1. The document describes the design of a prodrug for Albendazole to reduce its side effects. It involves synthesizing 5,6-dibromo benzimidazole, which is expected to have less toxicity. 2. The synthesis was carried out using normal techniques and the compound was evaluated using melting point, TLC, chemical tests and solubility studies. It showed less solubility, indicating lower adverse reactions. 3. The aim is to overcome side effects of Albendazole through structural modification via a prodrug approach to reduce adverse drug reactions.

1. Prodrug Design Approach
INDEX
SR. NO. CONTENT’S PAGE NO.
1 Abstract 2
2 Introduction 3
3
Literature survey
9
4
Aim and objective
10
5
Material method
10
6
Evalution parameter
11
7 Result and discussion 14
8
Conclusion
16

2. Prodrug Design Approach
Abstract:-
Albendazole was observed number of side effect and toxic effect.Hence their is
need to synthesize potent and less toxic compound for anthelmintic
activity.Albendazole having heterocycle benzimidazole shows number of activity
such as antibacterial,antiviral,antimalarial,antileprotic activity.
Hence we approached to words prodrug technique to reduce such a type of side
effects.We synthesized 5,6 dibromo benzimidazole having less side effect and
adverse drug reaction.The synthesis was done by normal technique and evaluated by
Melting point,TLC,chemical test,molar refractivity.Solubility of compound was
checked in water and showed less solubility hence it was confirmed less adverse
reaction.Percentage practical yield was reported and submitted.

3. Prodrug Design Approach
Introduction:-
PRODRUGS
Discovery-
The term prodrug was coined by Albert.
Another similar term drug latenatiation proposed by Harper (1959); is defined as the
chemical modification of a biologically active compaund to foem a new compaund
which, upon in vivo enzymatic attack , will librate the present compaund.
Definition-
Prodrug is chemically modified from of a drug which has a superior delivery
properties. Many drugs are biotransformed to pharmacologically active metabolites.
These metabolites may have significant activity that contributes substantially to the
pharmacological or toxicological effect ascribed to the parent drug occasionally.
The parent compound is inactive when administered and must be metabolically
converted to a biologically active drug (metabolite) these types of compound ate
refered to as “Prodrug”.
If refers to a pharmacologically inaction compaund hat is converted to an action
rud by a metabolic biotransformation at appropriate time and place in the body
without substantial direct eliminatiion or outward metabolism. This activation may
occur at any time during absorption, distribution or metabolism. If refers as precursor
of drug. Prodrug thus may be considered as drug containing specialized non-toxic
protective alter or eliminate undesirable properties in the parent drug.
Use prodrug :
1. Improved patient acceptability (decrease pain on injection)
2. Alter or improve absorption.
3. Alter biodistribution.
4. Alter metabolism.
5. Alter elimination.

4. Prodrug Design Approach
Functional group derivative in prodrug :
-COOH Carboxylic acid
-NH2
Amine
-OH
Alcohol
-COOH
Carboxylic acid
Characteristics of a prodrugs :
In recent year numerous prodrug have been designed and developed to overcome
barriers to drug utilization, such as low oral absorption properties, lack of site
specificity, chemical instability, toxicity, bad test, odour, pain at application site, etc.
It has been suggested that the following characteristics of a prodrug must be
improved for site-spicific drug delivery.
1. The prodrug must be reability transported to the site of action.
2. The prodrug must be selectively cleaved to the active drug utilizing special
enzymatic profile of the site.
3. Once the prodrug is selectively generated at the site of action, the tissue must
retain the active drug without further degradation.
Development of prodrug :
 To improve membrane transport
 Prolonged activity
 Masking from other Enzyme
 Tissue specific prodrug design
 Prodrug design based on site-specific conditions
 Enzyme specific prodrug design
Prodrug designing :-
Prodrug designing is required to overcome many formulation pharmacokinetic

5. Prodrug Design Approach
or phrmacodynamic drawbacks
 unpleasant taste or odour (gastric irritation)
 A wide range of adverse effects
 Shorter duration of action.
 Instability
 Site non -specificity
 Poor absorption or distribution
 Poor water solubility
Types of prodrug -
A.Mutual carrier linked prodrug
B.Carrier linked prodrug
C.Bioprecursor
A. Mutual carrier linked prodrug-
Promoiety and active drug both are active because of that this is called as mutual
carrier linked prodrug.
Example-Estramustine

6. Prodrug Design Approach
O
CH3
OPO3Na2
N
OCI
CI
OH2
OH
CH3
OPO3Na2
NH
Cl
Cl
CO2
+
Non-
Mustasted
17alpha estradial
+
B.Carrier linked prodrug-

7. Prodrug Design Approach
It is a compound that contains an active drug linked to a carrier group that can be
removed enzymatically,such as easter which is hydrolysed to an active carboxylic
acid containing drug.The carrier group must be non-toxic & biologically inactive
when detached from the drug. It should be released efficiently in vivo. The most
common vacation for activation of carrier-linked prodrug is hydrolysis.
A simple hydrolysis reaction cleaves the transport moiety at the adequate rate
(Examples- Chloramfenicol)
O2N
H
N
O
CHCH2
HO
OH
O2N
H
N
O
CHCH2
O
OH
C
O
ONa
O
sodium 3-(2-acrylamido-3-hydroxy-3-(4-nitrophenyl)propoxy)-3-oxopropanoate
chloramphenicol
C. Bio precursor-
The bioprecursor does not contain a temparary linkage between the active drug & a
carrier moiety, but designed from a moleculer modification of the active principle

8. Prodrug Design Approach
itself.Numerous drugs are currently known which exert pharmacological effect after
their conversion into active metabolite.
CH3
OH2
N
H
N
S
O
O
NH2
N
NH
O
O
N
S
S
CH3
CH3
COOH
CH3
-C-CH3
O
Hectacillin
+
Eg.2
CH2
-CH2
-C-CH3
MeO
O
CH2
-COOH
MeO
Nabumetone
Literature survey :-
a) Surender kumar et al,. “synthesis, characterization and pharmacological, activity
ex. Ester prodrugs of Naproxan.” Asian journal of pharmaceutical and clinical
research, 3(3), 2010, 208-211.
b) Y. M. varsha et al,. “cutting adge Approach on prodrug contrivance for target

9. Prodrug Design Approach
drug delivery.” Open access journal, 3(11), 2011, 286-290.
c) Kristiina M. Huttunen, et al,. “The first bioreversible prodrug of Metformin with
improved lipophilicity and enhanced intestinal absoption” journal of medicinal
chemistry, 52(14), 2009, 4142-4148.
d) Patil S. J. et al., “An effective solution to over come side effects” International
journal of medical and pharmaceutical sciences. 1,(7), 2011.
e) Rafik karaman,et al,. “Design, synthesis and in vitro kinetic study of Atenolol
prodrug for the use in aqueous formulation” The scientific world journal, 2014.
f) Ratnadeep V. Ghadage “Prodrug design for optimized drug dilivery systems”
Journal of biological and scientific opinion, 1,(3), 2013, 255-262.
g) Jolanta B. Zawilska, et al. “Prodrugs: A challenge for the drug development.”
Pharmasutical report, 1(14), 2013, 1140-1734.
h) Alka verma, et al,. “Prodrug as a chemical delivery system” Asian journal
research chemistry, 2(2), 2009, 100-103.
Aim and objective:-
a) To overcome the side effect and toxic effect of Benzimidazol by prodrug
approch (structural modification).
b) To reduce advers reation of drug.
Material method:-
Reaction-

10. Prodrug Design Approach
NH2
NH2
HCO2H
O-Phenylene diamine
Formic acid
Benzimidazole
N
H
N
N
H
N
Br20-2°c
Br
Br
5,6-dibromo-1H-benzo[d]imidazole
PROCEDURE:For synthesis of benzimidazole
Place 27gm (0.25mol)of o-phenylenediamine in a 250 ml round bottom flask &
add 17.5 gm (16 ml,0.34 mol )of 90%formic acid. Heat the mixture on water bath at
100°C for 2hrs. Cool,add 10% sodium hydroxide solution slowly,with constant
rotation of the flask,untill the mixture is just alkaline to litmus, filter of the crude
benzimidazole at the pump .wash with ice cold water drain well and wash again with
25 ml of cold water.
Formulation table:
Table No 2:
Sr.No Name of Ingredient Qty.given Qty.taken
1. o-phenylenediamine 27 gm 3 gm
2. Formic acid 17.5gm(16ml) 1.94gm(1.77ml)
3. NaOH 2ml 0.22ml
4. Ice-cold water 25ml 2.77ml
5. Bromin
6.

11. Prodrug Design Approach
Evalution parameter-
1.DETERMINATION OF MELTING POINT:
The melting point of an organic solid can be determined by introducing a tiny amount
into a small capillary tube, attaching this to the stem of a thermometer centred in a
heating bath, heating the bath slowly, and observing the temperatures at which
melting begins and is complete.
The Thiele tube is a glass tube
designed to contain heating oil and a
thermometer to which a capillary tube
containing the sample is attached. The
shape of the Thiele tube allows for
formation of convection currents in
the oil when it is heated. These
currents maintain a fairly uniform
temperature distribution throughout
the oil in the tube. The side arm of the
Sr.
No.
Test Observation Inference
1. Liebermann nitroso anine
test-
Dissolve little amount of compaund
in dil HCL and cool to 0c . Add
about 1ml ice cold solution of
sodium nitrite. After 5 min ,add 5ml
of ether shake n let stand. Remove
ethereal solution by pipette and
evaporate ether by placing test tube
in electrical water bath.
-intense green or geenish
blue colour
- on dilution it turms pale
red
- on addition of excess of
NAOH solution it turms
deep blue or green
-a
secoundary amin
2. Melting point 170-172°C 165°C

12. Prodrug Design Approach
tube is designed to generate these convection currents and thus transfer the heat from
the flame evenly and rapidly throughout the heating oil. The sample, packed in a
capillary tube is attached to the thermometer, and held by means of a rubber band or
a small slice of rubber tubing. It is important that this rubber band be above the level
of the oil (allowing for expansion of the oil on heating). Otherwise, the oil softens the
rubber and allows the capillary tubing to fall into the oil. The Thiele tube is usually
heating, the rate of temperature increase should be carefully controlled. Usually one
holds the burner by its base and, using a small, gentle flame, moves the burner slowly
back and forth along the bottom of the side arm of the Thiele tube. If the heating rate
is too fast, the burner is removed for a few seconds before resuming the heating
process. The rate of heating should be slow near the melting point (about 1-2⁰C per
minute) to ensure that the rate of temperature increase is not faster than the ability of
the heat to be transferred to the sample being observed. At the melting point it is
necessary that the thermometer bulb and the sample in the capillary tube be at
thermal equilibrium.
Observed melting point for Benzimidazole derivative - 165°C
2.DETERMINATION OF RETENTION FACTOR BY USING TLC METHOD:
Thin-layer chromatography (TLC) :
The stationary phase is applied onto the plate uniformly and then allowed to dry and
stabilize. These days, however, ready-made plates are preferred.
1. With a pencil, a thin mark is made at the bottom of the plate to apply the sample
spots.
2. Then, samples solutions are applied on the spots marked on the line in equal
distances.
3. The mobile phase is poured into the TLC chamber to a leveled few centimeters
above the chamber bottom. A moistened filter paper in mobile phase is placed
on the inner wall of the chamber to maintain equal humidity (and also thereby
avoids edge effect this way).
4. Now, the plate prepared with sample spotting is placed in TLC chamber so that
the side of the plate with the sample line is facing the mobile phase. Then the
chamber is closed with a lid.
5. The plate is then immersed, such that the sample spots are well above the level of

13. Prodrug Design Approach
mobile phase (but not immersed in the solvent — as shown in the picture) for
development.
6. Allow sufficient time for the development of spots. Then remove the plates and
allow them to dry. The sample spots can now be seen in a suitable UV light
chamber, or any other methods as recommended for the said sample.heated
using a micro burner with a small flame but a Bunsen burner can also be used.
Result and discussion:
Table No. 3:
TLC Plate:
Fig No.3:TLC plate showing differential spot of standard and synthesized product:
Name of product 5,6 dibromo benzoimidazol
Molecular formula C7H4Br2N2
Therotical Yield 3.27gm
Practical yield 2.8gm
% Yield 85.62gm
Melting Point 165°C
Molar Refractivity 52.79 cm3
Rf value by TLC 0.703

14. Prodrug Design Approach
Chemical Tests -
Table No.4:
Sr.ṇ
o
Test Observation Inference
1. Liebermann nitroso anine test-
Dissolve little amount of
compaund in dil HCL and cool to
0c . Add about 1ml ice cold
solution of sodium nitrite. After 5
min ,add 5ml of ether shake n let
stand. Remove ethereal solution by
pipette and evaporate ether by
placing test tube in electrical water
bath.
-intense green or geenish
blue colour
- on dilution it turms pale
red
- on addition of excess of
NAOH solution it turms
deep blue or green
-a
secoundary amin
2. Melting Point 170-172 165°C

15. Prodrug Design Approach
Conclusion:
New chemicalentity 5,6 dibromo benzimidazole synthesize by refluxing ortho-phenyl
diamine with formic acid.
Characteristic done by melting point, chemical test, molar refraction.

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