BP501T MED CHEM UNIT-V Download Notes PDF BPharmacy 5th Semester 2022

📑 BP501T Medicinal Chemistry II

Title:	BP501T MED CHEM UNIT-V
Course:	BPharmacy
Semester/Year:	5th Semester
Subject:	BP501T Medicinal Chemistry II
Session:	2022
Category:	Notes
`BPharmacy` `Handwritten Notes` `BPharm 5th Semester` `Medicinal Chemistry` `Important Exam Notes`

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BP501T Medicinal Chemistry II BPharmacy 5th Semester

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B.Pharm 5th semester
BP501T. Medicinal Chemistry-II
Unit-V
Antidiabetic agents
Local Anaesthetics
Compiled by: Dr Manoj Kumar Mahapatra
Associate Professor
KMIPS, Rourkela
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
ANTIDIABETIC AGENTS
Agents which are used in the treatment of diabetes are called as antidiabetic agents. They
used to lower the blood sugar level in patients suffering from hyperglycaemia. These are also
called as anti-hyperglycaemic agents.
Diabetes mellitus: It is a chronic metabolic disorder which is characterized by
hyperglycaemia (increased blood sugar level). The common symptoms are polydipsia (excess
thirst), polyphagia (excess hunger), and polyurea (excess urination). The classification of
diabetes has been presented in Table-1.
Table-1: Classification of diabetes mellitus
Type-1 (IDDM) Type-2 (NIDDM)
Insulin dependent diabetes mellitus
Juvenile onset diabetes mellitus
Occurs in children
Non-insulin dependent diabetes mellitus
Adult onset diabetes mellitus
Occurs in adults
Pancreatic β-cells are destroyed
No insulin secretion
Less insulin secretion or insulin resistance
(cells don’t respond to insulin)
Treatment: insulin injection Treatment: oral hypoglycaemic agents
Insulin: It is a peptidic hormone secreted by β-cells of pancreas. It was discovered by Banting
& Best in 1921. It regulates metabolism of carbohydrate, lipids and proteins. It decreases
blood sugar level by decreasing gluconeogenesis, increasing glucose uptake and increasing
glycogen synthesis.
Insulin structure: Its full structure was elucidated by Sanger in 1956. It is a polypeptide
hormone with a molecular weight of 6000 Da. Inside body, the inactive pro-insulin is
converted into active insulin which is composed of 2 chains (A & B). A chain has 21 amino
acid residues, whereas B chain has 30 amino acid residues and both the chains are attached to
each other by 2 disulphide (-S-S-) bonds. The structure of insulin has been depicted in
Figure-1.
Sources of insulin: Bovine, Porcine, Recombinant human insulin
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Figure-1: Structure of insulin
Insulin preparations: Various insulin preparations has been classified and presented in Table2, according to their onset of action.
Table-2: Classification of various insulin preparations
Short acting Intermediate acting Long acting
Regular Isophane (NPH) Protamine zinc
Lispro Lente Ultra Lente
Insulin zinc Biphasic insulin aspart Insulin glargine
Insulin aspart Insulin detemir
Insulin degludec
Regular insulin: Also called as neutral or soluble insulin. Rapid acting with 0.5-1 hr duration
of action.
Lispro insulin: Rapid acting with 6-8 hr duration of action. In the carboxyl terminal of Bchain, lysine and proline residues are reversed. It is a recombinant human insulin.
Insulin Zinc: It is a suspension of insulin and zinc chloride, having 6-8 hr duration of action.
Insulin aspart: Synthetic form of human insulin where a single amino acid, proline (B-28) is
replaced by aspartic acid. It has 3-5 hr duration of action.
Isophane insulin: Also called as Neutral Protamine Hagedorn (NPH) insulin. It is
intermediate acting with 18-24 hr duration of action. It is composed of zinc, protamine, and
regular insulin.
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Lente insulin: It is intermediate acting with 18-24 hr duration of action. It is composed of
acetate buffer, zinc, and regular insulin.
Biphasic insulin aspart: It is intermediate acting with 24 hr duration of action. It is
composed of 30% soluble insulin aspart and 70% protamine bound insulin aspart.
Protamine zinc insulin: It is composed of insulin, zinc chloride, and protamine. It has
duration of action upto 36 hrs.
Ultra lente insulin: It contains 65% of lente insulin, having duration of action upto 36 hrs.
Insulin glargine: It is obtained by addition of two arginine residues in B-chain carboxy
terminal and by replacement of asparagine with glycine in A-21 position of human insulin. It
has duration of action upto 24 hrs.
Insulin detemir: It is obtained by addition of a fatty acid (myristic acid) to lysine residue in
B-29 position of human insulin. It has duration of action upto 24 hrs.
Insulin degludec: It is obtained by addition of hexadecanedioic acid to lysine residue in B-29
position of human insulin. It has duration of action upto 24 hrs.
Oral hypoglycaemic agents
Sulfonyl ureas: These are the first class of oral hypoglycaemic agents used for treatment of
diabetes. They are also called as insulin secretagogues.
Mechanism of action- They bind to the sulfonyl urea receptors present in pancreatic β-cells. It
leads to closure of ATP-sensitive K+
channels and depolarises the β-cell membrane. Then it
opens voltage gated Ca+2 channels and stimulates β-cells to secrete more insulin.
1
st generation- Chlorpropamide, Tolbutamide, Acetohexamide
2
nd generation- Glibenclamide, Glipizide, Glyburide
3
rd generation- Glimepiride
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Chlorpropamide- 1-(p-chlorophenyl)-sulfonyl-3-propyl urea
More resistant to metabolism than tolbutamide. So, it has longer duration of action. Used as
oral hypoglycaemic agent for treatment of type-2 diabetes.
Tolbutamide- 1-(p-tolyl)-sulfonyl-3-butyl urea
It is the least potent and short acting sulfonyl urea. It is safely used for treatment of type-2
diabetes in elderly patients and those prone to hypoglycemia.
Synthesis:
Glipizide- 1-cyclohexyl-3-[p-[2-[5-methyl pyrazin-2-yl]carboxamido]ethyl]phenyl]-sulfonyl
urea
It has quick onset of action. Used as oral hypoglycaemic agent for treatment of type-2
diabetes.
Glimepiride- 1-[p-[2-[3-ethyl-4-methyl-2-oxo-3-pyrrolin-1-carboxamido]-ethyl]-phenyl]
sulfonyl-3-(p-methyl cyclohexyl) urea
It’s a long acting potent sulfonylurea. Used as oral hypoglycaemic agent for treatment of
type-2 diabetes.
Biguanides: Phenformin, Metformin, Butformin
Mechanism of action- They reduce hepatic gluconeogenesis, decrease intestinal absorption of
glucose, increase glucose uptake and utilization to decrease the blood sugar level. As they
improve the insulin resistance, they are also known as insulin sensitizers.
Metformin- N,N-dimethyl biguanide
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Used for treatment of type-2 diabetes in obese patients. Also used for treatment of polycystic
ovarian syndrome.
Thiazolidinediones: Pioglitazone, Rosiglitazone
Mechanism of action- They binds to and stimulates Peroxisome Proliferator Activated
Receptor-γ (PPAR-γ), due to which they are also known as PPAR- γ agonists. They increase
the expression of GLUT-1 & GLUT-4 receptors on cell surface to increase glucose uptake.
They reduce insulin resistance and hepatic gluconeogenesis. They decrease the post-prandial
glucose level and also HbA1c level.
Pioglitazone- 5-[4-[2-[5-ethyl pyridin-2-yl]ethoxy]benzyl]thiazolidin-2,4-dione
Used as oral hypoglycaemic agent for treatment of type-2 diabetes.
Rosiglitazone- 5-[4-[2-[N-methyl-pyridin-2-yl]amino]ethoxy]benzyl]thiazolidin-2,4-dione
Used as oral hypoglycaemic agent for treatment of type-2 diabetes.
Meglitinides: Repaglinide, Nateglinide
Mechanism of action- Same as that of sulfonylureas. They bind to the sulfonyl urea receptors
present in pancreatic β-cells. It leads to closure of ATP-sensitive K+
channels and depolarises
the β-cell membrane. Then it opens voltage gated Ca+2 channels and stimulates β-cells to
secrete more insulin. These agents are also known as insulin secretagogues.
Repaglinide- 2-ethoxy-4-[2-[3-methyl-1-[2-(piperidin-1-yl)phenyl]butylamino]-2-oxo-ethyl]
benzoic acid
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It induces fast onset and short-lasting insulin secretion. Administered before each meal to
control post-prandial hyperglycaemia.
Used as oral hypoglycaemic agent for treatment of type-2 diabetes.
Nateglinide- N-[{4-(propan-2-yl)cyclohexyl}carbonyl]-D-phenylalanine
It’s a phenylalanine derivative. Causes faster onset and short-lasting insulin secretion than
repaglinide. Used as oral hypoglycaemic agent for treatment of type-2 diabetes.
Glucosidase inhibitors: Acarbose, Voglibose
Mechanism of action- They delays the absorption and metabolism of carbohydrates by
inhibiting α-glucosidase enzyme found in the brush border epithelium of small intestine. αglucosidase helps in hydrolysing polysaccharides and oligosaccharides into monosaccharides
and helps in their absorption. Flatulence and loose motion are the common side effects of this
class of drugs. These drugs produce anti-hyperglycaemic effect but do not produce
hypoglycaemia.
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Acarbose- It is a complex oligosaccharide which is isolated from cultures of actinoplanes (a
bacteria). It is composed of acarviosin moiety and a maltose moiety.
Used for treatment of type-2 diabetes.
Voglibose- 5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cylcohexan-1,2,3,4-
tetraol It is obtained from validamycin-A (metabolic product of Streptomyces hygroscopius).
It is a valiolamine derivative.
Used for treatment of type-2 diabetes.
References:
1. Wilson & Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry.
2. Text book of Medicinal Chemistry- S. N. Pandeya
3. William Foye’s Principles of Medicinal Chemistry.
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LOCAL ANAESTHETICS
These are agents which upon topical application or local injection cause reversible loss of
pain sensation in a restricted area of the body. They act by blocking both sensory and motor
nerve conduction to produce temporary loss of sensation without loss of consciousness.
Mechanism of action- These drugs reversibly prevent the generation and propagation of
impulses in all excitable membranes including nerve fibre by stabilising the membrane. Local
anaesthetics block the nerve conduction by decreasing the entry of Na+
during action
potential. They interact with a receptor situated within the voltage sensitive Na+
channel and
raise the threshold of Na+
channel opening. Therefore, Na+
can’t enter into the cell in
response to an impulse which prevents depolarisation. Thus, action potential is not generated.
This action affecting the depolarisation which leads to failure of conduction of impulse
without affecting the resting membrane potential (RMP) is known as membrane stabilising
effect.
Uses- These are used for i) temporary relief of localised pain
ii) itching due to minor burns, insect bites & allergy
iii) minor surgery and in dentistry
Methods or sites of administration:
1. Surface anaesthesia- Applied directly to the mucosal surfaces of nose, mouth,
bronchial tree, oesophagus & genito-urinary tract
2. Infiltration anaesthesia- It is injected under the skin in the area of operation
3. Nerve block anaesthesia- It is injected around the nerve trunks or plexuses. Used for
peripheral anaesthesia.
4. Spinal anaesthesia- It is injected into the sub-arachnoid space so that the local
anaesthetic mixes with the spinal fluid. Lower abdomen and hind limbs are paralysed.
Used for operation in lower limbs, pelvis, abdomen, prostatectomy, fracture setting,
obstetric procedures, caesarean surgery etc.
5. Epidural anaesthesia- It is injected into a narrow spinal dural space containing
semiliquid fat where the nerve roots pass.
Ideal characteristics of Local anaesthetics:
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1. Non-irritating to the tissue.
2. Doesn’t cause damage to the nerve structure.
3. Rapid onset & short duration of action.
4. Low systemic toxicity.
5. Must be effective whether injected or topically applied.
CLASSIFICATION
1. Benzoic acid esters- Cocaine, Hexylcaine, Meprylcaine, Cyclomethycaine,
Piperocaine
2. p-Aminobenzoic acid esters- Benzocaine, Butamben, Procaine, Butacaine,
Propoxycaine, Tetracaine, Benoxinate
3. Amide/Anilide derivatives- Lignocaine/Lidocaine/Xylocaine, Mepivacaine,
Prilocaine, Etidocaine
4. Miscellaneous agentsAmidine derivative- Phenacaine
Carbamate derivative- Diperodon
Quinoline derivative- Dibucaine
Cocaine- 2-methoxy carbonyl-tropan-3-yl-benzoate
It is a natural alkaloid, isolated from the leaves of Erythroxylon coca. It is the first drug to be
used as local anaesthetic.
Used as anaesthesia for eye, ear, nose & throat.
Hexylcaine- 1-cyclohexyl amino-propan-2-yl-benzoate
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Used as surface anaesthesia.
Meprylcaine- 2-methyl-2-(propylamino) propyl benzoate
O
O
H
N
CH3
H3C CH3
Used for dental anaesthesia.
Cyclomethycaine- 3-(2-methyl-1-piperidinyl) propyl-p-(cyclohexyloxy) benzoate
Used as topical anaesthesia.
Piperocaine- 3-(2-methyl-1-piperidinyl) propyl benzoate
Used as ocular anaesthesia.
Benzocaine- Ethyl-p-aminobenzoate
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O
O CH3
H2N
Used to reduce pain due to sunburn, teeth pain, piles, vaginal/rectal irritation.
SynthesisButamben- Butyl-p-aminobenzoate
O
O CH3
H2N
Used as surface anaesthesia for relief of pain and itching associated with anorectal disorders.
Procaine- Also called as novocaine.
2-(diethylamino) ethyl-p-amino benzoate
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Used as infiltration, nerve block and spinal anaesthesia. It is a vassodilator. So, adrenaline is
added to it to retard the absorption and prolong its duration of action.
SynthesisButacaine- 3-(dibutylamino) propyl-p-amino benzoate
Used as topical anaesthesia.
Propoxycaine- 2-(diethylamino)ethyl-2’-propoxy-4’-amino benzoate
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Used as dental anaesthesia.
Tetracaine- 2-(dimethylamino)ethyl-p-(butylamino) benzoate
Used as topical and spinal anaesthesia.
Benoxinate- Also called as oxybuprocaine.
2-(diethylamino)ethyl-3’-butoxy-4’-amino benzoate
Used in ophthalmology.
Lignocaine- Also called as Lidocaine or Xylocaine.
2-(diethylamino)-N-2,6-(dimethyl phenyl) acetamide
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Used as infiltration, nerve block and surface anaesthesia. Also used for dental anaesthesia.
Mepivacaine- 1-methyl-N-(2,6-dimethyl phenyl)piperidin-2-carboxamide
Used as epidural and nerve block anesthesia. Also used in dental procedures.
Prilocaine- N-(2-methyl phenyl)-2-propylamino propenamide
Used for infiltration, nerve block anaesthesia. A mixture of prilocaine and lignocaine
(eutectic mixture) is used as topical dosage form.
Etidocaine- N-(2,6-dimethyl phenyl)-2-(ethyl propyl amino)-butanamide
Used along with adrenaline for infiltration, epidural and nerve block anaesthesia.
Phenacaine- Also known as holocaine.
N,N’-bis(p-ethoxyphenyl)ethan imidamide
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Used in ophthalmology.
Diperodon- 3-(1-piperidinyl)-1,2-propandiol-bis-(phenyl carbamate)
Used as topical anaesthetic.
Dibucaine- Also known as Cinchocaine. It is the most potent, most toxic, longest acting local
anaesthetic.
N-(2-diethyl amino ethyl)-2-butoxy-quinolin-4-carboxamide

Dibucaine is used as surface anaesthetic on less delicate mucous membrane like anal canal.
Can be used parenterally for spinal anaesthesia only.
SAR OF LOCAL ANAESTHETICS
1. Ester derivativesDownloaded from HK Technical PGIMS (pgims.hktechnical.com)
i) Presence of electron withdrawing group at 2nd position of aryl moiety provides rapid onset
of action. Eg- Chloroprocaine has more rapid onset of action because it is 4 times faster
hydrolysed than procaine.
ii) Presence of non-polar groups on aromatic N atom imparts greater lipid solubility and good
absorption. Eg- Tetracaine
iii) Aryl group- It is attached directly to the carbonyl moiety.
 Conjugation of aromatic moiety with carbonyl group enhances local anaesthetic
activity.
 Substituents like amino, alkoxy, alkyl amino groups increase the electron density on
carbonyl oxygen and enhances the activity.
 Presence of alkyl group in between aryl and carbonyl results in inactive compounds.
iv) Bridge X- X may be C, O, N, or S
Anaesthetic potency: S > O > C > N
Amides (X=N) are resistant to metabolic hydrolysis.
v) Amino alkyl group- Tertiary amines have longer duration of action, but they are more
irritating than primary amines. Alkyl groups also influence the lipid solubility.
2. Amide derivativesDownloaded from HK Technical PGIMS (pgims.hktechnical.com)
These are essentially anilide derivatives having the general structure:
Aryl group- Phenyl group is attached to the sp2
‘C’ atom through nitrogen bridge.
Substitution of phenyl group with a methyl in 2 or 6 position enhances the activity. It
provides steric hindrance to hydrolysis and also increases the coefficient of distribution.
The amide bond is more stable to hydrolysis than esters.
Substituent X- X may be C (eg- isogramine), O (eg- lidocaine), N (eg- phenacaine)
Amino alkyl group- It is the hydrophilic part which helps in salt formation.
1° and 2° amines are more irritating than 3° amines.
References:
1. Wilson & Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry.
2. Text book of Medicinal Chemistry- S. N. Pandeya
3. William Foye’s Principles of Medicinal Chemistry.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)

BP501T MED CHEM UNIT-V Download Notes PDF BPharmacy 5th Semester 2022