Diuretics

Development of Benzothiadiazine
Diuretics
Cl

H2NO2S SO2NH2
H
Chlo rphe na m ide N CH3

O
H2NO2S SO2NH2

NH2 Acetylation

H2NO2S SO2NH2 N CH3

NH
H2NO2S S
O O

Possess diuretic activity independent of CAI

New series of diuretics called Benzothiadiazine
10:05 AM was discovered 2
 SAR of Benzothiadiazine
Diuretics

Cl N R

NH
H2NO2S S

O O

Ge ne ric Tra d e Struc ture Re la tive Dura tio n

Na m r Na me Po te nc y hr

Chlo ro o thia zid e Diuril R=H 0.8 6-12

Be nzo thia zid e Exna R= S 1.3 12- 18

 Substitution at 3-position affect potency and duration of action, when H is replaced by

CH2Cl gives activity up to 24 h. while –CH2-S-CH2-CF3 increase up to 48h and benzyl (18h).

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 SAR of Benzothiadiazine
Diuretics
H H
R2 N R1

N
H2NO2S S R3
O O

Ge ne ric Tra de Struc ture Re la tive Dura tio n

Na mr Na m e Po te nc y hr
R1 R2 R3

Hyd ro c hlo rthia zide Esid rix H Cl H 1.4 6-12

Tric hlo ro m e thia zid e Me ta hyd rin CHCl2 Cl H 1.7 24

Me thyc lo thia zide End uro n CH2 Cl Cl CH3 1.8 > 24

Po lythia zide Re ne se -CH2 -S-CH2 -CF3 Cl CH3 2 24- 48

Hydro flum e thia zide Diuc a rdin H CF3 H 1.3 18- 24

10:05
Be nd roAM
flum e thia zid e Na ture tin b e nzyl CF3 H 4
1.8 6- 12
 SAR of Benzothiadiazine
Diuretics
N
5 4
6 3

7 2
8 1 NH
H2NO2S S

O O

 The hydrogen atom at 2-N is the most acidic because of the electron-
withdrawing effects of neighboring sulfone group
 The sulfonamide group that is substituted at C-7 provide an additional point of
acidity in the molecule but is less acidic than the 2-N proton
 The acidic protons make possible the formation of water-soluble sodium salt
that can be used for IV administration
N
N

Na OH N Na
NH
H2NO2S S
H2NO2S S
O O
O O
Wa te r-so luble so d. sa lt
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 SAR of Benzothiadiazine
Diuretics
N
5 4
6 3

7 2
8 1 NH
H2NO2S S

O O

 An electron-withdrawing group is necessary at position 6 for diuretic

activity
 Little activity is seen with a hydrogen atom at position 6, whereas
compounds with chloro or trifluoromethyl substitution are highly active
 The trifluoromethyl substituted diuretics are more lipid-soluble and have a
longer duration of action than their chloro-substituted analogs
 When electron-releasing groups, such as methyl or methoxy, are placed at
position 6, the diuretic activity is markedly reduced

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 SAR of Benzothiadiazine
Diuretics
N
5 4
6 3

7 2
8 1 NH
H2NO2S S

O O

 Replacement or removal of the sulfonamide group at position 7 yields

compounds with little or no diuretics activity.
 Saturation of the double bond to give a 3,4-dihydro derivative produces a
diuretics with 10 times more active than the unsaturated derivative.
 Substitution with a lipophilic group at position 3 gives a marked increase in the
diuretic potency.
 Haloalkyl, aralkyl, or thioether substitution increases the lipid solubility of the
molecule and yield compounds with a longer duration of action.
 Alkyl substitution on the 2-N position decrease the polarity and increase the
duration of diuretic action

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 Mechanism of action of Benzothiadiazine
Diuretics
 It has the ability to inhibit the Na+ -Cl- symportor located in distal convoluted
tubule (DCT)
 The major site of action of these compounds is in the DCT, where they
compete for the chloride binding site of the Na+ -Cl- symportor and inhibit the
reabsorption of Na+ and Cl- ions
 For this reason, they referred to Saluretics

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 Therapeutics Application of Benzothiadiazine
Diuretics

Administered once daily or in divided doses

The majority of these compounds not metabolized and
excreted unchanged in the urine
Are used to treat edemas caused by cardiac failure as well
as in hepatic or renal disease
Are commonly used in the treatment of hypertension, as it
reduce the blood volume and has direct relaxation of
vascular smooth muscle

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Thiazide-like Diuretics
 Quinazolinone Derivatives

N N

NH NH
S

O O O

Be nzo thia dia zine Quina zo lin-4-o ne

 The structural difference between the quinazolinone and thiazide is the

replacement of the sulfone group (-SO2 -)with a keto group (-CO-)
 Because of their similar structure, the quinazolinone have diuretic effect
similar to that of Thiazide
 The mode of action is similar to that of Thiazide diuretics

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 Quinazolinone Derivatives
Cl N CH3
CH3 Cl N C2H5

N
H2NO2S NH
H2NO2S
O
O
Me to la zo ne
(Za ro xylo n) Quine tha zo ne
(Hydro m o x)
7-c h lo ro -2-m e th yl-4-o xo -3-o -to lyl-3,4-
d ih yd ro q u in a zo lin e -6-su lfo n a m id e 7-c h lo ro -2-e th yl-4-o xo -3,4-
d ih yd ro q u in a zo lin e -6-su lfo n a m id e

Duration: 12-24 h Duration: 18-24 h

 They have a long duration of action usually as a result of protein

binding

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 Phithalimidine Derivatives
O “Chlorthalidone”
HO Cl
NH NH

NH SO2NH2
O iso ind o le
Phtha lim id e
O
H Chlo rtha lid o ne
N (Hyg ro to n)
NH
2-c h lo ro -5-(1-h yd ro xy-3-o xo iso in d o lin -1-
yl)b e n ze n e su lfo n a m id e

iso indo line

indo le Duration: 48-72 h
 This compounds may be named oxo-isoindoline or phthalimidine
 Although the molecule present in the phthalimidine form, the ring may be
opened to form benzophenone derivative
O Cl

HO Cl
NH2 SO2NH2

NH SO2NH2
O

O
Be nzo phe no ne fo rm
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Phtha lim idine fo rm 13
 Indoline Derivatives
“Indapamide”
O

SO2NH2
HN

N
Cl
CH3

4-c hlo ro -N-(2-m e thylindo lin-1-yl)-3-sulfa m o ylbe nza mide

 Indapamide contains a polar chlorobenzamide moeity and a non polar lipophilic

methylindoline moeity
 It is rapidly and completely absorbed from the GIT and reaches its peak plasma
level in 2-3 hrs with a duration of action up to 8 weeks
 The prolonged duration of action is associated with its extensive binding with
CA in the erythrocytes.
 Used in the treatment of essential hypertension and edema due to congestive
heart failure
 The duration of action is approx. 24hrs with normal dose 2.5 mg given each
morning
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