This document discusses prodrugs, which are pharmacologically inactive derivatives of active drugs that are designed to improve drug properties like solubility, absorption, and site-specific delivery. Prodrugs are converted to the active drug within the body through enzymatic or non-enzymatic reactions. The document classifies prodrugs according to their functional groups and provides examples like ester prodrugs that are hydrolyzed by esterases. It also discusses the pharmaceutical applications of prodrug design like improving patient acceptance, increasing solubility and absorption, targeting specific sites, and providing slow and prolonged drug release.

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PRODRUGS
KRISHNAPRIYA K R
M.PHARM 2nd SEM
PHERMACEUTICAL CHEMISTRY

2. INDEX
• Introduction
• Classification According to Functional Groups
• Pharmaceutical applications of prodrug design
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3. Introduction
• Prodrugs are pharmacologically inactive derivatives of active drugs.
• These are designed to maximize the amount of active drug that reaches its site of
action, through manipulation of physicochemical, biopharmaceutical and
pharmacokinetic properties of drug.
• They are converted into active drug within the body through enzymatic or non
enzymatic reactions. Also called drug latentiation.
• Basic concept of Prodrugs is to improve patient acceptability, Drug solubility, Drug
absorption and distribution, site specific drug delivery and sustained drug action.
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4. Classification According to Functional Groups
1. Carboxylic acids and alcohols-Ester
 Agents that contain carboxylic acid or alcohol functional groups can be prepared by
conversion to an ester.
 Most common type of prodrugs because esters can easily be hydrolysed to give the
active drug.
 Hydrolysis is carried out by esterase enzymes such as Ester hydrolase, Lipase,
Cholesterol esterase, Acetylcholine esterase etc.
Eg : Dipivefrin HCl is a prodrug of epinephrine
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5. NH
CH3
OH
O
O
CH3
C
H3
C
H3
O
O
C
H3
CH3
C
H3
NH
CH3
OH
O
H
O
H
OH
O
CH3
C
H3
CH3
Esterase
2
+Cl-
2
+Cl-
+ 2
Dipivefrin Hcl
Epinephrine Pivalinic acid
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6. 2. Azo Linkage
 Amines may be incorporated into an azo linkage to produce a prodrug.
• Eg : Sulfasalazine the linkage is broken in the guts by azo reductase enzymes
produced by microflora. Releases amino salicylic acid.
• Generation of amino salicylic acid prior to absorption, prevents the systemic
absorption and helps to concentrate the active agent at its site of action.
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7. O
H
O
OH
N
N S
O
O
NH
N
O
H
O
OH
NH2
N
H2 S
O
O
NH
N
Salfasalazine
Amino salicylic acid Sulfa pyridine
+
azo reductase
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8. 3. Amides
 Derivatization of amines to give amides is not widely used because of the high
chemical stability of amide linkage and lack of amidase enzymes.
• Eg. Use Mannich base as a prodrug form of amines.
• The effect of Mannich base is to lower the basicity of amines and there by increasing
lipophilicity and absorption.
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9. N
N
N
H
CH3
C
H3
O O
S
CH3
CH3
O
O
H
N
NH
NH2
O O
S
CH3
CH3
O
O
H
C
H3
CH3
O
Hetacillin
H2O
Ampicillin Acetone
+
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10. APPLICTIONS OF PRODRUG DESIGN
1. PRODRUGS TO IMPROVE PATIENT ACCEPTENCE
 Improvement of taste
• Esterification with long chain fatty acids makes the drug less water soluble, resulting
into non bitter taste.
• Eg: Chloramphenicol has a bitter taste but its palmitate ester has non bitter taste.
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11. N
O
O
CH
CH3
CH
NH
C O
CH3
CH2 O C
O
CH2 CH3
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N
O
O
CH
CH3
CH
NH
C O
C
H
CH2 OH
Cl
Cl
Lipase
Chloramphenicol palmitate Chloramphenicol
Parent drug Drug with improved taste
Chloramphenicol Palmitate ester
Clindamycin Palmitate ester
Sulfisoxazole Diacetate ester
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12.  Improvement of odour
• The odor of the compound depends upon its vapor pressure.
• Eg: ethyl mercaptan is a foul smelling liquid of boiling point 35° C. It is converted
into its phthalate ester, diethyldithio-isophthalate ester which is odorless and has
higher boiling point.
O S
CH3
S
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
CH3
O C
H3
CH2
SH
Thioesterase
Diethyldithio-isophthalate Ethyl mercaptan
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13.  Reduction of pain on injection
• Drug precipitates or penetrates into the surrounding tissues.
• The solution is strongly acidic, alkaline or alcoholic.
Clindamycin-2’-phosphate ester Clindamycin
Phosphatase
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14. 2. PRODRUGS FOR INCREASED WATER SOLUBILITY
 The hydrophilic characteristic of a drug can be improved by the formation of hemi-
succinates, hemi-glutarates, hemi-phthalates, or meta-sulpho- benzoates which then
serve as a site of formation of water-soluble sodium, potassium or amine salts.
• Eg: Chloramphenicol- Chloramphenicol Succinate
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15. NH
OH
O
Cl
Cl
O
O
O
O
Na
N
+
O
OH
-
NH
OH
O
Cl
Cl
N
+
O
OH
OH
O
O
O
Na
- +
Chloramphenicol succinate
Chloramphenicol Sodium succinate
H2O
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16. Eg. Aminoacid amide of benzocaine to benzocaine to improve solubility.
O O CH3
N
H
O
R
N
+
H
H
H
O O CH3
NH2
Amino acid amide of Benzocaine Benzocaine (local anesthetics)
Amidase
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17. 3. PRODRUGS FOR IMPROVED ABSORPTION & DISTRIBUTION
 Drugs applied to skin are poorly absorbed.
• Eg: Dipivefrin, a pro-drug for epinephrine, has better cornea penetration rate than
epinephrine and is used in the treatment of glaucoma.
O
H
O
H
NH
CH3
OH
O
O
CH3
C
H3
C
H3
C
H3
CH3
C
H3
O
O
NH
CH3
OH
Epinephrine Dipivefrin
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18. • Ampicillin when administered orally only about 40% of dose is absorbed. Therefore,
ampicillin when presented in the form of its esters has increased absorption.
• Eg: Pivampicilline and Becampicillin
NH2
NH
O N
O
S
CH3
CH3
O
O
H
NH2
NH
O N
O
S
CH3
CH3
O
O
C
H3
O O
O
CH3
H
Pivampicilline Becampicillin
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19. 4. PRODRUGS FOR SITE SPECIFICITY
 The approach is based on attaching a lipophilic carrier to a hydrophilic drug in a
loosely bound form.
 The complex releases hydrophilic drug in the CNS
• Eg: capecitabine requires a series of enzymatic steps for conversion to the active anti-
tumour drug, 5-flurouracil.
 Esterase enzymes present in liver hydrolyse the drug followed by oral administration.
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20. N
N
H
O
N
H O
O
O
H
O
H CH3
F
O
CH3
Capecitabine
N
N
H
O
NH2
O
O
H
O
H CH3
F
N
N
H
O
O
O
H
O
H CH3
F
O
NH
N
H
O
F
O
5-Fluorouracil
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21. 5. PRODRUGS FOR SLOW AND PROLONGED RELEASE
 By making a long chain aliphatic ester because these esters hydrolyse slowly.
• Eg: antipsychotic agent fluphenazine enanthate & decanoate have duration of action of
about a month in comparison to plain fluphenazine (6-8 hrs).
S
N
F
F
F
N
N
O
O
CH3
S
N
F
F F
N
N
OH
Fluphenazine enanthate Fluphenazine(antipsychotic)
(duration of activity~1 month) (duration of activity~6-8 hrs)
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22. •Eg: antipsychotic agent haloperidol deconate have duration of action of about a month in
comparison to plain haloperidol (2-6 hrs).
F
O
N
Cl
O
CH3
O
F
O
N
Cl
OH
Haloperidol decanoate (activity ~1 month i.m.) Haloperidol (tranquilizers)
(peak plasma ~2-6 hrs oral)
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23. 6. PRODRUGS TO LOWER TOXICITY PROFILE
 To reduce the toxicity level of drug molecule.
• Eg: The side effects associated with the use of aspirin are gastric irritation & bleeding.
Esterification of aspirin greatly suppresses gastric ulcerogenic activity.
O
O
CH2
O
C
H3 O
N
H
R
OH
O
O
C
H3 O
Ester derivative of aspirin aspirin (anti-inflammatory)
(without gastric irritation)
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24. 7. PRODRUG FOR STABILTY
 The extensive first pass metabolism in liver is the most important cause that restricts
oral effectiveness of many drugs.
• Eg. Propranolol undergoes extensive first pass metabolism, which can be overcome by
converting them to its glucuronide derivative.
O
NH CH3
C
H3
O
H
O
NH
C
H3
CH3
O
O
OH OH
OH
O
O
H
Glucuronidation
Propranolol (antihypertensive) Propranolol-o-glucuronide
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25. REFERENCE
•Andrejus Korolkovas.ESSENTIAL OF MEDICINAL CHEMISTRY.2nd ed. New Delhi: A
Wiley-Interscience Publication;2011. pg.no:101-113
•K.Ilango and P.Valentina. Text book of Medicinal chemistry.Vol.1.Chennai:Keerthi
publishers;2007. pg.no:94-98
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26. Thank you