Prodrugs_Medicinal Chemistry

1.  In 1958, Albert coined the term “Prodrug”………….
A pharmacologically inactive compound that is
converted to an active substance (drug) by either
chemical or metabolic means in vivo
(biotransformation).
 Prodrug-drug transformation could be enzymatic
and nonenzymic or chemical e.g., oxidation,
reduction, hydrolysis etc.).
 Prodrug-drug conversion could occur before,
during, after absorption or at a specific site in the
body.
 Ideally, conversion happens as soon as the target
site is reached.

2.  The prodrug design approach is also referred
as Drug Latentiation.
An ideal prodrug:
 Should not have intrinsic pharmacological
activity
 Should rapidly transform into the active form
where desired
 Metabolic fragments, apart from the active
drug should be nontoxic

3. A. Pharmaceutical applications:
1. Improvement of taste (e.g. Chloramphenicol-Palmitate, Sulfisoxazole-Acetyl)
2. Improvement of odor (e.g. Ethyl mercaptan (foul smell), -Phthalate ester)
3. Reduction of G. I. irritation (e.g.Salicylic acid-Aspirin, Kannamycin-Pamoate)
4. Reduction of pain on injection (Clindamycin, low solubility-Phosphate ester)
5. Enhancement of drug solubility and dissolution rate (hydrophilicity)
e.g. Metrodidazole-Amino acid ester
6. Enhancement of chemical stability
(e.g. Azacytidine-Bisulfite (Stable at acidic PH, more water soluble)
B. Pharmakokinetic applications:
1. Enhancement of bioavailability (lipophilicity) e.g. Bacampicillin (98% OB)
2. Prevention of presystemic metabolism e.g. Triamcinolone acetonide
3. Prolongation of duration of action e.g. Testosterone cypionate (i.m depot)
4. Reduction of toxicity e.g. Sulindac (sufoxide)-sulfide (active)
5. Site specific drug delivery (Drug-targeting) e.g. Acyclovir (Anti-HIV
bioprecursor)
Reasons for Prodrug /Applications of prodrug approach

4. Types of prodrugs
Carrier-linked prodrug (or simple prodrug):
an active drug covalently linked to an inert removable carrier or
transport moiety (usually hydrolyzable group such as ester, amide,
etc.)
Bipartate prodrug: one carrier (inert) attached to one drug
Tripartate prodrug (Double prodrug (or) pro-prodrug: one carrier
connected to a drug through a linker (diseter of pilocarpic acid)
Mutual prodrug: two synergistic drugs attached to each other
(Benorylate-Aspirin+Paracetamol)
Bioprecusor or metabolic precursors:
Inert molecules obtained by chemical modification of the active drug
but do not contain a carrier.

5. Bipartate
Tripartate
Bioprecusor
Carrier-linked
prodrug
biotransformation
linker
Carrier

6. Carrier-linked prodrugs
A. Alcohols and carboxylic acids
(Ester prodrug)
 Carrier/promoiety is lipophilic in nature
 Lipophilicity of active drug is greatly modified
 Lipophilicity: Prodrug > active drug
 Esterase are ubiquitous (hydrolytic cleavage)
 Example:
Chloramphenicol palmitate  Chloramphenicol (in blood)

7. Drug C
O
O Promoiety
or
Drug O C Promoiety
O
Drug C
O
OH
Drug OH Promoiety
+ OH Promoiety
C
O
HO+
 Ester prodrug: Drug molecule contains either alcohol or
carboxylic acid functionality
Esterase enzymes: Capable of hydrolysing ester linkage of
prodrugs
 Ester hydrolase/Lipase/Cholesterol esterase/Ach esterase etc.

8. Non-polar (lipophilic carrier) alcohol or
carboxylic acid (Promoiety)
 Decreased water solubility i.e., hydophilicity
 Benefits:
 Increased absorption (% OB, lipophilic form)
Example:
 Dipivefrin HCl, prodrug (diester of pivalic acid) of
Epinephrine, Adrenomimetic, used in Open-angle
glaucoma
Has 10 times more ocular penetrability than active
drug
 Nadolol: Diacetate ester is 20 times more lipophilic
and 10 times more readily absorbed ocularly

9. Decreased dissolution (greater stability in
g.i.f-->absorption)
Example:
Chloramphenicol palmitate, Antibacterial
Reduced solubility in saliva and lower
affinilty to taste receptors, bitterness is
reduced

10.  Prolonged duration of action (extended absorption)
 Controlled release
Example: (lipophilic ester)
i.m. depot inj. of Testosterone cypionate
Fluphenazine enanthate-antipsychotic
 Controlled conversion/activation
Example:
Diester of pilocarpine-Glacucoma (Better & slow
absorption)

11.  Reduction of dosage (increased OB,
increased lipophilicity)
Example: Becampicillin is as effective as
ampicillin in just 1/3rd the dose of latter.

12.  Ester linkage: Catechol hydroxyl groups of epinephrine with
pivalic acid
 Increased lipophilicity allows high intraocular concentration
 Hydrolysis of ester function occurs then in eye to generate the
active form, epinephrine
OH
NH2O
OO
O
Cl
OH
NH2HO
HO
Cl
OH
O
Epinephrine
Pivalic acidDipivefrin HCl
Esterase
+

13. O2N
H
N
OH
O
CHCl2
O
O
Chloramphenicol palmitate
O2N
H
N
OH
O
CHCl2
OH
+
Chloramphenicol
H2O
Esterase
CH3(CH2)14
O
OH
CH3(CH2)14
Palmitic acid
 Chloramphenicol (parent drug): Bitter taste due to increased dissolution
in mouth and therefore capable of interacting with taste receptors.
 Hydrophobic palmitate ester (prodrug): Reduced water solubility does not
dissolve to any appreciable extent in the mouth and therefore does not
react with taste receptors.
 Ester moiety: Subsequently hydrolysed in the g.i.t and the agent is
absorbed as chloamphenicol.

14. Polar alcohol or carboxylic acid (Promoiety)
 Increased water solubility i.e., hydrophilicity
 Benefit :
 Increased parenteral administration
 Reduction of pain at the site of injection (Clindamycin-Phos)
 Example: Chloramphenicol succinate
Chloraphenicol has low water solubility
 Succinate ester has increased solubility in the administered
solvent, and facilitate parenteral administration

15. O2N
H
N
OH
O
CHCl2
O
O
ONa
O
Chloramphenicol succinate
O2N
H
N
OH
O
CHCl2
OH+HO
O
ONa
O
ChloramphenicolSod. succinate
H2O
Esterase

16. Some common examples of
ester prodrugs
 Chloramphenicol palmitate
 N-Acetyl sulfisoxazole
 N-Acetyl sulfamethoxypyridazine
 Erythromycin estolate (lauryl sulfate salt of
erythromycin propianate)
 Clindamycin palmitate

17.  Polar Drug - Soluble in g.i.t -> destabilization in
acid
 Caridacillin (a ∞-indalol ester)-Carbenicillin
(antibiotic)
 Stable at gastric pH (low solubility)
 Stable at pH >7.0 in intestine and hydrolyzed under
such condition

18. B. Amines (Carrier)
 N-Mannich bases increase lipophilicity, variable hydrolysis rate
 Schiff base, increased lipophilicity

19. HN
N
CH3
CH3
O N
S
COOH
O
H2O
NH2
H
N
O N
S
COOH
O
+CH3COCH3
Hetacillin
Ampicillin
Acetone
Mannich bases (reaction of two amines with an aldehyde and
ketone)
Lower the basicity of amines
Increase lipophilicity and absorption

20. C. Azo linkage:
H2N N N S
O
O
NH2
NH2
Azoreductase
H2N S
O
O
NH2
NH2
Prontosil
H2NNH2
Sulfanilamide
(active drug)
+
1. Prontosil

21. 2. Sufasalazine
HO
HOOC
N N S
O
O
NH
N
Sulfasalazine
Azoreductase
HO
HOOC
NH2 H2N S
O
O
NH
N
+
Aminosalicylic acid Sulfapyridine

22. C. Carbonyl
 Schiff base increase lipophilicity
 Oxime increase hydrophilicity
 oxazolidines, thioxazolidines adjust lipophility.

23. More examples of Carrier-linked Bipartate Prodrugs
A. For Increased Water Solubility
R= R’=H, Prednisolone
R= CH3, R’=H, Methylprednisolone
Both are water-insoluble
Ideal prodrug: shelf life > 2 yrs;
activated < 10 min in vivo
Prodrug: R=CH3, R’=COCH2CH2CO2Na
shelf life<48hrs, others > 2 yrs
R=H, R’=phosphate, good
H3N
O
O
HN
O
O
H3N
R
O
Bezocaine
Local anesthetic
Low solubility
Bezocaine prodrug
stable, long shelf life
high solubility, activated readily
MeHO
Me
R
OH
O
O
OR'

24. B. For Improved Absorption and Distribution
Cortisosteroid
Inflammation,
Allergy
Pruritic skin conditions
Epinphrine, R = H
Antiglaucoma

25. C. For site specificity
OH
OH CH2 CH
COOH
NH C
O
CH2CH2 CH
NH2
gama-Glutamyl DOPA (Prodrug)
gama-Glutamyl transferase
OH
OH CH2 CH
COOH
NH2 C
O
CH2CH2 CH
NH2
COOHOH+
DOPA (Bioprecursor) Glutamic acid
CO2
OH
OH CH2CH2NH2
DOPAMINE
Renal vasodilation
by increasing renal blood flow
L-aromatic amino acid decarboxylase
(treatment of renal hypertension)
Selectively accumulate in the
kidneys & bind to specefic
receptor
(released active drug locally)
COOH

26. D. For Stability E. Prolonged Release
H3C N
R
O
CH3
Naltrexone(R=H), opiod addiction
Not stable in the first pass
R= CO-o-NO2Ph, bioavailability 45
times
R= CO-o-AcOPh, bioavailability 28
times
Tolmetin sodium(R=O-Na+),
antiarthritis
Peak concentration duration: 1
hr.
R= NHCH2COOH, peak
duration: 9 hrs.
ORO
OH
N
O

27. F. To Minimize Toxicity G. To Encourage Patient
Acceptance
H. Elimination of
Formulation Problems
Aspirin: gastric irritation
and bleeding
When R=CH2CONR1R2, no
problems
Sulfa drug: pediatric
antibiotics, bitter taste
(R=H)
When R=CH3CO,
tastless
Prodrug for formaldehyde:
release HCHO in acidic
condition
Used as urinary tract
antisep

28. Carrier-linked Tripartate prodrugs
(Double prodrug approach)
 Double ester approach: Penicillin/ Cephalosporin esters
 An additional ester or carbamate function is incorporated into the
molecule
 Advantages are:
To improve the absorption or to reduce dissolution
 And subsequent acid-catalysed decomposition (in the stomach)
 These drugs are orally active
 Examples: Cefpodoxime Proxetil, Cefuroxime Axetil, Ampicillin,
Becampicillin

29. NH
N
S
O
O
NH2
Ph
O
O O
R
R'
O
Esterase
2. Ampicillin
NH
N
S
O
O
NH2
Ph
O
O
H
H
C O
O
OCH2CH3
CH3
1. Becampicillin

30. H
N
N
S
O
O
NH2
Ph
O
O OH
R
OH R'
O
+
When R'= OEt
EtOH + CO2
RCHO
H
N
N
S
O
O
NH2
Ph
O
O
AMPICILLIN

31. Mutual prodrugs (Carrier-linked)
OPO3Na2H3C
O
O
N
Cl
Cl
Estramustin, mutual prodrug
Antineoplastic
used in prostate cancer
Carbamate linkage
Hydrolysis

32. OH
H3C
HO
+
17alpha-Estradiol, steroid portion
Helps to concentrate the drug in the
prostate
Antiandrogenic effect, slows the growth of
cancer cells
NH
Cl
Cl
+ CO2 + PO4
-2
+ 2Na
Normustard
Alkylating agent
Cytotoxic effect

33. Bioprecursor prodrugs
In vivo reactions that can activate a bioprecursor
• Oxidative activation
• Reductive activation
• Nucleotide activation
• Phosphorylation activation
• Decarboxylation activation

34. Oxidative activation
 Oxidative activation ( by Cyt. P450): NSAID Nabumetone
 Exhibits reduced gastric irritation compared with other NSAIDs
 It contains no acidic functionility and produce no gastric irritation while
passing through the stomach
 Subsequently absorbed through intestine, and metabolized in liver to
produce active drug O
CH3
H3CO
Nabumetone
Prodrug
COO
H
H3CO
Active drug
Oxidative bioactivation
Cyt P450

35. Activation of cyclophosphamide

36. Reductive activation
 Antineoplastic agent mitomycin C, used in bladder and
lung cancer.
 Mitomycin C contains a quinone functionality that
undergoes reduction to give a hydroquinone.
 Hydroquinone has an e-withdrawing effect on the e-
pair of the N atom, which allows the e to participate in
the expulsion of methoxide ion and, subsequently,
 The loss of carbamate to generate a reactive species,
which may alkylate DNA.

38. Phosphorylation activation
Acyclovir, antiviral drug
Genital herpes simplex virus
infection
 Incorporated into DNA as a G
after triple phosphorylation in
infected cells
Acyclovir (R=H)
R=triphosphate, recognized as a dG by
viral DNA polymerase
but not recognized by normal cellular
DNA polymerase

39. Nucleotide activation
 Anticancer agent, Acute childhood leukemias
 de novo DNA synthesis
 Incorporated into DNA after nucleotide formation

40. Site specific chemical delivery system
 The drug may lead to undesirable toxic effects in the nontarget
tissues
 The problem can be overcome by targeting the drug to its site of
action
 The approach of prodrug design is one of the several
approaches of drug targeting
 Site-specific chemical delivery requires that the prodrug to
reach the target site
 Specific enzymatic or chemical process exists at the target site
 The conversion of prodrug to the active drug takes place at the
target site

41. Examples
1. Antiviral drug: Iodoxuridine
 Iodoxuridine (prodrug) is specific for those sites at which it serves as a
substrate for phosphorylating enzymes found in viruses.
The prodrug is readily abale to penetrate into the virus, and the increased
polarity of the phosphorylated derivative would serve to retain that active
species inside the virus.
The phosphorylated species: active antiviral agent
The active phosphorylated species is incorporated into viral DNA, disrupting
viral replication and thus producing the antiviral effect.

42. HO
OH
N
HN
O
O
I
Viral Thymidine Kinase
O
OH
N
HN
O
O
I
P
O
O
O
O
OH
N
HN
O
O
I
P
O
OP
O
O
OPO
O
O
O
Inhibit DNA polymerase incorporated into DNA

43. 2. Urinary tract antiseptic: Methenamine
 The increased acidity (low pH) of the urine
promotes the hydrolysis to formaldehyde, active
antibacterial agent.
 The rate of hydrolysis at plasma (pH 7.4) is low
preventing systemic toxicity from formaldehyde.
 Dissolution in stomach and premature hydrolysis
in the highly acidic environment of the stomach
can be prevented by enteric-coating (tablet).

44. N N
N
N
Methenamine
H
6CH2O + 4NH3
Formaldehyde Ammonia

45. 3. L-Dopa
 L-Dopa: Site specific chemical delivery system delivering the
drug dopamine into the brain.
 L-Dopa is transported into the CNS by an active transport
system and once across the BBB, the L-Dopa undergoes
decarboxylation to yield the active metabolite, dopamine.
 Direct systemic administration of dopamine does not produce
significant brain levels of the drug due to its high polarity, and
poor membrane permealibility, as well as it facile metabolic
degradation by oxidative deamination.

46. HO
HO
H2
C
H
C NH2
COOH
L-Dopa
HO
HO
H2
C
H2
C NH2
Dopamine
Decarboxylation
Conversion of L-Dopa to Dopamine in Brain