e-content of analog design for M.pharm students

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ANALOG DESIGN
Presenting by:
Mr. PURUSHOTHAM K N
Assi.Professor of Ph. Chemistry
SACCP, B.G.Nagara
2021-2022

2. CONTENTS
 INTRODUCTION
 GOALS OF ANALOG DESIGN
 CATEGORIES OF ANALOGS
 STRATERGIES OF ANALOG DESIGN
 BIOISOSTERIC REPLACEMENT STRATERGIES
 TYPES OF BIOISOSTERS
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3. INTRODUCTION
ANALOG DESIGN:
 Modification of a drug molecule or of any bioactive compound in order to prepare a new
molecule showing chemical and biological similarity with the original model compound .
 The concept of analog design pre-supposes that a lead has been discovered that is a chemical
compound has been identified that possesses some desirable pharmacological property.
 It is most fruitful in the study of pharmacologically active molecules that are structurally
specific, their biological activity depends on the nature and the details of their chemical structure.
 It recognized that the newly created analog are chemical entities different from the lead
compound.
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4. GOALS OF ANALOG DESIGN
 To modify the chemical structure of the lead compound to retain or to reinforce the
desirable pharmacological effect while minimizing unwanted pharmacological and
physical and chemical properties which may result in a superior therapeutic agent.
 To use target analogs as pharmacological probes to gain better insight into the
pharmacology of the lead molecule and perhaps to reveal new knowledge of basic
biology .
 To predict optimum chemical structural parameter for a given pharmacological
action .
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5. CATEGORIES OF ANALOGS
A. Analog possessing chemical and pharmacological
similarities
B. Analog possessing only chemical similarities
C.Compounds chemically different but displaying similar
pharmacological properties
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6. STRATERGIES
1. Bioisosteric replacement
2. Design of rigid analogs
3. Homologation of alkyl chains
4. Alteration of stereochemistry
5. Design of fragments of the lead molecule that contain the pharmacophoric
group
6. Alteration of interatomic distances within the pharmacophoric group or in other
parts of the molecule.
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7. BIOISOSTERIC REPLACEMENT
 The concept of isosterism to modify biological activity has been rise to term Bioisosterism.
 Bioisosteric replacement are chemical substituents or groups with similar physical or chemical properties which
produce broadly similar biological properties to another chemical compound
OR
 Bioisosters are compounds or groups that essentially possess near equal molecular shapes and volumes ,
approximately the same distribution of electrons and that exhibit similar physical characteristics such as
hydrophobicity.
 Bioisosteric compounds affect the same biochemically associated system as agonist or antagonist and thereby
produce biological properties that are more or less related to each other.
 It reduce toxicity, change bioavailability or modify activity of the lead compound ,alter the metabolism of the
lead.
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8. Why bioisosteres ?
 Improved selectivity
 Fewer side effects
 Decreased toxicity
 Improved pharmacokinetics:solubility/hydrophobicity
 Increased metabolic stability
 Simplified synthetic routes
 Patented lead compounds
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9. CLASSIFICATION OF BIOISOSTERS
CLASSICAL BIOISOSTERS
Univalent bioisosters
Bivalent bioisosters
Trivalent bioisosters
Tetra-substituted atom
Ring equivalent
NON CLASSICABIOISOSTERS
Exchangeable groups
Cyclic v/s non cyclic
structure
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10. Classical bioisosters
 Classical bioisosters have similarities in shape and electronic configuration of atoms, groups and
molecules which they replace.
 It was originally formulated by James Moir and refined by Irving Langmuir as a response to the
observation that different atoms with the same valence electrons structure had similar biological
properties.
 Example :
Hydrogen replaced by Fluorine : Monovalent isosteric replacement
 Replacement of hydrogen atom with a fluorine atom at a site of metabolic oxidation in a drug
candidate may prevent such metabolic from taking place.
 Fluorine being the most electronegative element in the periodic table .Therefore, the augmentation in
the biological profile of drugs containing fluorine may be attributed to this specific characteristics.
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11.  Formation of an extremely therapeutically potent antineoplastic
 Longer half life because of blocked pathway for metabolism drug.
 F is most electronegative, H replacement with F alter the biological activity as fluorine exerts
strong field and inductive effects.
URACIL 5-FLUROURACIL
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12. 1. Univalent
Eg:
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13. 2. Bivalent
 This class includes replacement such as C=S,C=O,C=NH,C=C .
4-Thiouracil Uracil
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14. In local anaesthetics bioisosteric replacement of ester function in
procaine by amide function gives procainamide(useful anti-
arrhythmatic drug).
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15. 3. Tervalent
This class includes replacement of –N=.-CH=,-P=,-As=
Cholesterol Diazocholesterol
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16. 4. Quadrivalent /Tetra-substituted atoms
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17. 5. Ring equivalent
The use of benzene, thiopene and pyridine resulted in analogues with
retention of biological activity within different series of pharmacological
agents.
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19. NON CLASSICAL BIOISOSTERS
 Non classical bioisosters are structurally distinct usually comprised of different number of atoms and do not obey
the steric and electronic definition of classical isosters but it gives similar biological activity.
 It is dependent on the specific binding needs of the ligand in question.
 Substitute a linear functional group for a cyclic moiety, an alkyl group for a complex heteroatom moiety or other
changes atom for atom switch.
 Non classical bioisosters have one of the following characteristic features,
• Electronic properties
• Physicochemical properties
• Spatial arrangements
• Functional moiety critical for biological activity
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21. Exchangeble groups
1) Carbonyl group
2) Carboxylic acid group
3) Amide group
4) Hydroxy group
5) Catechol
6) Halogen
7) Thioether
8) Thiourea
9) Pyridine
10)Hydrogen
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22.  Carbonyl group
 Carboxylic group
2,6-Difluorophenol as a COOH mimetic
The introduction of fluorine atoms the 2- and 6- positions of phenol
increase the acidity, prompting the hypothesis that this functionality may
function as a lipophilic COOH mimetic
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24. 3.Amide bioisosters
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25. a
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29. REFERENCE
1. Textbook of Medicinal Chemistry vol 1 by Burger’s
2. Textbook of medicinal Chemistry by Ashutoshkar
3. Medicinal chemistry 1, P V textbook
4. Bioisosterism slideshare
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30. THANK YOU ;)
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