and a heme

unit (not used by the parasite). During this process, the parasite releases the toxic
and soluble molecule heme. The heme moiety consists of a porphyrin ring called
Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite
biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in
the digestive vacuole as insoluble crystals.[citation needed]
• Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite
cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the
digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by
diffusion. Chloroquine caps hemozoin molecules to prevent further
biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to
heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to
the cell and disrupts membrane function. Action of the toxic FP-chloroquine and
FP results in cell lysis and ultimately parasite cell autodigestion. [32] Parasites that do
not form hemozoin are therefore resistant to chloroquine.[3

11/18/2023 78
• The lysosomotropic character of chloroquine is believed to account for much of its

antimalarial activity; the drug concentrates in the acidic food vacuole of the
parasite and interferes with essential processes. Its lysosomotropic properties
further allow for its use for in vitro experiments pertaining to intracellular lipid
related diseases,[29][30] autophagy, and apoptosis.[31]
• Inside red blood cells, the malarial parasite, which is then in its
asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids,
which the parasite requires to construct its own protein and for energy
metabolism. Digestion is carried out in a vacuole of the parasitic cell. [citation needed]

11/18/2023 79
Resistance in malaria[edit]
• Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant
strains have appeared throughout East and West Africa, Southeast Asia, and South America.
The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the
parasite evolved.
• Resistant parasites are able to rapidly remove chloroquine from the digestive vacuole using a
transmembrane pump. Chloroquine-resistant parasites pump chloroquine out at 40 times the
rate of chloroquine-sensitive parasites; the pump is coded by the P. falciparum chloroquine
resistance transporter (PfCRT) gene.[34] The natural function of the chloroquine pump is to
transport peptides: mutations to the pump that allow it to pump chloroquine out impairs its
function as a peptide pump and comes at a cost to the parasite, making it less fit. [35]

11/18/2023 80
• Resistant parasites also frequently have mutation in the ABC transporter P.

falciparum multidrug resistance (PfMDR1) gene, although these mutations are
thought to be of secondary importance compared to PfCRT. An altered
chloroquine-transporter protein, CG2 has been associated with chloroquine
resistance, but other mechanisms of resistance also appear to be involved. [36]
• Verapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine
concentration ability and sensitivity to this drug. Other agents which have been
shown to reverse chloroquine resistance in malaria are chlorpheniramine,
gefitinib, imatinib, tariquidar and zosuquidar.[37]

11/18/2023 81

11/18/2023 82
USES
•Chloroquine is the preferred drug for clinical cure of
 Vivax
 Ovale
 Malariae
 some sensitive falciparum strains
 Causes rapid clearance of fever & Parasitaemia

11/18/2023 83
SIDE EFFECTS
• Include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea,
swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness,
easy bruising/bleeding, hearing and mental problems. [14][15]
• Unwanted/uncontrolled movements (including tongue and face twitching) [14]
• Deafness or tinnitus.[14]
• Nausea, vomiting, diarrhea, abdominal cramps[15]
• Headache.[14]
• Mental/mood changes (such as confusion, personality changes, unusual
thoughts/behavior, depression, feeling being watched, hallucinating) [14][15]
• Signs of serious infection (such as high fever, severe chills, persistent sore throat) [14]
• Skin itchiness, skin color changes, hair loss, and skin rashes

11/18/2023 84
CHEMISTRY OF MACROLIDE ANTIBIOTICS

✓ The term Macrolide was originally given to antibiotics
produced by species of Strptomyces.
✓ In 1950 the first drug of this class was isolated:Picromycin
✓ In 1952 Erythromycin and Carbomycin were introduced
•

11/18/2023 85
They all contain three characteristics parts in the molecule:
✓ A highly substituted macrocyclic lactone: aglycone.
✓ A ketone group.
✓ An amino desoxysugar: glycon, and in some of the
macrolides, a neutral desoxysugar which are glycosisically
attached to
the aglycone ring.

11/18/2023 86
✓ The lactone ring usually has 12, 14, or 16 atoms and is often
unsaturated & conjugated with the ketone group.
✓ Having a dimethyl amino group on the glycon part, macrolide

antibiotics are weak bases and different salts with pKa range
of 6.0-9.0 can be formed on the amino group.
✓ Macrolides are water-insoluble molecules.
✓ Macrolides are stable in aqueous solutions at or below room

temperature.

11/18/2023 87
MOA
✓ Macrolides attach to the 50s portion of bacterial ribosomes
and inhibit the protein synthesis (interferes with
Translocation).
▪ Suppression of RNA-dependent protein synthesis
✓ They block the enzymes that catalyse the transfer of the new
amino acid residue to the peptide chain, that is, prevent
elongation in prokaryotic cells.
✓ Macrolides typically display bacteriostatic activity, but may be
bactericidal when present at high concentrations against very
susceptible organisms

11/18/2023 88
Β- LACTAM ANTIBIOTICS
 Beta lactam antibiotics: beta lactam ring
• Penicillin
• Cephalosporins
 Others
• Monobactam
• Carbapenems

11/18/2023 89
• General Structure of penicillin and cephalosporin

11/18/2023 90
GENERAL MECHANISM OF ACTION:

 Interfere with the synthesis of bacterial cell wall.
 Bacteria synthesizes UDP-NAM and UDP-NAG.
 Cleavage of terminal D-Ala by transpeptidases
 Inhibits the transpeptidases which constitute penicillin
binding proteins (PBPs)
 When bacteria divides in presence of beta lactam
antibiotics-CWD-swell- burst-lysis.

11/18/2023 91
CEPHALOSPORIN
• Derived from Cephalosporin-C obtained from a fungus

cephalosporium.
• Nucleus:
• Beta lactam ring
• Dihydrothiazine ring
• Bactericidal
• Divided into 4 generations based on overall antibacterial
spectrum and potency.

11/18/2023 92
CLASSIFICATION
• FIRSTGENERATION: Cefadroxil, Cefazolin,
Cephalothin
• SECOND GENERATION: Cefaclor,
Ceforanide, Cefoxitin, Cefprozil, Cefuroxime, Cefuroxime
axetil.
• THIRD GENERATION: Cefdinir, Cefditoren pivoxil,
Ceftibuten, Cefixime, Cefotaxime, Cefpodoxime proxetil,
Ceftizoxime, Ceftazidime, Cefoperazone, Ceftriaxone.
• FOURTH GENERATION: Cefepime, Cefpirome
• FIFTH GENERATION: Ceftaroline, Ceftobiprole

11/18/2023 93
MODE OF ACTION

11/18/2023 94
Faculty Video Links/ Youtube & NPTEL Video Links and Online
Courses Details (if any)
• Self Made Video Link:
• Youtube/other Video Links

https://a.impartus.com/ilc/#/course/154412/742
https://www.youtube.com/watch?v=FR0WumvmjSI
https://www.youtube.com/watch?v=JZt1MiygQHY

11/18/2023 95
Summary
This unit is designed to impart fundamental knowledge on the

use of natural products for different type of pharmacological
actions. Natural products are described with their mechanism
of action and chemistry with their biological sources.This also
covers use of those natural compounds as lead for new drug
discovery.
By this power point presentation all parts of this unit of
syllabus has been emphasised and discussed as per the need of
syllabus

11/18/2023 96
Daily Quiz
• Write two examples of drugs obtained frmom natural sources

• What are curare alkaloids
• Give biological source of morphine
• Discuss the uses of cephalosporins
• Explain mechanism of action of beta lactams
• What are neuromuscular blocking agents
• Expalin mechanism of action of etiposide
• Write the biological source of paclitaxel

11/18/2023 97
Weekly Assignment
• Briefly describe use of natural compounds as anticancer agents
• Explain the appilications of morphine for drug discovery and
derivatization
• What are the natural CVS agents mechanism of action
• Give short note on neuromuscular agents

11/18/2023 98
MCQ s
1) What is meant by a semi-synthetic approach in drug synthesis?

i) The synthesis of a drug from a natural product
ii) The synthesis of a drug where part of the synthetic route
involves the use of enzymes
iii) The use of genetically modified microorganisms to produce a
drug or its analogues
iv) The synthesis of a structure, which is then fed to a micro-
organism and converted to the drug by a biosynthetic pathway

11/18/2023 99
MCQ s
2) Which of the following compounds is a useful starting

material for the semi-synthetic formation of artemisinin?
i) Acetyl coenzyme A ii) Farnesyl diphosphate
iii) Amorpha-4,11-diene iv) Artemisinic acid
3) Which must eliminate parasites from both liver and

erythrocytes:
i) Chloroquine ii) Mefloquine iii) Pyrimethamine
iv) Primaquine

11/18/2023 100
MCQ s
4) Which of the following antimalarial drugs inhibit
dihydrofolate reductase enzyme?
i) Chloroquine ii) Mefloquine
iii) Pyrimethamine iv) Primaquine
5). Of the plasmodium species causative for human malaria, the

one producing most serious complications:
i)Plasmodium vivax ii) Plasmodium malariae
iii) Plasmodium ovale iv)) Plasmodium falciparum
6) Best drug to eradicate P. vivax infection is/are

i) Chloroquine ii) Mefloquine iii) Quinine iv) Primaquine

MCQ s
8) Cefazolin belongs to which generation of cephalosporins

i) First generation ii) Second generation iii) Third generation
iv) None
9) Best drug to eradicate P. vivax infection is/are
i) Chloroquine ii) Mefloquine iii) Quinine iv) Primaquine
10) Cefadroxil belongs to which generation of cephalosporins
i) First generation ii) Second generation iii) Third generation
iv) None
Answer key
1) i 2) ii 3) i 4) iii 5) iv
6) i 7) ii 8)i 9) i 10) i

11/18/2023 102
Old Question Papers of AKTU

11/18/2023 103
Old Question Papers of AKTU

11/18/2023 104
Expected Questions for University Exam
• Discuss on the role of natural compounds as lead for new drug

discovery
• Explain the antimalarial drugs obtained from natural source
with examples
• Write about the role of curaare alkaloids with their mechanism
of action
• Explain and discuss role of paclitaxel as anticancer drugs
• Write about the sources of natural copmpounds for anticancer
agents

11/18/2023 105
References and Books to be followed
Text Books:
• Kar Ashutosh, Text book of Medicinal chemistry; published by
New age international(p) limited, New Delhi; Revised &
expanded Fourth edition; Page no. 344-370
References:
•https://www.slideshare.net/rahulbs89/role-of-natural-product-in-
drug-discovery
•https://pubchem.ncbi.nlm.nih.gov/compound/dicumarol#section
=2D-Structure
.
•https://www.slideshare.net/anbudinesh/taxanes-and-podophyllot
oxins
•https://www.slideshare.net/rakeshsahu1100/cardiovascular-drugs
-naturally-occupying-drugs
11/18/2023 106
Noida Institute of Engineering and Technology
(Pharmacy Institute) Greater Noida
Thank You!!!!!!!!!!

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Noida Institute of Engineering and Technology

(Pharmacy Institute) Greater Noida

Chemistry of Natural Products Dr. Rakhi Mishra

Dr.Rakhi Mishra MPC 104T Unit I

11/18/2023 Dr.Rakhi Mishra MPC 104T Unit I 2

• β - Lactam antibiotics (Cephalosporins and Carbapenem)

• Classification of Anti-malarial drugs and analogues

Dr.Rakhi Mishra MPC 104T Unit I

After Completion of Course Students May be Able to

CO1.1 Discuss the role of natural products obtained from

Dr.Rakhi Mishra MPC 104T Unit I

11/18/2023 Dr.Rakhi Mishra MPC 104T Unit I 7

PO2 An ability to write and present a substantial technical

PO3 Students should be able to demonstrate a degree of master

11/18/2023 Dr.Rakhi Mishra MPC 104T Unit I 8

Mapping of Course Outcomes with POs

PO PO1 PO2 PO3

11/18/2023 Dr.Rakhi Mishra MPC 104T Unit I 9

Unit Topic Mapping with CO1.1

This subject illustrates the therapeutic importance of natural

products obtained from plant sources and also their role as

lead compounds. This subject also focus on principle and

applications of recombinant DNA technology with use of

different spectral techniques for structural elucidation of

11/18/2023 Dr.Rakhi Mishra MPC 104T Unit I 12

Dr.Rakhi Mishra MPC 104T Unit I

ROLE OF NATURAL PRODUCTS IN DRUG

Dr.Rakhi Mishra MPC 104T Unit I

Dr.Rakhi Mishra MPC 104T Unit I

Drugs affecting the central nervous system: Morphine

• Morphine is a potent suppressor of pain and is a very useful

Dr.Rakhi Mishra MPC 104T Unit I

Morphine obtained from Papaver Somniferum

Dr.Rakhi Mishra MPC 104T Unit I

• Barely eighteen years after morphine was discovered, it was

• In fact the name morphine comes from the Greek ‘god of

Dr.Rakhi Mishra MPC 104T Unit I

• Opioids activate 7- transmembrane GPCRs located

• High densities of opioid receptors known as mu, delta and

Dr.Rakhi Mishra MPC 104T Unit I

• Most currently used opioid analgesics act mainly at mu-

• Morphine acts at kappa receptors in lamina 1 and 11 of the

Dr.Rakhi Mishra MPC 104T Unit I

Dr.Rakhi Mishra MPC 104T Unit I

Anticancer drugs: Paclitaxel and Docetaxel, Etoposide, and

• Most natural anti-neoplastic drugs often do not kill tumor

Dr.Rakhi Mishra MPC 104T Unit I

• DNA topoisomerase I (Topo I) is an essential enzyme involved

• The inhibition of Topo I is an important anti-cancer pathway.

• A large number of anti-cancer drugs combat cancers through

Dr.Rakhi Mishra MPC 104T Unit I

 Cancer begins when genetic changes occurs.

Dr.Rakhi Mishra MPC 104T Unit I

 A tumor can be cancerous or benign.

 A cancerous tumor is malignant, it can grow and spread to

Dr.Rakhi Mishra MPC 104T Unit I

 The prototype taxane is the natural product paclitaxel ,

 Docetaxel is a semi-synthetic analogue of paclitaxel.