Antibiotica et Chemotherapia, vol. 14, pp.

179-215 (Karger, Basel/New York 1968)

Department of Clinical Research, F. Hoffmann-La Roche & Co. Ltd., Basle

Long-Acting and Short-Acting Sulfonamides.

Recent Developments

TH. STRULLER

1. Introduction

It was PAUL EHRLICH, the founder of modern chemotherapy,

who initiated the brilliant-if not entirely accurate-hypothesis of
the superiority of azo dyes as anti-infective agents. This theory was
confirmed but, singularly enough, refuted soon afterwards: confirmed
by the discovery of the antibacterial effect of sulfachrysoidine (1) in
December 1932 by DOMAGK, in that sulfachrysoidine does in fact
belong to the large family of azo dyes; and refuted in 1935 (3), because
it was found to be the 'colourless' portion of the molecule that was
responsible for the antibacterial effect, and not the portion on
which its pigmenting properties were based.
The first clinical experience with sulfachrysoidine was published
in February 1935 (1,2). It is doubtless no exaggeration to regard this
date as a milestone of an era which, through the continued develop-
ment and the availability of new antibacterial substances, saw the
majority of infectious diseases brought under control to an extent
hitherto considered impossible.
The discovery by NITTI, BOVET, TREFOUEL and FOURNEAU at the
Institut Pasteur (3) in 1935 of the active principle, sulfanilamide (Il),
a chemical known already for many years, initiated a spate of synthetic
activity unparallelled in the history of medicine. Instantaneously, so
to speak, hundreds and then thousands of derivatives of the parent
compound were produced and subjected to pharmacological, toxico-
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logical and clinical screening such as no other dass of related sub-

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180 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments

stances had yet seen. According to FRISK, more than 4,500 t of sulfo-
namides, a quantity sufficient to treat well over a hundred million
patients, had been produced in the U.S.A. by 1943 (4).

NH.

HCI· NH. --ö- N =N -0- SO. - NH. (I) Sulfachrysoidine

NH, -0- SO. - NH. (I1) Sulfanilamide

NH. -0- COOH (III) p-Aminobenzoic acid

OH CHO
I I COOH
~/N~-CH.-NH-o-~ C-NH-CH
I
N I - 11 I
H.N ~ ./"<
11
/
I
0 CHI
'N N I
H CH,
I
COOH
(IV) Formyltetrahydrofolic acid

What a transformation the therapy of infectious diseases has since

undergone! It is already a rustorical fact that only three decades
ago two to three thousand women died each year of puerperal fever
in countries such as Germany and England. Had the mortality rate
of pneumonia in England remained at the same level as before the
chemotherapy era, the annual number of deaths today would be more
than 25,000, compared with the actual figure of 6,000 (5).
Meningitis, which was epidemie in many countries, also lost its
horror, and the mortality rate fell from 70% to 10-15%. For the first
time it became possible to attack a great number of infectious diseases
such as bacillary dysentery at their very roots. It thus comes as no
surprise that the mean life expectancy of man is ever on the increase,
a development in which effective anti-infective drugs have played an
important part.
However gratifying these observations may be, there is still no
getting away from the fact that P. EHRLICH'S aim of eradicating in-
fectious disease is still far from being realised. Interest in antibacterial
substances is as strong as ever, and they still account for a large
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proportion of the drugs prescribed.

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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 181

2. Definitions

2.1 Definitions of the Terms 'Baeteriostasis» 'Half-Life' and

, Long-Aeting Sulfonamide'

If an attempt is made to draw a dear distinetion between the short-

aeting and the long-acting sulfonamides, two dosely related concepts
immediately eome to the forefront : 'bacteriostasis' and 'half-life'.

2.2 Baeteriostasis

The mode of action of the sulfonamides is thought to be as

follows: Sulfanilamide (I1), a weak acid, permeates into the baeterial
cell in non-ionized form, where, after partial dissociation, it competes
in ionized form with ionized para-amino-benzoic acid (III) for hydro-
xymethylglyoxal. If, through its para-amino group, sulfanilamide suc-
eeeds in preventing the eondensation of the para-amino group of para-
aminobenzoie acid with hydroxymethylglyoxal, production of formyl-
tetrahydrofolic acid (IV), a coenzyme of the C 1-synthesis essential for
the baeteria, is inhibited (6).
Sulfonamides have no effeet on baeteria in the resting state, sinee
there is no requirement for the coenzyme at this time; it is only during
the reproduetive stage that they exert a baeteriostatic effeet, after a
latent period which depends on the amount of para-aminobenzoie
acid stored. This latent period ean last for up to six generations of the
baeterial strain (11).
A eomparison between sulfonamides and baetericidal substanees
gives the following picture:
A baetericidal effeet generally requires high eoncentrations of a
drug over a short period, while the reverse is true for the baeteriostatic
sulfonamides. Here, baeteriostatic eoncentrations must be maintained
until the physiologieal defenee meehanisms of the host (7) are able
to eombat the baeteria. Whereas the body ean look on passive1y, so to
speak, when baetericidal substanees are given, its aetive participation
is required when bacteriostatie eompounds are used. The organism
requires a eertain time before it ean produce antibodies and this gap
must be bridged by the sustained action of an effective bacteriostatie
agent. Baeteriostasis thus automatieally demands that the drug have a
protraeted action, and this is the basis of the interest in long-aeting
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sulfonamides.
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182 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments

As will be seen below, some of the earliest sulfonamides used

clinically were long-acting, but were not recognized as such since the
basic pharmacokinetic principles had not yet been grasped. True, a
start had been made in this direction, but the various findings were
not generally accepted by the research centres. Too much attention
was paid to the linear 'pathogen-drug' complex, and not enough
to the triangular 'man-pathogen-drug' complex. Only later have
we come to appreciate the dose relations hip existing between
the frequency of administration and the length of time a drug, and a
sulfonamide in particular, remains in the organism. A short-acting drug
not only requires to be given repeatedly, but also puts a heavy burden
on the doctor and nursing staff who must supervise its regular ad-
ministration. Furthermore, substances with a more prolonged activity,
by virtue of the relatively low doses that can be given, are generally less
inclined to cause toxic side effects than rapidly eliminated preparations
which have to be given in higher daily doses (8, 9, 10).

2.3 Half-Life

The length of time a sulfonamide remains in the organism is

defined in terms of the biological half-life, a practical measure of which
is the speed with which the sulfonamide is eliminated from the blood-
stream. Like most drugs, sulfonamides are eliminated at a more or
less constant rate which can be expressed mathematically as an
exponential function of time, i.e. the half-life is the time taken for a
given blood level to be reduced by half. Thus, if at a given moment a
short-acting sulfonamide with a half-life of 6 h has a blood level of
10 mg%, the concentration will fall to 5 mg% within the next 6 h,
to 2.5 mg% during a further 6 h, to 1.25 mg% within a further 6 h, and
so on. A long-acting sulfonamide with a half-life of 24 h would show
corresponding levels only after 1, 2 and 3 days respectively. Thus,
the latter preparation is eliminated four times as slowly as the former.

2.4 Classification of Sulfonamides According to their Half-Life

Various suggestions for the dassification of sulfonamides have

been made (11-15).
They have been subdivided into five groups-ultrashort-, short-,
medium-long-, long-, and ultralong-acting; into three groups-short-,
medium-long-, and long-acting; and, finally, into two groups-long-
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and short-acting sulfonamides.

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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 183

If these three classifications are put side by side the following pic-
ture results (Table I):
The half-life has been found to be a very usable criterion for
classifying sulfonamides, because it permits the appropriate interval
between the doses, or the right number of doses daily, to be deter-
mined. There is a plausible relationship between the half-life of a drug
and the number of daily doses required and also between the number
of daily doses and their size. For a given interval of dosage the single
dose is mainly determined by the antibacterial activity as shown below.
WeIl founded doubts have recently been expressed about some
dosage recommendations for sulfonamides given in the literature
(see below).
Classification of the sulfonamides into the three or five groups
mentioned above is of most interest for research purposes, while for
practical use the division into two groups would appear to be entirely
adequate. That many authors prefer the two-group system is evident
from the fact that recent sulfonamides with a half-life of 10-11 h
-sulfaphenazole, sulfadimethyloxazole and sulfamethoxazole-are
frequently classified as long-acting sulfonamides, whereas under the
three-group or five-group system they would definitely have to be
termed medium-long-acting.
On the basis of the two-group classification long-acting sulfon-
amides need to be taken only once to three times daily and short-
acting four to six times daily. This is the salient difference between the
two. While the rate of administration of the long-acting preparations
remains weH within usual limits, four to six daily doses of the short-
acting sulfonamides impose a heavy burden on the nursing staff and
the patient hirnself.

2.5 Other Designations of Long-Term Sulfonamides

The use of the term 'retard' for long-acting sulfonamides is quite

justified, since it expresses the fact that a single dose of long-acting
sulfonamides remains in the organism for more time than a single
dose of short-acting sulfonamides. The term 'depot sulfonamide', on
the other hand, is in most cases amisnomer. The aim in administering
adepot preparation, for example by intramuscular injection or in an
oral slow-release form, is to allow the active substance to pass only
gradually into the blood or tissues. The dose given does not become
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available in toto within a short period of time, as occurs with long-ac-

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 ~
-
Ul
Table I ....
....
~

Classification of sulfonamides into:

"....
5 groups 3 groups 2 groups ~
-------~
No of Noof -- No of ~
Half-life daily doses II Half-life daily doses [ Half-life daily doses "S'
OQ

~
Ul
h
I Ultra-short I < 4 I 6 I g
Short < 8h 4-6 Short < 8h 4-6 ~
, Short I 4- 8h I 4 I S'
OQ
Ul
~
I , [ g;
Mcdium- 8-16h 2-3 Medium- 8-16h 2-3
long long
?'
1-3
1
Long I 16-60h I 4 Long >811 (or weekly) [
h
4
Long >16 tj
(or weekly)
Medium-
f Ultra-long 8-16h
Medium- !
I

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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 185

ting sulfonamides. Adepot preparation has to contain at least twice

the single dose - a measure unnecessary withlong-acting sulfonamides.
Thus depot preparations do not permit the dose to be reduced, whereas
there is sometimes a very real reduction in the dose of long-acting sul-
fonamides. The term 'depot sulfonamide' is applicable only in those
few cases where the active substance of short-acting and long-acting
sulfonamides is presented in slow-release form.
In the following text the term 'long-acting sulfonamide' will be
used according to the three-group classification for theoretical pur-
poses and the two-group system for discussion of practical questions
such as the interval between the doses. To avoid confusion it will
always be qualified as follows:
long-acting sulfonamide with a half-life of more than 8 h or
long-acting sulfonamide with a half-life of more than 16 h.
Such definitions are generally not given when long-acting sulfon-
amides are compared with short-acting sulfonamides in the literature.
There is a tendency to use the term 'long-acting sulfonamide' for
preparations introduced in the last ten years, i.e. since sulfametho-
xypyridazine, and 'short-acting sulfonamides' for all earlier ones.
Such a distinction is not consistent with reality, however, since
the new sulfonamides include some with a short, medium-Iong and
long action, and there have always been short-acting, medium-Iong-
acting and long-acting sulfonamides among the older preparations.
This question will be discussed in detail in the next section.

3. Cbronological Review 01 tbe more lmportant Sulfonamides

Although several thousand derivatives of the parent substance

sulfanilamide have been synthesized to date, scarcely more than
twenty to thirty of them are of particular interest for therapy on the
strength of their efficacy and tolerance (see list in appendix).
Among the earliest, which were investigated between 1936 and
1938, were sulfapyridine (No 2) and sulfacetamide (No 3). Sulfathiazole
(No 4) followed in 1939, and sulfadiazine (No 5), sulfamerazine (No 6)
and sulfathiocarbamide (No 7) in 1940-41. Of the seven compounds
mentioned so far, five have an average half-life of more than 8 h (12,
16-23). Retrospectively, therefore, these five can as justifiably be
termed 'long-acting' as later sulfonamides with a similar half-life.
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Sulfadiazine and sulfamerazine actually have an average half-life of

13 Antihiotica et Chemotherapia. vol. 14

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186 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments

17 and 24 h respectively. In ignorance of this fact (24) they were fre-

quently overdosed, with the result that side effects were frequent and
the use of the preparations alone was unjustly condemned (25, 26).
Other derivatives that followed were in chronologieal order
sulfaethidole (No 8), sulfadimidine (No 9), sulfadicramide (No 10),
and sulfabenzoylamide (No 11), and the short-acting preparations sulfa-
carbamide (No 12), sulfisomidine (No 13), sulfisoxazole (No 14)
and sulfamethylthiadiazole (No 15), which were often used in urinary
tract infections. All these sulfonamides were characterized by a
basieally similar, relatively broad, antibacterial spectrum which,
apart from a specific selectivity whieh varied from drug to drug,
embraced pneumococci, streptococci, meningococci, staphylococci,
E. coli, Shigella, Brucella and other organisms.
The years after 1945 saw the world-wide introduction of penicillin,
and this and subsequent discoveries in the antibiotic field diminished
the interest of hospitals, practitioners and research workers in the
sulfonamides. However, the pendulum has swung back again in the
last ten years. The main impetus comes from the concept of 'long-
acting sulfonamides' that has developed. Given in low doses which
are effective for a strikingly long period of time, they go a long way
towards meeting the needs of doctor and patient and, in addition, are
less likely to cause non-allergie side effects. Whilst long-acting sul-
fonamides are as old as the sulfonamides themselves, the new feature
with them is the surging interest in pharmacokinetic principles
and its consequences for dosage recommendations.
The modern sulfonamide age was heralded by a mixture of sulfame-
razine (No 6) and sulfaproxyline (No 16), which have a half-life of
approx. 24 and 12 h respectively. This was the first sulfonamide prep-
aration for which a three-times-daily dosage was recommended, al-
though in the light of present-day knowledge still fewer doses would
have been sufficient.
The older sulfonamides mentioned thus far can be classified
according to the two-group and three-group divisions defined above
as shown in the table opposite.
Sulfamethoxypyridazine (No 17), the first sulfonamide to be given
in a single daily dose, appearedin 1956. Its half-life, the longest known
at that time was some 34 h.
Sulfaphenazole (No 18) has a somewhat shorter half-life and is
comparablein this respect to two other sulfonamides, sulfadimethylox-
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azole (No 21) and sulfamethoxazole (No 22).

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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developrnents 187

Classification into 2 groups 'Older sulfonamides' Classification into 3 groups

Sulfathiazole
Sulfathiocarbamide
Sulfaethidole
Sulfadimidine
Short-acting short-acting
Sulfacarbamide
Sulfisomidine
Sulfisoxazole
Sulfarnethylthiadiazole
Sulfanilamide
Sulfapyridine
Sulfacetamide
Long-acting
Sulfadicramide
Sulfabenzoylamide
Sulfaproxyline
} rnediurn-Iong-acting

Sulfadiazine
Sulfarnerazine } long-acting

No
No
No No
o
o
o 11h
11h ~ N" 11

o
J- CHI

No

No 18** No 21 No 22
Sulfaphenazole Sulfadirnethyloxazole Sulfamethoxazole
half-life half-life half-life
10 h 11h 11h

In 1959 sulfadimethoxine (No 19), which has a half-life of appro-

ximately 40 h, was introduced into therapeutic practice. It was fol-
lowed a year later by sulfamethyldiazine (No 20), which is chemically
closely related to sulfamethoxydiazine (No 24). In both cases the sulfo-
namide radical is in position 2 and the methyl or methoxy group in
position 5 of the diazine ring. Their half-life is also very similar -
approximately 36 h.
The run of long-acting sulfonamides was interrupted by the intro-
duction of a short-acting drug, sulfachloropyridazine, and comes to
an end with the long-acting sulfamethoxypyrazine, sulfamethomidine
and sulformethoxine. The sulfonamides introduced during the last
ten years can be grouped as follows:

* SA = Sulfanilamide group.
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** See formulae in table at end of paper.

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188 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments

Classification into 2 groups 'Recent sulfonamides' Classification into 3 groups

Short-acting { Sulfachloropyridazine
Sulfaphenazole } short-acting

Sulfadimethyloxazole
Sulfamethoxazole } medium-long-acting

Sulfamethoxypyridazine
Sulfadimethoxine
Long-acting Sulfamethyldiazine
Sulfamethoxydiazine long-acting
Sulfamethoxypyrazine
Sulfamethomidine
Sulformethoxine

This chronological review shows again clearly that the simplifi-

cation often found in the literature-that 'recent' sulfonamides are syn-
onymous with 'long-acting' sulfonamides and 'older' sulfonamides
with 'short-acting' sulfonamides-is an unreliable guide. To avoid
confusion it is of the utmost importance that authors specify exactly
what sulfonamide they mean when they speak of 'long-acting' or
'short-acting' sulfonamides.
This chronological review of the more important sulfonamides
will have to be supplemented by the discussion of some present
problems.

4. Some Present Problems

Among the problems confronting us at the present time are the

following:

4.1 Is there any Difference in the in vitro Activity of Long-Acting

and Short-Acting Sulfonamides?

The point of view that is regularly put forward in the literature is

that long-acting sulfonamides Ce.g. with a half-life of more than 16 h)
are no more effective in vitro than short-acting, and that the only
difference is a pharmacokinetic one, a consequence of physical and
chemical properties not yet fully understood. In none of the articles
in which this rather facile opinion is maintained, however, is there any
reference to a systematic investigation of the in vitro activity of these
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two groups of substances. The literature in fact abounds in descrip-

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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 189

tions of sueh investigations, but these either embraee such a small

number of sulfonamides that statistical evaluation is impossible, or
they deal with preparations with practically no difference in their half-
life, or they report on trials in which the nutrient media are not free
or almost free of antagonists. The only investigation which does
not appear to violate any of these three principles is that carried out by
KRÜGER-THIEMER cf al. (17,21,23), who used Sauton nutrient media
to test a number of sulfonamides for their in vitro activity against Eschc-
richia coli. Among their aims these workers attempted to set up guiding
principles for the proper dosage of sulfonamides. Although they did
not carry out a direct comparison of the in vitro activity of short-acting
and long-acting sulfonamides, this question ean be answered on the
strength of their findings. Fig. 1 is agraphie representation of the in
vitro aetivity of short-aeting (above) and long-aeting sulfonamides
with a half-life of over 16 h (below), in inverse proportion to the length
of the bars.

Reference Halt-lif~ Minimum bact~riostatic concentration E.coUI}.lMol/ij

number [hour!Ü
12 Sulfacarbamide 3 i~ 32.21

7 Sulfathiocarbamide 3 ~s: 6.3 1

14 5 ulf isoxazole 6 2.15
8 Sulfaethidole 7 2.0

9 Sulfadimidine 7 1.7

4 Sultathiazole 4 1.6
13 Sulf isom idine 7 1.5

24 Sultamethoxydiazlne 37 2.0

25 Sultamethoxypyrazine 65 1.85
17 Sultamethoxypyri dazl ne 37 1.0
20 Sulfamethyldiazlne 35 1.0
11
6 Sulfamerazine 24 0.95

5 Sulfadiazine 17 0.9

27 Sultormethoxine 150 0.8

19 Sulfadimethoxine 40 0.7

Fig. 1. Comparison of the in vitro activity of short- and long-acting sulfonamides

(I short-acting sulfonamides with a half-llfe of less than 8 h, IIlong-acting sulfonamides
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with a half-life of more than 16 h).

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190 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments

Statistical analysis by means of the rank test yielded a highly

significant difference (p < 0.01) in favour of the long-acting sulfon-
amides (27). In other words, on the basis of these results, long-acting
sulfonamides are more effective in vitro against the tested strain of E.
coli than short-acting sulfonamides. This result stands in contrast
to the opinion generally held, which, let us repeat, has not been
systematically substantiated. Confirmation of these findings, possibly
using other pathogens, is therefore desirable. It is still too early to
conclude that a direct relationship exists between prolonged action
and high in vitro activity-although such a relationship may not a
priori be ruled out.

4.2 How far Does the Half-Life Depend on Chemical Structure?

An understanding of which chemical configuration confers a long

half-life on a sulfonamide would be useful in the methodical synthesis
of other classes of substances in which no long-acting preparations as
yet exist but are nevertheless desirable.
As early as 1945 it was observed (28) that the excretion of a sulfon-
amide was delayed by substitution of a methoxy group. The same
phenomenon was observed independently with 2-sulfanilamido-4,6-
dimethoxypyrimidine in 1947 (29). The latter sulfonamide has a half-
life of 40 hand is distinguished chemically from sulfadimidine (No 9)
only by having two methoxy instead of methyl groups. It thus re-
mains in the organism five to six times longer than the latter.

CHI OCH.

rn.(J-~ I'N
CH8~"W~-~
No 9
Sulfadimidine 2-Sulfanilamido-4,6-dimethoxypyrimidine
half-life half-life
7h 40h

Like its isomer 2-sulfanilamido-4,6-dimethoxypyrimidine (30), sul-

fadimethoxine (6-sulfanilamido-2,4-dimethoxypyrimidine, No 19) has
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a half-life of approximately 40 h.
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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 191

CH. OCHs
I I
,f'N ,f'N
SA I~ L
'~N/ CH • ~~NY-OCH.
No 13 No 19
Sulfisomidine Sulfadimethoxine
half-life half-life
7h 40 h

Sulfadimethoxine (No 19) is again distinguished from the short-

acting sulfonamide sulfisomidine (No 13) only by the replacement of
the two methyl groups by methoxy groups, whereby the half-life is in-
creased six-fold to approx. 40 h.
Side by side with these examples based on the substituted pyrimi-
dine ring there are others in the pyridazine, pyrazine and pyrazol
series. Thus the half-life of sulfamethoxypyridazine (No 17) is about
twice that of sulfapyridazine, which lacks the methoxy group:

the / =
~~ ""
,.y- 0CH.
of of ~ N-N 7

No 17
Sulfapyridazine Sulfamethoxypyridazine
half-life half-life
16 h 37 h

A secondary finding that has emerged is that replacing a methyl

group by chlorine as in sulfachloropyridazine (No 23) seems to reduce
the half-life, for it is only about 7 h:

/ >--
~-'\ N-N § Cl

No 23
Sulfachloropyridazine
half-life
7h

An example which indicates how the addition of a methoxy group

also lengthens the half-life in sulfonamides with a pyrazine ring, is
sulfamethoxypyrazine (No 25), which has a half-life of as long as 65 h
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compared with 16 h for sulfapyrazine without a methoxy group:

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192 StruBer, Long-Acting and Short-Acting Sulfonamides. Recent Developments

by OCH. --fN)
the
by ~-~N/
No 25
Sulfapyrazine Sulfamethoxypyrazine
half-life half-life
< 16 h 65 h

Sulfonamides with a pyrazol ring also acquire an increased half-

life an methoxylation.

that
the the &;;---~N-l""'-
I I OCHs
the
the the
I
C.H. C.H.
No 18
Sulfaphenazole 5-Sulfanilamido-1-phenol-3-
half-life methoxy-pyrazole
10 h half-life
50 h

These examples show that the effect of those sulfonamides to

which the methoxy group is added is prolonged. It is interesting to
note that none of the short-acting sulfonamides used therapeutically
incorporates a methoxy or other alkoxy group. It is unlikely to be a
matter of chance that all sulfonamides possessing an alkoxy group
studied up to now are long-acting preparations.
That other factors mayaiso influence the half-life of sulfonamides
in man is exemplified by sulfisomidine (No 13). If the sulfa group is
moved from position 6 in the pyrimidine ring to position 5 (I), the
resulting substance has a five times longer half-life.

eH. CHI

~(~m fSAf-~N
- ~NjJ.-CH.
No 13
Sulfisomidine 5-Sulfanilamido-2,4-dimethyl-
half-life pyrimidine
7h half-life
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35 h
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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 193

Sulfamethyldiazine (No 20) and sulfamethoxydiazine (No 24) also

show that the presence of a radical in position 5 of the pyrimidine
ring produces sulfonamides with a long half-life.

CH'-('N CH'O-('N
(JN
~N -y-fSAl ~m ~NjJ~
No 5 No 20 No 24
Sulfadiazine Sulfamethyldiazine Sulfamethoxydiazine
half-life half-life half-life
17 h 35 h 37 h

After the foregoing it is not surprising that sulformethoxine

(No 27), which has two methoxy groups, one of which is in position 5
of the pyrimidine ring, has an exceptionally long half-life of about
150 h:
long

ring, No
has No
No 27
Sulformethoxine
half-life
150 h

No prolongation of the half-life can probably be obtained by the

replacement of the free position 2 by the sulfonamide group or a
methoxy group. This is shown by a comparison of 4-sulfanilamido-6-
methoxypyrimidine, sulfadimethoxine (No 19) and 2-sulfanilamido-
4,6-dimethoxypyrimidine, all of which have a similar half-life:

have OCHs have

the
of !'N
~hNY-OCH. which
of
and
of of
No 19
4-Sulfanilamido-6- Sulfadimethoxine 2-Sulfanilamido-4,6-
methoxypyrimidine half-life dimethoxypyrimidine
half-life 40 h half-life
193.51.85.197 - 1/8/2020 9:47:29 PM

35 h 40 h
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194 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments

4.3 What Relationship Exists Between Ionization of a Sulfonamide

and its in vitro Effect? Do Short-Acting and Long-Acting Sulfonamides
Differ in this Respect?

An important physicochemical property of sulfonamides is their

degree of ionization in aqueous solution; this depends on the pH
value according to the law of mass action. The action of drugs such
as sulfonamides is a product of both their undissodated molecular and
ionic forms. The former is important for permeation of membranes,
and the latter for the chemotherapeutic effect. When the pK. of a
sulfonamide equals the pH of the solution, the compound will be
50% ionized and 50% non-ionized. As Figure 2 shows, such a situa-
tion occurs when sulfonamides with a pK. of 7.4 are dissolved in the
blood, the pH of which is also 7.4.

pKa- values of sulfonamides

1.0r---r---I-;;;;;;;::::::r--:::::=r-;:::;:::::=o-r-::::::~!='--:::;::;:::o..,

0 . 8r-~------4---~--r_--~r+--~~~--~~------~

0.6r-~------4-f_----t_+-----t--A-H--_H~--~-----~

c
.S! dissolved the the the the
~0.4r-~----~y-----~r---~~~rT-++-----~------~
o
.~
"ÖO.2r-~--~--4--7~--r-~-7~~~--~----~------~
...;;,
IV
C pK
4 pK pK pK pK pK 10
pH of the sol ution

Fig.2. Comparison between degree of dissociation and pKa values of sulfonamides.

Figure 2 also shows that:

a sulfonamide with a pK. of 5 is 99.5% dissodated
a sulfonamide with a pK. of 6 is 95.5% dissodated
a sulfonamide with a pK. of 7 is 70.0% dissodated and
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a sulfonamide with a pK. of 8 is 20.0% dissodated in the blood. It

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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 195

must be emphasized, however, that the chemotherapeutic effect de-

pends on the pB of the bacteria, and not on that of the blood.
On the theory that there is a relationship between the degree of
ioruzation and antibacterial action, BELL AND ROBLIN (31) in 1942
determined the pK. values of a number of sulfonamides and corre-
lated these with the minimum bacteriostatic concentration effective
against astrain of E. coN. Plotted as a graph, the results take the form
of a parabolic curve passing through a maximum in the region of pK.
= 6 to 7. Sulfonamides with a pKa of 6-7 therefore have a greater
antibacterial efficacy than other compounds. This phenomenon has
been associated with the electron-attracting properties of the R group :

NH.-Q-SO.-NHR

On the basis of the relative electron-attracting power of the N-

substituent, the authors (31) were able to predict the efficacy of any
given sulfonamide. COWLES (32) explains the shape of the curve as
being due to the fact that the cell wall is impermeable to ions. On the
assumption that the ionic form is the active one, a high ion con-
centration of the substance will have access to the bacteria if the
pK. value is dose to that of the pH at the site of action. KLOTZ
(33, 34) related the shape of the curve to the behaviour of sulfon-
amides toward enzymes.
Since maximum efficacy was observed to be associated with certain
pKa values, it was believed in 1942 that the preparations known at
that time had reached a maximum in this respect, and were unlikely
to be surpassed by any compounds discovered subsequently. The theo-
ry was prodaimed as crowning the development of increasingly
effective sulfonamides. This was true neither with respect to the linear
'pathogen-drug' complex, nor with respect to the triangular 'man-
pathogendrug' complex, as will be shown below.
Fig.3 shows the theory of BELL AND ROBLIN (31) applied to the
major sulfonamides that have made their appearance since 1942. The
in vitro data given in Figure 1 have been correlated with the pKa
values published variously (17, 18, 35-40).
Since long-acting sulfonamides (half-life > 16 h) have been shown
statistically to have significantly greater bacteriostatic powers against
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the tested strain of E. coH than short-acting (Figure 1), it is logical to

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196 StruB er, Long-Accing and Short-Accing Sulfonamides. Recent Developments

expect that the former will be found above a11 in the top reaches of
the curve (Figure 3), and the latter outside this range. The fo11owing
compilation shows that such is in fact the case:

Sulfonamides with pK. of 6-7

No. Name Half-life in hours

27 Sulformethoxine 150
25 Sulfamethoxypyrazine 65
19 Sulfadimethoxine 40
24 Sulfamethoxydiazine 37
20 Sulfamethyldiazine 35
6 Sulfamerazine 24
5 Sulfadiazine 17
22 Sulfamethoxazole 11

Sulfonamides with pK. <6and>7

No. Name Half-life in hours

17 Sulfamethoxypyridazine 37
11 Sulfamethoyl 14
3 Sulfacetamide 12
16 Sulfaproxyline 12
2 Sulfapyridine 12
10 Sulfadicramide 11
21 Sulfadimethyloxazole 11
18 Sulfaphenazole 10
8 Sulfaethidole 7
13 Sulfisomidine 7
9 Sulfadimidine 7
14 Sulfisoxazole 6
4 Sulfathiazole 4
7 Sulfathiocarbamide 3

From this table it will be seen that the most active preparations on
the curve described by BELL AND ROBLIN (31) are in the main the
long-acting sulfonamides. Since this is unlikely to be a coinddence,
the question arises, as to how far the good bacteriostatic activity of
the long-acting sulfonamides in vitro against the tested strain of E.
coli is due to their favourable pKa values. No satisfactory answer can be
given at present. Investigations in this field might make a contribu-
tion to understanding the mecharusm whereby sulfonamides exert
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their effect.
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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 197

o I I
I I
Sulfadiazine I
Sulfamethoxazo

Sulfadimethox Sulfamethyld iazine

Sulfamethoxazo I Developments
Sulfamethoxazo I Developments
Sulfamethoxazo Developments
Degree Developments
u.i Degree Degree Developments
c
o Degree Developments
~ Developments Developments
1:
4>
Developments
g-2 Developments Developments
o
u
u
~ Developments
'lii Developments
.g
4>
ti
Developments
.:g-3
I Sulfanilamide
E I
:::J
I
E
'c I
i
'E 99.5 99 98 95 9'0 ab 6'0 40 40 40 40 40 40 40
--
o
Cl
Degree of dissociation at pH 7.4

.9 1'0
1'0 1'0 1'0 1'0 1'0
pKa-values of sulfonamides

Fig.3. Comparison between pKa value of sulfonamides and minimum bacteriostatic

concentration against E. coli.

Perusal of Figure 3 leads to conjecture as to whether the curve as

plotted by BELL AND ROBLIN for E. coli can be reproduced for other
organisms, i.e. whether the data obtained for E. coli are generally valid
and can thus be taken as representative of the activity of a sulfonamide
against a variety of pathogens.
The in vitro findings of KRÜGER-THIEMER ct al. may be of help in
answering this question, for they have published not only findings on
E. coli but also the minimum bacteriostatic concentrations effective
against astrain of M ycobacterium smegmatis.
These bacteriostatic concentrations of various sulfonamides have
been correlated with the pK. values. Here too (41) the curve has a
parabolic form, very similar to that obtained for E. coli. Thus, the
efficacy of the various sulfonamides against E. coli corresponds largely
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198 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments

100+1--------~----,_+_--_+----+_--_+_r------~

80+1----~--~----~+_--_+----+_--_+_r------~

Fig.
4. 4. 4.4.
4. 4.
4.
~ 20t4----~--~--~~~~~~Vtt~~~~------~
:J 4.
o
L
4. 4. 4.
4.
c 10~~~~~~~~~~,W~~~~~~~------~
~ 8~~~~~~~~~~~~~~~~~~------~
D 4. 4. 4.
4.
'E
~ 4~~~~~~~~~~~~~--+_--_+_r------~
4.
o
.....
:J
'" 4.
b
QI
:'::
I 1+4----~--~----~+---_+----+_--_+_r------~
1ii 0.8 t4----~------'----~+---_+----+_--_+_r------~
I
1 2 4 8 10 20 40 80100
OJoLiposolubility in ethylene dichloride

Fig. 4. Comparison between half-life of sulfonamides in hours and % liposolubility in

ethylenedichloride (18): 1 Sulfanilamide ; 4 Sulfathiazole; 5 Sulfadiazine; 6 Sulfamerazine;
7 Sulfathiocarbamide; 8 Sulfaethidole; 9 Sulfadimidine; 13 Sulfisomidine; 14 Sulfisox-
azole; 17 Sulfamethoxypyridazine; 18 Sulfaphenazole; 19 Sulfadimethoxine; 20 Sulfa-
methyldiazine ; 21 Sulfadimethyloxazole; 22 Sulfamethoxazole; 23 Sulfachloropyridazine;
24 Sulfamethoxydiazine; 29 5-Sulfanilamido-2,4-dimethylpyrimidine; 30 4-Sulfanilamido-
6-methoxypyrimidine.

to their efficacy against the strain of Mycobacterium smegmatis

tested. Closer examination, however, will reveal a slight shift to the
more acid side as against the E. eoli curve. It would be interesting to
discover whether this shift is due to chance or whether it in fact cor-
responds to a biological reality. If the last possibility did hold good,
at least to some extent, and there are reasons for thinking it does so,
it would not be inconceivable that dissociation-activity curves could
be constructed for different species or groups of species of bacteria.

4.4 What Relationship Exists Between Half-Life, Liposolubility

and Protein Binding of Sulfonamides?

In the organism the sulfonamide has to permeate various cell

membranes. Good liposolubility of the undissociated molecule faci-
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litates and accelerates this process. The liposolubility of a substance

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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 199

can be measured by the percentage of the sulfonamide whieh, during

equilibration, passes from the aqueous phase at pH 7.4 into an equal
volume of the organic solvent. In order to find out whether there is
any relationship between the time needed by the organism to eliminate
the sulfonamide and its liposolubility the author studied the solubility
of sulfonamides in various lipid solvents with graduated dielectrical
constants.
Fig. 4, in which the half-life of sulfonamides is correlated with their
solubility in ethylene diehloride as established by RIEDER, shows that
the half-life is prolonged in proportion to the liposolubility. On the
whole, the long-acting sulfonamides are therefore more liposoluble
than short-acting compounds. This finding is important since it is
known nowadays that the permeation of membranes-such as the
gastric and intestinal mucosae and the blood brain barrier-by drugs
is facilitated by high liposolubility of the non-ionized moleeules
(43-45). Yet the various sulfonamides mentioned in Fig. 4 show a
relatively wide dispersion within this general trend which suggests
that the described relationship is influenced by a number of factors
not sufficiently known at the time. One is tempted to suppose that pro-
tein binding of the sulfonamides is of these. There can indeed be no
doubt that the binding to plasma proteins will affect at least the glo-
merular filtration of drugs into the primary urine, since only their un-
boundmolecules can normally pass through the glomerular membrane,
which in the healthy condition is impermeable to proteins.
RIEDER (18) has shown however that, in general, there is no cor-
relation between the percentage of protein binding of sulfonamides
and their half-life in man. It must therefore be assumed that the latter
will only be determined by the plasma protein binding in those sul-
fonamides which are not to a large extent reabsorbed or excreted
through the epithelium of the renal tubuli. In all other sulfonamides
one or both of these functions will rule out the importance of protein
binding. Once the sulfonamide is in the primary urine, either by pure
filtration or with additional secretion, the amount that is reabsorbed
through the tubular membrane-which is very rieh in lipids-depends
on the flow rate, the pH and the liposolubility of the sulfonamide. It
can be said that in general the amount of sulfonamide that is returned
into the blood increases in proportion to its liposolubility.
In Figure 6 the sulfonamides are classified into four groups ac-
cording to their plasma protein binding and their molecular weight.
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The close relationship that exists between protein binding and mole-
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 8
C/l
Sulfacarbamide Sulfathiazole Sulfadimethyl- Sultamerazine Sulfamethoxy- Sultadi- ......
oxazole diazine methoxine
Solubility n
=-...
in chloroform low 7% 35 % 49 % 51 °10 74 %
b
in ethylene
low 15 % 41 % 62 0 / 0 64 0 /0 79 %
dichloride

Amount of diffu- ° 23 % 12 % 25 °/0 13 °/0 1%

1
~.
si ble sulfonamide 9S 10
[

f
()Q
C/l
j e.

Way of renal filtration filtration pure filtration filtration

T [
filtration
!"

sulfon .- ex- plus secrMion ~

plus secretion plus seC retion filtration plus reabsorption plus reabsorption plus reabsorption
cretion
~
t:J
Half-life 3h 4h ll h 24 h 37 h 40 h

Fig. 5. Renal excretion of 6 sulfonamides.

1
!'"

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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 201

Plasma Molec. Names of Half-life in hours Solubili1y in tylinimum bac1erio-

Protein weight sulfonamides ethylene dichloride static conc. E.coli[.uMoIJ!)
bin ding

{ r"~;OOI'
c::::J 7 06 2.01 I
99 % 284
-100"10 -310
Sulfaphenazole c:::J 10 I 681 1.0 c:::J
Sulfadimethoxine I ~0tQJ 1 'jgl 0.70

~"{267 f'' '=.'

c::J 6 05 2.15 I I
Sulfisomidine c::::I 7 c::::::J 19 c:::::::::J
1. 5
-90% -280
Sulfamethaxydiazine I ~I I §!tI 2.0 I I
Sulfamethoxypyridazine I 371 I 70 I 1.0 r::::J

75%
-85%
{ {'""".....
255
267 Sulfamerazme
.

SUlfamethyldiaZine I
04
1 124
351
c:::J 15
1
I
~2 I
7Q I
1.6 I
1.0
1.0 c:::J
I
c::::::J

<75"10 {
172
-253
r~,·mld'
Sulfamethoxazole
Sulfadiazine I
c:::::J 11
c:::::J 11
117
011
c::::J 21
c:::=:J 26
[ßDi
0.8
0.9
c::J
c:::J
I

Fig. 6. Comparison between plasma protein-binding, molecular weight, half-life, lipo-

solubility and bacteriostatic concentration.

cular weight can also be seen from Figure 7. Figure 6 shows further
that sulfonamides with a similar protein binding but with a higher
solubility in lipids solvents have also a longer half-life. It seems there-
fore that the liposolubility of sulfonamides greatly influences their
half-life. This illustration proves also that the minimum bacteriostatic
concentration of a sulfonamide for the strain of E. coH mentioned
decreases, i.e. the antibacterial activity increases, in proportion to the
half-life of the sulfonamides.
This observation gave rise to the question whether sulfonamides
with higher liposolubility are more active than those with a low lipo-
solubility. As this problem does not seem to have been treated so far
in the literature it will be discussed below.

4.5 Relationship Between in vitro Activity and Liposolubility

In order to establish a possible relationship between in vitro

activity and liposolubility, the in vitro activity (17, 21, 23) was plotted
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14 Antibiotica et Chemotherapia, vol. 14

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202 Strullet, Long-Acting and Short-Acting Sulfonamides. Recent Developments

% Sulfaphenazole
Sulfadimethoxine ____ ""
100 Sulfaethidole.O ~.... ""'-'~
Sulfamethoxpyridazine -0 .
5-Sulfa-2/4-dimethylpyrimidine Sulformethoxlne .
. y.,..Sulfachlorpyndazlne
Sulflsoxazole •0 O+-Sulfamethoxydiazine
Sulfamethyldiazine - 0 q0.t-Sulfa~6-methoxy-
60 Sulfadimethyloxazole ----.. 0\ f'ynmldlne
Sultathiazole •0 \ Sulfisomidine
~ Sulfamethazine
5ulfamerazine
Sulfadimethyloxazole

60

5ulfamerazine
40

0>
~ 20
c sulfonamides protein-binding
D sulfonamides
I
C
'j;
b O+Sulfacarbamide
t1. 0
160 200 220 240 260 280 360 320
Molecular weight

Fig. 7. Comparison between molecular weight and protein-binding of sulfonamides

as a percentage.

on the ordinate and the solubility of sulfonamides in ethylene di-

chloride (18) on the abscissa (Fig. 8). The majority of sulfonamides,
namely 10 out of 14, are practically on the descending curve; this
means that strong in vitro activity coincides with higher solubility in
ethylene dichloride. However, sulfamethoxazole and sulfadiazine are
more active against E. eoli than their liposolubility would lead one to
expect. The contrary is true for sulfadimethyloxazole and sulfameth-
oxydiazine. So far, we havefound no explanationfor these exceptions.
The relationship is more complicated than can be established by
plotting the two parameters for such small numbers of sulfonamides.
As a whole it can be said that apparently high liposolubility of
sulfonamides predominantly coincides with marked antibacterial ac-
tivity, whereas poor in vitro activity is observed with sulfonamides of
193.51.85.197 - 1/8/2020 9:47:29 PM

low liposolubility.
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 StruBer, Long-Acting and Short-Acting Sulfonamides. Recent Developments 203

co4 SulfadimethyloxazoleoO
.Q ::;:

~~
t=
.. 0
Sulfathiazole Sulfamethoxydiazine
g ~2 Sulfathiazole
b
oUJ
u
u
Sulfathiazole
Sulfathiazole
• Sulfathiazole
SUlfaphenazole
~o /Sulfamethyldiazine

.
'e
2 Sulfadiazine -""'0 Sulfamethoxypyridazine

~
.0 Sulfamethoxazole
~ SUlfaphenazole
5 0.5 SUlfaphenazole
E
'e
~
2 5 10 20 50 100%
SolUbility of sulfonamideS in ethylene dichloride

Fig.8. Comparison between solubility of sulfonamides in ethylene dichloride and

minimum bacteriostatic concentration against E. co/i.

4.6 Is there a Relationship Between the Required Dosage of Sulfon-

amides and their Half-Life?

Since it is very difficult to determine the optimal dose of a sulfon-

amide in humans, a great number of experiments was carried out
in order to establish some guide lines. These experiments led to
important results. For instance the elose relationship between the
frequency oE administration per day and the half-life of the sulfon-
amide was again confirmed.
Figure 9 shows on the right the number of sulfonamide tablets of
500 mg recommended in the literature as average maintenance dose
(17,26,46). On the left side the sulfonamides are grouped according
to their average half-life (12, 16-23), the short-acting on top, the long-
acting below. The first 7 preparations belong to the short-acting
group, the remaining to the long-acting with a half-life of more than
8 h (hatched).
A comparison of the half-life with the number of tablets recom-
mended in the literature as average maintenance dose shows that with
some exceptions fewer tablets of long-acting sulfonamides have
to be administered than of short-acting preparations. Thus the
relation between dosage and activity is better with long than with
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short-acting sulfonamides.
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 204 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments

Number rrReterence number Number of tablets per day for average

of rHalf-lite in hours maintenance dosis
daily
doses { 12 02 Sulfacarbamide 22 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 00 0 0 0
Ultra- 6
short 70 3 Sulfathiocarbamide 190000 000000000000000

4 D 4 Sulfathiazole 15000000000000000

14 [:::::J 6 Sultisoxazole 13 0 0 0 0 0 0 0 0 0 0 0 0 0

Short 4 14 SUlfamethoxYPyraZine} 12 0 0 0 0 0 0 0 0 0 0 0 0

14 SUlfamethoxYPyraZine} 12 0 0 0 0 0 0 0 0 0 0 0 0

14 SUlfamethoxYPyraZine} 10 0 0 0 0 0 0 0 0 0 0

14 SUlfamethoxYPyraZine} 300 0

14 SUlfamethoxYPyraZine} Sulfonamides.
Medium- _ 14
long 2 3 SUlfamethoxYPyraZine} 20 0

14 SUlfamethoxYPyraZine} 9 0 00000000

14 9000000000
SUlfamethoxYPyraZine}
14 SUlfamethoxYPyraZine} 100000000000

14 SUlfamethoxYPyraZine} 70000000

14 1 .LJ..L.J.JIIL.U..LJ.J.l.II 35
L.l.J.llJ...I.JJL.U..LJ...L..LJ..L..1...U..1...U.1.l. Sulfamethyldiazine 1 0

14 LU.J..J.J...L.LJ.l.J.JL.U..L.U..U-L.LJ..L.J..J.J...L.LJ.l.J.JL.U..u.LJ 37 Sulta methoxypy ridazi n e 1 0

Long 4
14 L.J.J.J..J.J..llJ.l.J.JL.U..L.U...LJ..L..1...U.J..J.J...L.LJ.llJL.U..u.LJ 37 Sultamethoxydiazine 1 0

14 LLJ...L.LJ.l.J.J.l.J.JL.J..L.U-LJ..U.J..J.J...L.LJ..L.LJ...L.L.JL.U..U-Lull.J.,l1l 40 Sulfadimethoxine 1 0

Ultra- { 14 IIIt lIID 65 SUlfamethoxYPyraZine} 2 4

long M'TTTlTrlTrlrTTrTrTTTTTTTTlTrl"TT1rrT"rTTTTTTT'T'7 - once
14 LLJ...L.LJ...L.L.JL..L.LJL.J..L.L.U.J..L.L.u1u.1... 'fC.
1 U-LU-LJ..J.J..J...U.l.J.JII.....I.uIIu.I...... iIII[]] 150 Sultormethoxine weekly

Fig. 9. Comparison between half-life in hours and number of tablets 500 mg per day for
average maintenance dosis.

There seem to be several reasons for thls favorable relation in the

case of long-acting sulfonamides. On the one hand there is the good
in vitro activity shown already in Figure 1 which depends on certain
pK. values and the corresponding degree of dissociation as shown in
Figure 3. On the other hand the half-life is in most cases influenced by
the liposolubility of the sulfonamide. Last but not least there is the
protein binding whlch shows a certain correlation with the half-life
of some sulfonamides defined under 4.4 and also with the molecular
weight of most preparations as illustrated in Figure 7. The interesting
comparison of protein binding and half-life on the one hand and in
vitro activity of sulfonamides on the other is discussed by us elsewhere
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(41).
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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 205

Figure 9 shows further that the recommended maintenance doses

of sulfapyridine, sulfacetamide, sulfadiazine and sulfamerazine seem
to be too high. This was in fact confirmed by KRÜGER-THIEMER
et al. (17,23, 26), in extensive investigations proving again how little
pharmacokinetics were considered in earlier times when establishing
dosage recommendations. Fortunatelythe side effects causedespecially
by sulfamerazine and sulfadiazine did not entail the withdrawal of
these valuable sulfonamides. The principle of sulfa combinations
which led to the creation of the weIl known triple sulfonamides made
it possible to reduce the side effects caused by overdosage to a large
extent.
It is to be hoped that present dosage recommendations can be still
further improved by supplementing present parameters with the use
of possibilities such as calculation of the degree of dissociation of the
sulfonamides and their binding to certain bacterial proteins.

4.7 Clinical Testing of Long-Acting Sulfonamides in the Light

of Present Knowledge

Finally, abrief example will show how the clinical testing of

antibacterial substances is being continually improved. In the case
of urinary tract infections the usual findings are now complemented
by a quantitative bacterial count. The diagnosis can thus be made with
a far greater degree of certainty, and the course of disease can be
more readily followed. These are important supplementary conditions
for a more accurate appreciation of the value of antibacterial agents.
In Figure 10 the number of bacteria found in patients with chronic
urinary tract infections (left) are set against the course of the treat-
ment with sulfamethoxazole (bottom) (47). As will be seen a distinct
reduction in the bacterial count was obtained in a large proportion of
cases. These data help the doctor to find the most appropriate treat-
ment in each case and provide an important indication of the useful-
ness of apreparation.
These examples, it is hoped, have given an idea of the importance
attached to research on the use of new sulfonamides in the therapy of
infectious diseases. Oral chemotherapeutics which remain in the
blood and tissues for a considerable length of time without losing their
bacteriostatic powers, and which are characterized by good efficacy and
193.51.85.197 - 1/8/2020 9:47:29 PM

tolerance, approach the ideal in chemotherapy. The progress made in

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206 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments

the neld of the sulfonamides can serve as a model to therapy in general.

What is possible today with sulfonamides, may be possible tomorrow
in other nelds of medical endeavour.

10 9
21

21
10 8
21
21
21
107
21

21
>.
a.
10 6
21
.'"
~
.J::.

'-
21
21
...! 10 5
'"
'0
21
C 21
21
'"
~
21
....
0 10 4 21

.
.0
21
C 21
'-
:>
10 3

E
'- 21
~ 102
1/1
21
21
.E
01
21
.....
0 101
~
.0
E
~ 10 0
21 21 21 21 21 21 21 21 21 21 chronic

Fig. 10. Number of bacteria found in 21 patients (numbered to the right) with chronic
urinary tract infections before and after therapy with sulfamethoxazole.

5. Final Remarks

The last period of the 35-year history of the sulfonamides is

characterized by intensive studies of pharmacokinetics. These have
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resulted among other things in the recognition that the main factor
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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 207

which influences the dosage of a sulfonamide is the length of time

it remains in the organism. Nowadays sulfonamides are known
the dosage of which has to be only a fraction of that required for the
short-acting compounds. Consequently also the dose-effect ratio is
often more favorable for the long-acting than for the short-acting
sulfonamides.
In spite of these discoveries it still happens that a few long-acting
sulfonamides are given in many times higher than the actually useful
one. This is particulady so in the case of some long-acting sulfonam-
ides which have already been available for about 25 years. Because
of the pattly enormous overdosage much of the literature on side
effects of sulfonamides is practically invalid and needs revising.
The present review shows also that, in genetal, long-acting
sulfonamides are more active than short-acting compounds. This is
true not only in vivo-as alteady known-but also in vitro against
a tested strain of E. eoli.
The teview of the histoty of sulfonamides indicates that thete is
a cleat ttend towatds incteasingly active substances. Seen as a whole
mote and mote effective compounds wete introduced. This fact is of
importance because it justifies the hope that this development of the
past will continue also in the future. The coming 10 or 20 yeats may
bting along some highly effective sulfonamides which will ovetshad-
ow the ptesent ptepatations.
The hope fot such ptogtess is futthet based on the following
considetations. Unlike in the past the chemical, physical and phatma-
cokynetic factors which are essential fot the activity of the sulfon-
amides are now known. Intensive and systematic studies of these fac-
tors which should lead to the discovety of exttemely active substances
have not been initiated so far but ate to be expected in the future.
The following factots, which are impottant for the activity of a
sulfonamide, may be mentioned.
As explained, some specific changes in the moleeule prolong the
length of time a sulfonamide remains in the otganism and improve
the dose-effect tatio in genetal.
Comparison of the moleculat weight with the protein binding
shows that among the sulfonamides tested those with a highet molec-
ulat weight ate mostly bound to a latget percentage to plasma pro-
tein than those with a lowet moleculat weight.
If the sulfonamides ate classified according to theit moleculat
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weight ot theit ptotein binding into 4 groups the following telations

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208 StruBer, Long-Acting and Short-Acting Sulfonamides. Recent Developments

can be observed: the more liposoluble a sulfonamide is, the longer

will be the length of time it remains in the orgarusm and the better, in
general, its in vitro activity against the tested strain of E. eoli.
Even without such classification it becomes clear that, with a few
exceptions, sulfonamides show an in vitro activity against the tested
strain of E. eoli which is the higher the more liposoluble the sulfonam-
ide iso
With respect to the degree of dissociation it can be said that
sulfonamides which are 70-95.5% dissociated in the blood are the
most active against the tested strain of E. eoli.
These examples show that it is at least not unlikely that thorough
and systematic studies of these and other relations between bacte-
riological, physical, chemical and clirucal criteria will lead to the dis-
covery of sulfonamides with particularly interesting effects.
This outlook in the field of the sulfonamides could be improved
still more by attempts to further elucidate their mecharusm of action.
An interesting start in this direction has recently been made by
LAMENSANS (48). The mecharusm of action of the sulfonamides is
apparently more complicated than had been anticipated. The example
of sulfabenzamine, for instance, shows that there may be other me-
charusms of sulfonamide action which have not yet been studied in
detail. It is quite possible that investigation of these mecharusms will
show the way to specific syntheses of new antibacterial compounds.

Summary

After outlining the historical background of sulfonamides, the

recently investigated relationships between the various properties of
these drugs are discussed. These include the dose-effect ratio and its
relation to chemical constitution, length of time a sulfonamide remains
in the orgarusm, protein binding, liposolubility, and degree of dis-
sociation.
Recently, there has been a development towards increasingly effec-
tive sulfonamides. Such a trend encourages hope in the discovery of
new sulfonamides with antibacterial activity superior to that of exist-
ing sulfa drugs. This hope is all the more justified if the above criteria
are systematically studied with respect to their influence on the activ-
ity and if investigations on the mechanism of sulfonamide action
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continue.
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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 209

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23. KRÜGER-THIEMER, E.: Influence of protein binding on dosage regimens of chemo-

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bereitung ihrer klinischen Prüfung. Klin. Wschr. 40: 153-158 (1962).
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cological behavior of some derivatives of sulfadiazin. J. Pharmacol. exp. Ther. 83:
203-212 (1945).
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Aminobenzenesulphonamido-4,6-dimethoxypyrimidine. Brit. J. Pharmacol. 2: 149-
162 (1947).
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Untersuchungen über den antibakteriellen Wirkungsmodus der Sulfanilamide und der
4-Aminosalicylsäure. Jb. Borstel5: 651 (1961).
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Serums. Arzneimittelforsch. 11: 707-720 (1961).
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 Struller, Long-Acting and Short-Acting Sulfonamides. Recent Developments 211

47. HOIGNE, R.; HODLER, J. und STRULLER, TH.: Bakteriurie und Pyurie bei chronischen
Harnwegsinfekten. Praxis 53: 406-410 (1964).
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(Verlag Wien. med. Akad. 1967).

Au/hor's addms: Dr. med. Th. Struller, F. Hoffmann- LaRoche & Co. Ltd., Grenzacherstr. 124, CH-4002 Basle (Switzer-
land).

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 N
Appendix ....
N

H 0 Amount ....Cf)
Lipo- In vitro
11 Empirical Mol. of Half- solu- effect Some
N
"'- -0- S-N / R formula weigbt
sulfanil- pK. life bility E . ,oli ttade marks e-"
amide ;;-
H / - 11 "'- H (h) (%) (j.lMol/l)
R (%)
0 ."
1. Sulfanilamide -H C.H.O,N.S 172.21 100 10.5 11 10.5 128.0 Prontalbin
b
::l
Ojl
ClIHlIO.N,S 249.3 69.1 8.4 12 4.8 Dagenan >
n
2. Sulfapyridine
-C Eubasin 5'
Oll
-C-CH. ~
C.H1OO.N.S 214.25 80.4 5.4 12 2.0 2.3 Albucid CI.
3. Sulfacetamide 11 Cf)
0 Beocid p-
O

C.H.O,N.S. 255.33 67.4 7.1 4 15.3 1.6 Cibazol

"
4. Sulfathiazole ~
n
-~J Eleudron
5'
Oll
Cf)
5. Sulfadiazine CloHlOO.N.S 250.29 68.8 6.4 17 26.4 0.9 Debenal t:
- < : :> Pyrimal g;
::l
CH. §.CI.
6. Sulfamerazine N- / ClIH ..O.N.S 264.31 65.1 7.0 24 62.0 0.95 Debenal-M
Pyrimal-M "!"
- < N _> :xs
!:j
"
7. Sulfathiourea -C-NH. a
11
C.H.H.S. 231.30 74.5 4.8 3 6.3 Badional t:J
Sulfathiocarbamide S <l
"
e.
0
N-N Globucid '"0
8. Sulfaethidole ClOH120,N.S. 284.37 60.6 5.6 7 6.2 2.0 Sulfa- 8
-ZS}-CH. - CH. Perlongit fl
'"

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 0 Amount Ul
H "'- 11 R Lipo- In JJilro
Empirical Mol. of Half- solu~ Some
cffcct
......
N-Q-S-N/ formula weight sulfanil- pK. life s::
bility E.&oli trade marks
amide (h)
H / - 11 "'-H R (%) (~Mol/l)
0 (%)
....
CH.
"t-<
0
p
9. Sulfadimidine N-/ CIll
Sulfamethazine -,/ > C..H ..O.N.S 278.34 61.9 7.4 7 1.7 Diazil
"'- N = g.>-
"'-CH. (JQ

/ CH. ~
10. Sulfadicramide Ul
-C-CH=C CllH140.N.S 254.31 67.7 5.4 10.5 5.7 Irgamid t:r'
0
Sulfacryl I! " CH. ...7'
0
>-
-C-Q-CH.
g.
(JQ
11. Sulfamethoyl C.H180.N.S 304.37 56.6 4.9 14 2.8 Irgafen
11 - Ul
Sulfabenzoylamide 0 Pratonal
CH. ~
-C-NH. ~
12. Sulfacarbamide C,H.O.N.S 215.24 73.8 1.8 2.4 32.2 Euvernil e.
Sulfanilylurea 11 5.5 Tonil
0 ~
CH. ~
1 n
n
13. Sulfisomidine C"H140.N.S 278.34 61.9 7.4 7.0 19.0 1.5 Aristamid g
Sulfasomidine N Elkosin t::l
n
11 <
~N /"'-CH, !!..
0
'0

14. Sulfisoxazole
Sulfafurazole
-c
H.C "'--------/

JI ß
CH.
C11H130.N.S 267.31 64.44 4.9 6.0 4.8 2.15 Gantrisin I
"'-0/ N
t.»
-

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193.51.85.197 - 1/8/2020 9:47:29 PM
 N
0 .-
H Amount
Lipo- In vi/rn "'"
Empirical of Half- effect Some
Mol. solu·
'" -0 N -S11 - N / R sulfanil- pKa life IJJ
formula weigbt bility E . ro!i trade marks
amide (h) ......
H / - 11 "' H (%) (Il Mol / l)
0 R (%) cl

N-N .......
15. Sulfamethizole C.HlOO,N.S. 270.34 63.7 2.2 2.5 Lucosil t""'
0
Sulfamethylthiadiazole 11
~ S /~H. 5.5 Urolucosil 0

~
16. Sulfaproxyline g.
C1Q
-C -0- ,y ~ O-CH / CH. C18H" O.N.S 334.4 51.5 4.9 12 4.4 in DosuHin
~
11 - '" CH. 0-
0 IJJ
0-
Davosin
17. Sulfamethoxy- -/=~-OCH. ...70
CllHlOO.N.S 280.31 61.4 7.2 37 70.4 1.0 Kynex
pyridazine ' \ N-N f" Lederkyn >
a.
0
C1Q
IJJ
-[1 cl
N/
18. Sulfaphenazole C" HHO.N.S 314.37 54.8 5.9 10 68.0 1.0 Orisul ä'0
.2.
...0-
!"

...~
19. Sulfadimethoxine
6
_ ( OCH.
C12HHO.N.S 310.34 55.5 6.1 40 78.7 0.7 Madribon
fl
g
-( ~ ...<t:l
N -<
!!..
OCHs 0
'0

20. Sulfamethyldiazine CllH"O.N.S 264.31 65.1 6.7 35 69.6 1.0 Pallidin ...30
- < :: > - CH. ;;;

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 0 Amount
Lipo- In tJilro Vl
H "" 11 R of Half- ~
Empirical Mol. solu- efi'ect Some ....
N-Q-S-N / sulfanil- pKa life
formula weight bility E.&oli trade marks ~
H/ - 11 "'- H amide (h)
(%) (JlMol/l)
0 R (%)
.....'"
21. Sulfamoxole N - -CHa 267.31 7.4 11 4.0 Sulfuno
ClIHuO.N.S 64.4 41.4 b
11 11_ CH. ::I
Sulfadimethyloxazole "- 0 / Tardamid
~
22. Sulfamethoxazole C,oHllOaN.S 253.29 68.0 6.0 11 20.5 0.8 Gantanol
"::Ic.
O"CI
~olCH3 ~
0.-
Vl
23. Sulfachlorpyridazine C.oH.O.N.SCI 284.74 60.5 5.9 7 14.8 Nefrosullin ::r
0
- '/\ N-N"'--Cl
f" ...
24. Sulfamethoxydiazine CllH1203N.S 280.31 61.4 7 37 64.0 2.0 Bayrena ~
Sulfamonomethoxine - <: =>-OCH3 Durenat a.
::I
Kiron O"CI
Vl
CO N
25. Sulfamethoxypyrazine H3 X ) ~
::I
CllH120.N.S 280.31 61.4 6.1 65 1.85 Kelfizina
Sulfalene ~/ "
'2.
0.-
~
'"
/ OCH3 ~
Cl
26. Sulfamethomidine
J--~ C.. H1403N,S 294.34 58.7 6.1 27 Deposulf '"
~ N =/ Duroprozin ä
Ö
"" CH. <
'"
OCH. OCHs 5-
'0
8
27. Sulformethoxine C..H ..O.N.S 310.34 55.5 6.1 150 0.8 Fanasil '"fit::I
~-( N =/
....N
'"

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