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SAR of Medicinal
Chemistry 1st
:- DARADE KRUSHNA KANIFNATH
Student of(A.k.c.o.b.pharmacy bodhegaon)
SAR :- Structure-Activity Relationship
•SAR is an approach designed to find relationships between the chemical structure (or structural-related
properties)
• of a molecule and its biological activity (or target property) of studied compounds.
•In other words, SAR helps us understand how changes in a molecule’s molecular structure can influence its
pharmacological effects.
Origin:
•The idea of SAR was first presented by Alexander Crum Brown and Thomas Richard Fraser as early as 1868.
•It establishes a link between a compound’s chemical composition and its physiological action.
Application:
•Medicinal chemists use SAR to:
•Determine the chemical group responsible for a specific biological effect.
•Modify the potency or effect of a bioactive compound (usually a drug) by altering its chemical structure.
•Build mathematical relationships known as Quantitative Structure-Activity Relationships (QSAR).
•QSAR models predict biological activity based on structural features and physicochemical properties.
Remember, understanding SAR is fundamental in drug discovery and plays a crucial role in optimizing drug design and development.
BY DARADE KRUSHNA 2
Structure Activity Relationship (SAR) = 9
• Structure Activity Relationship (SAR) = 9
• 1. SAR of Sympathomimetic agents
• 2. SAR of beta blockers
• 3. SAR of Parasympathomimetic agents
• 4. SAR of cholinolytic agents
• 5. SAR of Benzodiazepines
• 6. SAR of barbiturates
• 7. SAR of Phenothiazines
• 8. SAR of Anticonvulsants
• 9. SAR of Morphine analogues
BY DARADE KRUSHNA 3
1. SAR of Sympathomimetic agents
SAR of sympathomimetic agent was studied at 3 different position :-
1] Substitution at catechol ring
2] Substitution at ethylene linkage
3] Substitution at amino group
BY DARADE KRUSHNA 4
• 1. Phenylethylamine skeleton/ Catechol ring:The basic structure of
sympathomimetic agents consists of a phenylethylamine skeleton, which
includes a phenyl ring/ catechol ring and an ethylamine side chain.
• 2. Hydroxyl group:The presence of a hydroxyl group (-OH) on the phenyl ring
enhances activity. 3- hydroxy group essential for alpha activity or at 4- hydroxy
for beta activity.
• 3. Amino group:The presence of an amino group (-NH2) in the side chain is
essential for activity. Primary and secondary amine have good adrenergic
activity.
• 4.Ethylene linkage
• Alpha-carbon:The presence of a substituent on the alpha-carbon (the carbon
atom next to the amino group) increases potency. Substitution of alkyl group
decrease the metabolism.
• Beta-phenyl group:The presence of a phenyl group on the beta-carbon (the
carbon atom next to the alpha-carbon) increases potency. Ethyl group increases
the bulkiness and decrease activity.
BY DARADE KRUSHNA 5
• Examples of sympathomimetic agents and their SAR:-
• Epinephrine (Adrenaline):The most potent sympathomimetic agent, with a
hydroxyl group on the phenyl ring and a methyl group on the alpha-carbon.
• -Norepinephrine (Noradrenaline): Less potent than epinephrine, with a
hydroxyl group on the phenyl ring but no methyl group on the alpha-carbon.
• -Isoproterenol: A synthetic sympathomimetic agent with a hydroxyl group
on the phenyl ring and a isopropyl group on the alpha-carbon, making it
more potent than norepinephrine.
• -Phenylephrine: A synthetic sympathomimetic agent with a hydroxyl group
on the phenyl ring but no substituent on the alpha-carbon, making it less
potent than epinephrine.
BY DARADE KRUSHNA 6
➢ 2. SAR of beta blockers
• Beta - blockers are among the most widely
employed antihypertensive and are also
considered the first line treatment for glaucoma.
• Most of the B-blockers are in the chemical class of
aryloxypropanolamines.The first B- blocker,
dichloroisoproterenol was reported in 1958.
• Thus drug inhibits the action of catecholamine at
the beta receptor competitively.
• *
SAR:
1. Lengthening of side chain prevent appropriate binding of
required functional group to same receptor site.
2. Propranolol is the most lipophilic drug among the available
B-blockers.
BY DARADE KRUSHNA 7
• (1) Phenolic OH groups are important for adrenergic agonist activity. Removal of
the 4-OH leaves intact only alpha agonist activity, (e.g.,
phenylephrine,methoxamine - both vasoconstrictors used in treating hypotension
and nasal congestion),
• whereas removal of the 3-OH group abolishes both a- and ẞ-agonist activity.The 3-
OH group can, however, be replaced by a SO₂NH ₂ (soterenol) or a OHCH₃-
(salbutamol) group.
• 3-amino compounds can be extremely potent. Replacement of 4-OH group by any
such groups leads to an almost total loss of activity and compound may become an
antagonist.
• (2)The two-carbon side-chain is essential for activity.The benzylic carbon (next to
the ring) must have (R) absolute configuration.
• (3)The alcoholic OH can be replaced only by an amino or - CH₂OH group.
• (4) Small (-H, CH₂) N-substituents produce a-activity; larger ones [-CH-(CH): aryl]
produce ẞ-activity.
BY DARADE KRUSHNA 8
• Examples of beta blockers and their SAR:-
• Propranolol:A non-selective beta blocker with a hydroxyl group on the
beta-carbon and a naphthyl group on the aryl ring.
• - Metoprolol: A selective beta-1 blocker with a hydroxyl group on the beta-
carbon and a para-substituted phenyl ring.
• - Atenolol: A selective beta-1 blocker with a hydroxyl group on the beta-
carbon and a para-substituted phenyl ring.
• - Nebivolol: A selective beta-1 blocker with a hydroxyl group on the beta-
carbon and a para-substituted phenyl ring.
BY DARADE KRUSHNA 9
3. SAR of Parasympathomimetic agents
• Basic skeleton:The basic structure of parasympathomimetics consists of a nitrogen-containing ring (e.g.,
pyrrolidine, piperidine, or hexamethylene imine) attached to an acetyl or carbamyl group.
• 1. Quaternary ammonium group:The presence of a quaternary ammonium group (e.g., -N(CH₃)₃+) is
essential for activity, as it enhances binding to the muscarinic receptor. Sustitution of larger alkyl group
decrease activity.
• 2. Acetyl or carbamyl group:The presence of an acetyl (CH₃CO-) or carbamyl (-CONH₂) group attached to
the nitrogen-containing ring is essential for activity.
• 3.substitution at ethylene :-alpha substitution decrease the Muscarinic activity and beta will be both.
BY DARADE KRUSHNA 10
• Examples of parasympathomimetics and their SAR:-
• - Acetylcholine:The natural neurotransmitter, with a quaternary ammonium
group and an acetyl group.
• - Carbachol: A synthetic parasympathomimetic with a quaternary
ammonium group and a carbamyl group.
• - Bethanechol: A synthetic parasympathomimetic with a quaternary
ammonium group and a carbamyl group.
• - Pilocarpine: A natural product with a quaternary ammonium group and a
carbamyl group.
BY DARADE KRUSHNA 11
4. SAR of cholinolytic agents
I. Basic skeleton:The basic structure of cholinolytics consists of a nitrogen-containing ring (e.g., pyrrolidine,
piperidine, or hexamethylene imine) Tertiary amine (e.g., -N(CH₃)₂) attached to Lipophilic group (e.g., -
CH₂CH₂CH₃)
II. Solanaceous alkaloids and analogues- SAR: - Basic skeleton:Tropane or solanidine
synthetic cholinergic blocking agents- SAR: - Basic skeleton:Various (e.g., tropic acid, cyclopentane.
III. Tertiary amine:The presence of a tertiary amine (e.g., -N(CH₃)₂) is essential for activity, as it enhances binding
to the muscarinic receptor.
IV. Lipophilic group:The presence of a lipophilic group (e.g., -CH₂CH₂CH₃) attached to the nitrogen-containing
ring is essential for activity.
BY DARADE KRUSHNA 12
• The R1 or R2 groups must be carbocyclic or heterocyclic.
• The R3 group can be hydrogen, hydroxyl (-OH), hydroxymethyl (-CH2OH),
amide.
• The X is mostly Ester in most potent derivatives but it can be a ether oxygen
or absent completely.
• The N substituent can be both quaternary ammonium salt or tertiary amine
with different alkyl groups.
• The distance between the ring substituted carbon and nitrogen is not fixed
but maximum potency requires about 2 carbon units.
BY DARADE KRUSHNA 13
• Examples of cholinolytics and their SAR:
• - Atropine: A natural product with a tertiary amine and a lipophilic group.
• - Scopolamine: A natural product with a tertiary amine and a lipophilic
group.
• - Glycopyrrolate: A synthetic cholinolytic with a tertiary amine and a
lipophilic group.
• -Tiotropium: A synthetic cholinolytic with a tertiary amine and a lipophilic
group.
BY DARADE KRUSHNA 14
5. SAR of Benzodiazepines
• All benzodiazepines have a benzene ring attached to a diazepine ring.
• 1. Benzene ring:The presence of a benzene ring is essential for activity.
• 2. Diazepine ring:The presence of a diazepine ring (a seven-membered ring with two nitrogen atoms) is
essential for activity.
• 3. 5-aryl substituent:The presence of an aryl group (e.g., phenyl or chlorophenyl) at the 5-position of the
diazepine ring is essential for activity.
• 4. 1-methyl substituent:The presence of a methyl group at the 1-position of the diazepine ring can
increase potency.
• 5. 2-keto substituent:The presence of a keto group at the 2-position of the diazepine ring can increase
potency.
• 6. 4-substituent:The presence of a substituent (e.g., chloro or methyl) at the 4-position of the benzene
ring can increase potency.
BY DARADE KRUSHNA 15
• Examples of benzodiazepines and their SAR:
• - Diazepam (Valium): A classic benzodiazepine with a 5-phenyl substituent and a 1-methyl substituent.
• - Alprazolam (Xanax): A benzodiazepine with a 5-chlorophenyl substituent and a 1-methyl substituent.
• - Lorazepam (Ativan): A benzodiazepine with a 5-chlorophenyl substituent and a 2-keto substituent.
• - Clonazepam (Klonopin): A benzodiazepine with a 5-nitrophenyl substituent and a 1-methyl
substituent.
compound R1 R2 R3 R4
Diazepam CH3 H H Cl
Oxazopam H H OH Cl
Lorazepam H =O OH Cl
Clonazepam H =O Cl NO2
BY DARADE KRUSHNA 16
6. SAR of barbiturates
• 1. Barbituric acid skeleton:The presence of a barbituric acid skeleton (a six-membered ring with two
nitrogen atoms and a carbonyl group) is essential for activity.
• 2. 5,5-disubstitution:The presence of two substituents (e.g., methyl or ethyl groups) at the 5-position of
the barbituric acid skeleton is essential for activity.
• 3. 1,3-dimethyl substitution:The presence of methyl groups at the 1- and 3-positions of the barbituric
acid skeleton can increase potency.
• 4. 2-thio substitution:The presence of a sulfur atom at the 2-position of the barbituric acid skeleton can
increase potency.
• 5. Phenyl or aryl substitution:The presence of a phenyl or aryl group at the 5-position of the barbituric
acid skeleton can increase potency.
BY DARADE KRUSHNA 17
• Examples of barbiturates and their SAR:-
• - Phenobarbital: A classic barbiturate with 5,5-dimethyl substitution and a phenyl group at the 5-position.
• - Pentobarbital: A barbiturate with 5,5-diethyl substitution and a phenyl group at the 5-position.
• -Thiopental: A barbiturate with 5,5-dimethyl substitution, a 2-thio group, and a phenyl group at the 5-position.
• - Secobarbital: A barbiturate with 5,5-dimethyl substitution and a sec-butyl group at the 5-position.
compound R1 R2 R3 R4
Barbital H H C2H5 -C2H5
Amobarbital H H CH2CH2CH(CH3)2 -C2H5
Butabarbital H H C2H5 CH3CHCH2CH3
Pentobarbital H H C2H5 CH3CHCH2CH2CH3
Secobarbital H H -CH2CH=CH2 CH3CHCH2CH2CH3
BY DARADE KRUSHNA 18
7. SAR of Phenothiazines
• 1. Phenothiazine skeleton:The presence of a phenothiazine skeleton (a tricyclic ring with a sulfur and
nitrogen atom) is essential for activity.
• 2. Amino group:The presence of an amino group (-NH2) at the 10-position of the phenothiazine skeleton is
essential for activity.
• 3. Alkyl substitution:The presence of alkyl groups (e.g., methyl or ethyl) at the 1- and 3-positions of the
phenothiazine skeleton can increase potency.
• 4. Halogen substitution:The presence of halogen atoms (e.g., chlorine or fluorine) at the 2- and 8-positions
of the phenothiazine skeleton can increase potency.
• 5. Piperazine substitution:The presence of a piperazine ring at the 10-position of the phenothiazine
skeleton can increase potency.
BY DARADE KRUSHNA 19
• Examples of phenothiazines and their SAR:-
• -Chlorpromazine:A classic phenothiazine with an amino group, methyl groups at the 1- and
3-positions, and a chlorine atom at the 2-position.
• -Thioridazine:A phenothiazine with an amino group, methyl groups at the 1- and 3-
positions, and a sulfur atom at the 2-position.
• - Fluphenazine:A phenothiazine with an amino group, methyl groups at the 1- and 3-
positions, and a fluorine atom at the 2-position.
• - Perphenazine:A phenothiazine with an amino group, methyl groups at the 1- and 3-
positions, and a piperazine ring at the 10-position.
Name R1( 10th position ) R2( at 2nd position )
Chloropromazine -(CH2)3N(CH3)2 CL
Triflupromazine -(CH2)3N(CH3)2 CF3
Thioridazine SCH3
trifluperazine CF3
BY DARADE KRUSHNA 20
8.SAR of Anticonvulsants • Succinimides-
• SAR: 2,4-disubstitution- Mechanism: Inhibit GABA
transaminase, block sodium channels- Examples:
Phensuximide, Methsuximide
• Urea and monoacylureas-
• SAR: N-substitution- Mechanism: Inhibit glutamate
release, block sodium channels- Examples:
Phenacemide, Carbamazepine
• Benzodiazepines- [slide no. 14 seen]
• SAR: 1,4-substitution- Mechanism: Enhance GABA
activity, block sodium channels- Example: Clonazepam
• Miscellaneous-
• Levetiracetam: Inhibit glutamate release, block sodium
channels-Valproic acid: Inhibit GABA transaminase,
block sodium channels- Gabapentin: Inhibit glutamate
release, block sodium channels- Felbamate: Inhibit
glutamate release, block sodium channels
• Barbiturates- [slide no.16 seen]
• SAR: 5,5-disubstitution, 1,3-dimethyl substitution-
Mechanism: Enhance GABA activity, block sodium
channels- Examples: Phenobarbitone, Mephobarbital
• Hydantoins-
• SAR: 5,5-disubstitution, 1,3-dimethyl substitution-
Mechanism: Block sodium channels, inhibit glutamate
release- Examples: Phenytoin, Mephenytoin
• Oxazolidinediones-
• SAR: 2,4-disubstitution- Mechanism: Inhibit glutamate
release, block sodium channels-
• Example:Trimethadione.
BY DARADE KRUSHNA 21
9.SAR of Morphine analogues
• 1. Morphinan skeleton:The presence of a morphinan skeleton (a pentacyclic ring with a nitrogen atom)
is essential for activity.
• 2. Phenolic hydroxyl group:The presence of a phenolic hydroxyl group at the 3-position of the
morphinan skeleton is essential for activity.
• 3. Alcoholic hydroxyl group:The presence of an alcoholic hydroxyl group at the 6-position of the
morphinan skeleton is essential for activity.
• 4. N-methyl group:The presence of an N-methyl group at the 17-position of the morphinan skeleton can
increase potency.
• 5. C-ring substitution:The presence of a substituent (e.g., methyl or ethyl) at the 7-position of the
morphinan skeleton can increase potency.
BY DARADE KRUSHNA 22
• Examples of morphine analogues and their SAR:
• - Morphine:The natural product with a phenolic hydroxyl group, an alcoholic
hydroxyl group, and an N-methyl group.
• - Codeine: A methylated derivative of morphine with increased potency.
• - Heroin: A diacetylated derivative of morphine with increased potency and
addiction potential.
• - Hydromorphone:A hydrogenated derivative of morphine with increased
potency.
• - Oxymorphone:A hydrogenated derivative of morphine with increased
potency and a hydroxyl group at the 14-position.
BY DARADE KRUSHNA 23
Reference:-
➢David-a-williams-phd-essentials-of-foye-s-principles-of-medicinal-
chemistry-2016
➢Principle of medicinal chemistry by dr.s.s.kadam, dr.k.r.mahadik,
dr.k.g.bothara volume 2nd by Nirali prakashan
➢Google.com
➢Wikipedia.com
BY DARADE KRUSHNA 24

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SAR of Medicinal Chemistry 1st by dk.pdf

  • 1. SAR of Medicinal Chemistry 1st :- DARADE KRUSHNA KANIFNATH Student of(A.k.c.o.b.pharmacy bodhegaon)
  • 2. SAR :- Structure-Activity Relationship •SAR is an approach designed to find relationships between the chemical structure (or structural-related properties) • of a molecule and its biological activity (or target property) of studied compounds. •In other words, SAR helps us understand how changes in a molecule’s molecular structure can influence its pharmacological effects. Origin: •The idea of SAR was first presented by Alexander Crum Brown and Thomas Richard Fraser as early as 1868. •It establishes a link between a compound’s chemical composition and its physiological action. Application: •Medicinal chemists use SAR to: •Determine the chemical group responsible for a specific biological effect. •Modify the potency or effect of a bioactive compound (usually a drug) by altering its chemical structure. •Build mathematical relationships known as Quantitative Structure-Activity Relationships (QSAR). •QSAR models predict biological activity based on structural features and physicochemical properties. Remember, understanding SAR is fundamental in drug discovery and plays a crucial role in optimizing drug design and development. BY DARADE KRUSHNA 2
  • 3. Structure Activity Relationship (SAR) = 9 • Structure Activity Relationship (SAR) = 9 • 1. SAR of Sympathomimetic agents • 2. SAR of beta blockers • 3. SAR of Parasympathomimetic agents • 4. SAR of cholinolytic agents • 5. SAR of Benzodiazepines • 6. SAR of barbiturates • 7. SAR of Phenothiazines • 8. SAR of Anticonvulsants • 9. SAR of Morphine analogues BY DARADE KRUSHNA 3
  • 4. 1. SAR of Sympathomimetic agents SAR of sympathomimetic agent was studied at 3 different position :- 1] Substitution at catechol ring 2] Substitution at ethylene linkage 3] Substitution at amino group BY DARADE KRUSHNA 4
  • 5. • 1. Phenylethylamine skeleton/ Catechol ring:The basic structure of sympathomimetic agents consists of a phenylethylamine skeleton, which includes a phenyl ring/ catechol ring and an ethylamine side chain. • 2. Hydroxyl group:The presence of a hydroxyl group (-OH) on the phenyl ring enhances activity. 3- hydroxy group essential for alpha activity or at 4- hydroxy for beta activity. • 3. Amino group:The presence of an amino group (-NH2) in the side chain is essential for activity. Primary and secondary amine have good adrenergic activity. • 4.Ethylene linkage • Alpha-carbon:The presence of a substituent on the alpha-carbon (the carbon atom next to the amino group) increases potency. Substitution of alkyl group decrease the metabolism. • Beta-phenyl group:The presence of a phenyl group on the beta-carbon (the carbon atom next to the alpha-carbon) increases potency. Ethyl group increases the bulkiness and decrease activity. BY DARADE KRUSHNA 5
  • 6. • Examples of sympathomimetic agents and their SAR:- • Epinephrine (Adrenaline):The most potent sympathomimetic agent, with a hydroxyl group on the phenyl ring and a methyl group on the alpha-carbon. • -Norepinephrine (Noradrenaline): Less potent than epinephrine, with a hydroxyl group on the phenyl ring but no methyl group on the alpha-carbon. • -Isoproterenol: A synthetic sympathomimetic agent with a hydroxyl group on the phenyl ring and a isopropyl group on the alpha-carbon, making it more potent than norepinephrine. • -Phenylephrine: A synthetic sympathomimetic agent with a hydroxyl group on the phenyl ring but no substituent on the alpha-carbon, making it less potent than epinephrine. BY DARADE KRUSHNA 6
  • 7. ➢ 2. SAR of beta blockers • Beta - blockers are among the most widely employed antihypertensive and are also considered the first line treatment for glaucoma. • Most of the B-blockers are in the chemical class of aryloxypropanolamines.The first B- blocker, dichloroisoproterenol was reported in 1958. • Thus drug inhibits the action of catecholamine at the beta receptor competitively. • * SAR: 1. Lengthening of side chain prevent appropriate binding of required functional group to same receptor site. 2. Propranolol is the most lipophilic drug among the available B-blockers. BY DARADE KRUSHNA 7
  • 8. • (1) Phenolic OH groups are important for adrenergic agonist activity. Removal of the 4-OH leaves intact only alpha agonist activity, (e.g., phenylephrine,methoxamine - both vasoconstrictors used in treating hypotension and nasal congestion), • whereas removal of the 3-OH group abolishes both a- and ẞ-agonist activity.The 3- OH group can, however, be replaced by a SO₂NH ₂ (soterenol) or a OHCH₃- (salbutamol) group. • 3-amino compounds can be extremely potent. Replacement of 4-OH group by any such groups leads to an almost total loss of activity and compound may become an antagonist. • (2)The two-carbon side-chain is essential for activity.The benzylic carbon (next to the ring) must have (R) absolute configuration. • (3)The alcoholic OH can be replaced only by an amino or - CH₂OH group. • (4) Small (-H, CH₂) N-substituents produce a-activity; larger ones [-CH-(CH): aryl] produce ẞ-activity. BY DARADE KRUSHNA 8
  • 9. • Examples of beta blockers and their SAR:- • Propranolol:A non-selective beta blocker with a hydroxyl group on the beta-carbon and a naphthyl group on the aryl ring. • - Metoprolol: A selective beta-1 blocker with a hydroxyl group on the beta- carbon and a para-substituted phenyl ring. • - Atenolol: A selective beta-1 blocker with a hydroxyl group on the beta- carbon and a para-substituted phenyl ring. • - Nebivolol: A selective beta-1 blocker with a hydroxyl group on the beta- carbon and a para-substituted phenyl ring. BY DARADE KRUSHNA 9
  • 10. 3. SAR of Parasympathomimetic agents • Basic skeleton:The basic structure of parasympathomimetics consists of a nitrogen-containing ring (e.g., pyrrolidine, piperidine, or hexamethylene imine) attached to an acetyl or carbamyl group. • 1. Quaternary ammonium group:The presence of a quaternary ammonium group (e.g., -N(CH₃)₃+) is essential for activity, as it enhances binding to the muscarinic receptor. Sustitution of larger alkyl group decrease activity. • 2. Acetyl or carbamyl group:The presence of an acetyl (CH₃CO-) or carbamyl (-CONH₂) group attached to the nitrogen-containing ring is essential for activity. • 3.substitution at ethylene :-alpha substitution decrease the Muscarinic activity and beta will be both. BY DARADE KRUSHNA 10
  • 11. • Examples of parasympathomimetics and their SAR:- • - Acetylcholine:The natural neurotransmitter, with a quaternary ammonium group and an acetyl group. • - Carbachol: A synthetic parasympathomimetic with a quaternary ammonium group and a carbamyl group. • - Bethanechol: A synthetic parasympathomimetic with a quaternary ammonium group and a carbamyl group. • - Pilocarpine: A natural product with a quaternary ammonium group and a carbamyl group. BY DARADE KRUSHNA 11
  • 12. 4. SAR of cholinolytic agents I. Basic skeleton:The basic structure of cholinolytics consists of a nitrogen-containing ring (e.g., pyrrolidine, piperidine, or hexamethylene imine) Tertiary amine (e.g., -N(CH₃)₂) attached to Lipophilic group (e.g., - CH₂CH₂CH₃) II. Solanaceous alkaloids and analogues- SAR: - Basic skeleton:Tropane or solanidine synthetic cholinergic blocking agents- SAR: - Basic skeleton:Various (e.g., tropic acid, cyclopentane. III. Tertiary amine:The presence of a tertiary amine (e.g., -N(CH₃)₂) is essential for activity, as it enhances binding to the muscarinic receptor. IV. Lipophilic group:The presence of a lipophilic group (e.g., -CH₂CH₂CH₃) attached to the nitrogen-containing ring is essential for activity. BY DARADE KRUSHNA 12
  • 13. • The R1 or R2 groups must be carbocyclic or heterocyclic. • The R3 group can be hydrogen, hydroxyl (-OH), hydroxymethyl (-CH2OH), amide. • The X is mostly Ester in most potent derivatives but it can be a ether oxygen or absent completely. • The N substituent can be both quaternary ammonium salt or tertiary amine with different alkyl groups. • The distance between the ring substituted carbon and nitrogen is not fixed but maximum potency requires about 2 carbon units. BY DARADE KRUSHNA 13
  • 14. • Examples of cholinolytics and their SAR: • - Atropine: A natural product with a tertiary amine and a lipophilic group. • - Scopolamine: A natural product with a tertiary amine and a lipophilic group. • - Glycopyrrolate: A synthetic cholinolytic with a tertiary amine and a lipophilic group. • -Tiotropium: A synthetic cholinolytic with a tertiary amine and a lipophilic group. BY DARADE KRUSHNA 14
  • 15. 5. SAR of Benzodiazepines • All benzodiazepines have a benzene ring attached to a diazepine ring. • 1. Benzene ring:The presence of a benzene ring is essential for activity. • 2. Diazepine ring:The presence of a diazepine ring (a seven-membered ring with two nitrogen atoms) is essential for activity. • 3. 5-aryl substituent:The presence of an aryl group (e.g., phenyl or chlorophenyl) at the 5-position of the diazepine ring is essential for activity. • 4. 1-methyl substituent:The presence of a methyl group at the 1-position of the diazepine ring can increase potency. • 5. 2-keto substituent:The presence of a keto group at the 2-position of the diazepine ring can increase potency. • 6. 4-substituent:The presence of a substituent (e.g., chloro or methyl) at the 4-position of the benzene ring can increase potency. BY DARADE KRUSHNA 15
  • 16. • Examples of benzodiazepines and their SAR: • - Diazepam (Valium): A classic benzodiazepine with a 5-phenyl substituent and a 1-methyl substituent. • - Alprazolam (Xanax): A benzodiazepine with a 5-chlorophenyl substituent and a 1-methyl substituent. • - Lorazepam (Ativan): A benzodiazepine with a 5-chlorophenyl substituent and a 2-keto substituent. • - Clonazepam (Klonopin): A benzodiazepine with a 5-nitrophenyl substituent and a 1-methyl substituent. compound R1 R2 R3 R4 Diazepam CH3 H H Cl Oxazopam H H OH Cl Lorazepam H =O OH Cl Clonazepam H =O Cl NO2 BY DARADE KRUSHNA 16
  • 17. 6. SAR of barbiturates • 1. Barbituric acid skeleton:The presence of a barbituric acid skeleton (a six-membered ring with two nitrogen atoms and a carbonyl group) is essential for activity. • 2. 5,5-disubstitution:The presence of two substituents (e.g., methyl or ethyl groups) at the 5-position of the barbituric acid skeleton is essential for activity. • 3. 1,3-dimethyl substitution:The presence of methyl groups at the 1- and 3-positions of the barbituric acid skeleton can increase potency. • 4. 2-thio substitution:The presence of a sulfur atom at the 2-position of the barbituric acid skeleton can increase potency. • 5. Phenyl or aryl substitution:The presence of a phenyl or aryl group at the 5-position of the barbituric acid skeleton can increase potency. BY DARADE KRUSHNA 17
  • 18. • Examples of barbiturates and their SAR:- • - Phenobarbital: A classic barbiturate with 5,5-dimethyl substitution and a phenyl group at the 5-position. • - Pentobarbital: A barbiturate with 5,5-diethyl substitution and a phenyl group at the 5-position. • -Thiopental: A barbiturate with 5,5-dimethyl substitution, a 2-thio group, and a phenyl group at the 5-position. • - Secobarbital: A barbiturate with 5,5-dimethyl substitution and a sec-butyl group at the 5-position. compound R1 R2 R3 R4 Barbital H H C2H5 -C2H5 Amobarbital H H CH2CH2CH(CH3)2 -C2H5 Butabarbital H H C2H5 CH3CHCH2CH3 Pentobarbital H H C2H5 CH3CHCH2CH2CH3 Secobarbital H H -CH2CH=CH2 CH3CHCH2CH2CH3 BY DARADE KRUSHNA 18
  • 19. 7. SAR of Phenothiazines • 1. Phenothiazine skeleton:The presence of a phenothiazine skeleton (a tricyclic ring with a sulfur and nitrogen atom) is essential for activity. • 2. Amino group:The presence of an amino group (-NH2) at the 10-position of the phenothiazine skeleton is essential for activity. • 3. Alkyl substitution:The presence of alkyl groups (e.g., methyl or ethyl) at the 1- and 3-positions of the phenothiazine skeleton can increase potency. • 4. Halogen substitution:The presence of halogen atoms (e.g., chlorine or fluorine) at the 2- and 8-positions of the phenothiazine skeleton can increase potency. • 5. Piperazine substitution:The presence of a piperazine ring at the 10-position of the phenothiazine skeleton can increase potency. BY DARADE KRUSHNA 19
  • 20. • Examples of phenothiazines and their SAR:- • -Chlorpromazine:A classic phenothiazine with an amino group, methyl groups at the 1- and 3-positions, and a chlorine atom at the 2-position. • -Thioridazine:A phenothiazine with an amino group, methyl groups at the 1- and 3- positions, and a sulfur atom at the 2-position. • - Fluphenazine:A phenothiazine with an amino group, methyl groups at the 1- and 3- positions, and a fluorine atom at the 2-position. • - Perphenazine:A phenothiazine with an amino group, methyl groups at the 1- and 3- positions, and a piperazine ring at the 10-position. Name R1( 10th position ) R2( at 2nd position ) Chloropromazine -(CH2)3N(CH3)2 CL Triflupromazine -(CH2)3N(CH3)2 CF3 Thioridazine SCH3 trifluperazine CF3 BY DARADE KRUSHNA 20
  • 21. 8.SAR of Anticonvulsants • Succinimides- • SAR: 2,4-disubstitution- Mechanism: Inhibit GABA transaminase, block sodium channels- Examples: Phensuximide, Methsuximide • Urea and monoacylureas- • SAR: N-substitution- Mechanism: Inhibit glutamate release, block sodium channels- Examples: Phenacemide, Carbamazepine • Benzodiazepines- [slide no. 14 seen] • SAR: 1,4-substitution- Mechanism: Enhance GABA activity, block sodium channels- Example: Clonazepam • Miscellaneous- • Levetiracetam: Inhibit glutamate release, block sodium channels-Valproic acid: Inhibit GABA transaminase, block sodium channels- Gabapentin: Inhibit glutamate release, block sodium channels- Felbamate: Inhibit glutamate release, block sodium channels • Barbiturates- [slide no.16 seen] • SAR: 5,5-disubstitution, 1,3-dimethyl substitution- Mechanism: Enhance GABA activity, block sodium channels- Examples: Phenobarbitone, Mephobarbital • Hydantoins- • SAR: 5,5-disubstitution, 1,3-dimethyl substitution- Mechanism: Block sodium channels, inhibit glutamate release- Examples: Phenytoin, Mephenytoin • Oxazolidinediones- • SAR: 2,4-disubstitution- Mechanism: Inhibit glutamate release, block sodium channels- • Example:Trimethadione. BY DARADE KRUSHNA 21
  • 22. 9.SAR of Morphine analogues • 1. Morphinan skeleton:The presence of a morphinan skeleton (a pentacyclic ring with a nitrogen atom) is essential for activity. • 2. Phenolic hydroxyl group:The presence of a phenolic hydroxyl group at the 3-position of the morphinan skeleton is essential for activity. • 3. Alcoholic hydroxyl group:The presence of an alcoholic hydroxyl group at the 6-position of the morphinan skeleton is essential for activity. • 4. N-methyl group:The presence of an N-methyl group at the 17-position of the morphinan skeleton can increase potency. • 5. C-ring substitution:The presence of a substituent (e.g., methyl or ethyl) at the 7-position of the morphinan skeleton can increase potency. BY DARADE KRUSHNA 22
  • 23. • Examples of morphine analogues and their SAR: • - Morphine:The natural product with a phenolic hydroxyl group, an alcoholic hydroxyl group, and an N-methyl group. • - Codeine: A methylated derivative of morphine with increased potency. • - Heroin: A diacetylated derivative of morphine with increased potency and addiction potential. • - Hydromorphone:A hydrogenated derivative of morphine with increased potency. • - Oxymorphone:A hydrogenated derivative of morphine with increased potency and a hydroxyl group at the 14-position. BY DARADE KRUSHNA 23
  • 24. Reference:- ➢David-a-williams-phd-essentials-of-foye-s-principles-of-medicinal- chemistry-2016 ➢Principle of medicinal chemistry by dr.s.s.kadam, dr.k.r.mahadik, dr.k.g.bothara volume 2nd by Nirali prakashan ➢Google.com ➢Wikipedia.com BY DARADE KRUSHNA 24