SAR, MOH, TOXICITY AND SIDE EFFECT

OF INDAPAMIDE
Presented by:
GUIDED BY :
Hipparge Nurpasha
Dr. Mrs. Mayura Kale
M Pharm (PChem.) II Sem
Assistant Professor
Department of Pharm. Chemistry
GOVERNMENT COLLEGE OF PHARMACY
1

Internal Examiner

External Examiner

CONTENTS

Introduction

Literature survey

Plan of work

Feasibility

Problem

foreseen and solution

Expected

Outcomes

References

INDAPAMIDE:

Indapamideis athiazide-like diuretic [1]drugmarketed byServier, generally used in the

treatment

ofhypertension,

as

well

as

decompensatedheart failure.

Combination

preparations withperindopril(anACE inhibitorantihypertensive) are also available..

a benzamide-sulfonamide-indole. It is called a thiazide-like diuretic but structure is

different enough (lacking the thiazo-ring) so it is not clear that the mechanism is
comparable.

Chemical data
Formula

C16H16ClN3O3S

Molecular mass

365.835 g/mol

IUPAC Name

4-chloro-N-(2-methyl-2,3-dihydro1H-indol-1-yl)-3sulfamoylbenzamide

Description

This compound belongs to

the class of organic
compounds known as
benzenesulfonamides.
These are organic
compounds containing a
sulfonamide group that is
S-linked to a benzene ring.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivativ

es

Sub Class

Benzenesulfonamides

Direct Parent

Benzenesulfonamides

Categories

Antihypertensive Agents
Diuretics
Sodium Chloride Symporter
Inhibitors
5

Pharmacology

Indication

For the treatment of

hypertension, alone or in
combination with other
antihypertensive drugs, as
well as for the treatment of
salt and fluid retention
associated with congestive
heart failure or edema
from pregnancy
(appropriate only in the
management of edema of
pathologic origin during
pregnancy when clearly

Indapamide is an antihypertensive and a

diuretic. It contains both a polar sulfamoyl
chlorobenzamide moiety and a lipid- soluble
methylindoline moiety. Indapamide bears a
structural similarity to the triazide diuretics
which are known to decrease vascular smooth
muscle reactivity. However, it differs chemically
from the thiazides in that it does not possess the
thiazide ring system and contains only one
sulfonamide group. Indapamide appears to cause
Pharmacodynamics
vasodilation, probably by inhibiting the passage
of calcium and other ions (sodium, potassium)
across membranes. This same effect may cause
hypokalcemia in susceptible individuals.
Indapamide has also been shown to cause uterine
myometrial relaxation in experimental animals. 7
Overall, indapamide has an extra-renal
antihypertensive action resulting in a decrease in

Mechanism of action

Indapamide blocks the slow

component of delayed rectifier
potassium current (IKs) without
altering the rapid component
(IKr) or the inward rectifier
current. Specifically it blocks or
antagonizes the action the
proteins KCNQ1 and KCNE1.
Indapamide is also thought to
stimulate the synthesis of the
vasodilatory hypotensive
prostaglandin PGE2.

Absorption

Rapidly absorbed from

gastrointestinal tract.

SYNTHESIS OF INDAPAMIDE

G-QSAR:

GQSAR is a novel group (fragment) based QSAR

method developed by VLife Technologies Pvt. Ltd., which
significantly enhances capability of conventional QSAR.
Group or Fragment based QSAR is also known as
GQSAR
GQSAR allows flexibility to study various molecular
fragments of interest in relation to the variation in
biological response.
GQSAR provides site specific clues for designing new
molecules and quantitatively predicting their activity.
Group or Fragment based QSAR is also known as
GQSAR
10

JUSTIFICATION
Novelty:
Synthesis
Various

of the novel compounds having higher potency

biological activity

Usefulness:
Therapeutic

activity against various disorders like Cancer,

Bacterial infections, Ulcers,Viral infections etc.

11

PLAN OF WORK

Literature survey

Planning for synthesis, PASS studies and Toxicity risk

assessment studies

Synthesis of benzothiazolyl pyrimidine

Synthesis of derivatives

Characterization by spectral analysis

Screening of pharmacological activity (invivo studies)

QSAR analysis of screened compounds

12

LITERATURE SURVEY
Dong H., Quan B. et.al. synthesized 5-methyl-3-substituted1,2,4-triazolo[3,4-b] benzothiazoles (Journal of molecular
structure, 2002; 41-47)
Shivaraj H, Gazi S, Patil S, Surwas S. Synthesis and biological
evaluation of some benzothiazole derivatives. Asian J
Research Chem. 2010; 3(2):421-427.
P S Yadav et al Benzothiazole: Different Methods of
Synthesis and Diverse Biological ActivitiesBharathi
College of Pharmacy, Bharathinagara, Mandya,
Karnataka- 571422, India.

13

CONT..
Kuberkar S.V.,Pingle M .S et al.; A Convenient synthesis of
3-cyano-4-imino-2-methylthiyo-4H-pyrimido benzothiazole
and its reaction with selected nucleiophiles; ARKIVOC 2006
(X) 190-198.
H
Anhy.
H3C

NH2

S
N

SCH3

K2CO3

SCH3

H3C

H3C

SCH3

SCH3
O

N
CN
O

14

TOXICITY RISK ASSESSMENT STUDIES

It is done by Osiris Property Explorer and categorized in three risk levels-

1)High

risk alert

2)Medium
3)Low

risk alert

risk alert

)
Mutagenic

Medium risk

)
Tumerogenic)
Irritant-

Medium risk

Medium risk

15

PASS (PREDICTION OF ACTIVITY SPECTRA FOR

SUBSTANCES)
It

helps to find most probable new leads with

required activity spectra among the synthesized
compounds .
It helps to reveals new effects and mechanisms of
action for traded drugs.
It provides the basis for selection of the most
potential compounds for high throughput screening
from the set of existing samples.
16

FEASIBILITY

Following sources are feasible for project:

Process

Sources Available

Synthesis of compounds

Conventional apparatus, Microwave

To find functional group

IR spectometer

Weighing of product

Electonic balance

Drying of product

Hot air oven

Freezing or cold condition

Freezer

Pharmacological screening

Animals (After Approval)

Filtration

Suction & vacuum pump

17

PROBLEM ENCOUNTERED AND SOLUTION.

PROBLEM

SOLUTION

Unavailability of few important

chemicals in Institution

Purchase from market or Gift

samples

Unavailability of few important

instruments like NMR,MS

Analysis from other institution.

Recrystalization

Solvent combination

Approval for animal

experimentation by institutional
animal ethics committee

Presentation of research work

for animal experiments in front of
18
Animal ethics committee of this
Institution

EXPECTED OUTCOME

19

REFERENCES

P S Yadav et al Benzothiazole: Different Methods of

Synthesis and Diverse Biological ActivitiesBharathi
College of Pharmacy, Bharathinagara, Mandya, Karnataka571422, India.

Shivaraj H, Gazi S, Patil S, Surwas S. Synthesis

andbiological evaluation of some benzothiazole
derivatives. Asian J Research Chem. 2010; 3(2):421-427
20

CONT
Vogels

textbook of practical organic chemistry 5th edition by

B.S. furniss et al .

G-QSAR

of Novel 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}1Hbenzimidazole
Derivatives
MAYURA
KALE*,
GAJANAN SONWANE and RAJESH NAWALE
Department ofPharmaceutical Chemistry, Government
College of Pharmacy,Osmanpura, Aurangabad, Maharashtra,
India.
21

CONT..

Morrision,R.T.,Boyd,R.N.,Organic
Chemistry, Newyork-Pearson Education,VI
Edition,2003,504-505.

Gupta, R. R, Kumar, M.,Gupta, V,

Heterocyclic Chemistry, 1st edn., Springer
publicactions-New Delhi 110001,INDIA,
vol.1, 2005,47-48,55
22

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