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In Vitro Anti-Mycobacterium avium Activity of N-2-Hydroxyethyl-12-benzisothiazol-32H-one and -thione Carbamic Esters.

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42 1
In Vitro Anti-Mycohacterium avium Activity
In Vitro Anti-Mycobacterium avium Activity of
N- (2-Hydroxy eth yl)- 1,2-benzisothiazol-3(2H)-one and -thione
Carbamic Esters
Giuseppe Pagani,a) Pietro Borgna,a) Claudio Piersimoni,b) Domenico Nista, b, Marco Terrenia) and Massimo Pregnolato”’ a)
a)
Dipartimento di Chimica Farmaceutica, Universita degli Studi, via Taramelli 12, 27100 Pavia, Italy
b,
Dipartimento di Microbiologia Clinica, Policlinico “Umberto 1 - Torrette”, via Conca, 60020 Ancona, Italy
Key Words: N-[2-[(N-alkylcarbamoyl)oxy]ethyl]-l,2-benzis~thiazol-3(2H)-ones,
N-[2-[(N-alkylcarbamoyl)oxy]ethyl]-1,2benzisothiazol-3(2H)-thiones,Mycobacterium avium, anti-Mycobacterium activity
Summary
A series of N-(2-hydroxyethyl)- 1 . 2 - b e n r i ~ i a z o l - 3 ( ~ - 0 nand
e
-thionc carbamic esters have been synthesid and tested against
Mycokten’wn oriwn strains. The MIC values determined by the
radiometric broth dilution method w e n between 2 and 8 p@mL
for the benzimhiazolthione derivatives and between 16 and
32 pB/mL or higher for the corresponding benzisothiazolone denvati ves.
in order to assess the influence of the thiocarbonyl group and
of carbamoylation on activity.
Carbamic esters could be of interest in transport modulation
of alcohol derivatives in biological environments [I7]. The in
vitro activity of synthesised compounds on some M. avium
strains isolated from patients with AIDS (ISS 486 and AN
1-3) and on one type strain (ATCC 15769) were determined
by the radiometric broth dilution method.
Results and Discussion
Chemistry
Introduction
Disseminated infection with Mycobacterium avium complex (dMAC) is an increasingly frequent complication in
advanced human immunodeficiency virus (HIV) disease [1,21.
Unfortunately treatment of dMAC infection still remains a
challenge, mainly because no single drug or multidrug treatments seems to be able to eradicate dMAC in patients with
AIDS [3,41. Conventional antimycobacterial agents, such as
isoniazid and pyrazinamide are inactive against almost all
strains of M. avium;
drugs such as rifabutin, ethambutol,
and ciprofloxacin could be useful components of multidrug
treatment regimens of dMAC infection [8-91. The most valuable antimicrobial agents are the new macrolides azithromycin and clarithromycin [lo]. However, the selection of
resistant mutants occurs at a high rate even with macrolide
therapy and at the moment the most promising treatment
regimens are combinations of a macrolide and three or more
other drugs [*‘I.
The in vitro anti-M. tuberculosis activity seems not to be
related to the anti-M. avium activity; for instance, some new
pyrazinoic acid esters have interesting activity against M. tuberculosis but considerable lower activity against M .
avium [I2].
The 1,2-benzisothiazol-3(2H)-oneshave been reported as
antimicrobial agents of general interest [l3,l4I. Subsequent
studies demonstrated that N-hydroxyalkyl-l,2-benzisothiazol-3(2H)-one derivatives possess in vitro antibacterial activity against some strains of M. tuberculosis [I5]. Recently
the antimicrobial activity of some new N-hydroxyalkyl-1,2benzisothiazol-3(2H)-ones and -thiones have been reported [l6I. In this study, we report on the synthesis and activity
of new N-(2-hydroxyethyl)- 1,2-benzisothiazol-3(2H)-one
and -thione carbamic esters as potential anti M. avium agents,
Arch. P h a n . Phurm. Med. Chem.
Derivatives 3-7 were synthesised starting from N-(T-hydroxyethyl)-l,2-benzisothiazol-3(2H)-one2 [18-191 by treatment with the appropriate alkyl isocyanate in the presence of
catalytic amounts of diazobicyclo[2.2.2]octane(Dabco) or
ferric acetylacetonate Fe(acac)j (Scheme 1) C2O1.
3:R=C2H5
4: R=C3H7-n
5: R=C3H7-i
6: R=CqHg-n
7: R=CqHgf
)-NH*R
Scheme 1
Reaction of the 3H-1,2-benzodithiole-3-thione8 with
ethanolamine [21-22] gave a mixture of two isomers 9a and
9b in dynamic equilibrium and unseparable by conventional
preparative liquid chromatography (Scheme 2) [23-251.
The mixture 9a,b was reacted with the appropriate alkyl
isocyanate, by using Dabco or Fe(acac)3 as catalysts, to give
isomeric mixtures of N-(2-hydroxyethyl)- 1,Zbenzisothiazole-3(2H)-thione carbamic esters 10a-14a and N-(Zhydroxyethyl)-3-imino-3H- 1,2-benzodithiole carbamic esters
lob-14b. The identities of the two isomers were reliably
0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1996
036.5-6233/96/0809-0421 $5.00 + .25/0
422
Pregnolato and co-workers
9a
8
structure modification and the
anti-M. avium activity. The size of
the carbamoylic chains have no
substantial influence on the activity although could be more interesting in pharmacokinetic studies.
The severity of dMAC infection
in AIDS patients justifies further
SAR and toxicological studies on
more active compounds.
9b
NH-R
S
N w o Y
-
3
(cat.) o l Ne
~
0
@s
NR H
10a-14a
Scheme 2
Acknowledgements
lob-14b
Financial support for this research by the
Istituto Superiore Saniti - Roma (Progetto
tuhercolosi) is gratefully acknowledged.
We thank Prof. A. 1. Gamha for obtaining
the NMR spectra and Dr. D. Pezzuto for
technical assistance.
10: R=C2H5
11: R=CjH7-n
12: R=C3H7-i
13: R4q Hg -n
14: R=CdHg-t
confirmed by 'H, 13C NMR and MS analyses of representative compounds 14a and 14b separated as pure compounds by flash chromatography (eluent: hexane/ethyl
acetate (75 :25)). A diagnostic feature of isomers 14a and 14b
is the chemical shift of the methylene protons adjacent to the
nitrogen atom
the protons of isomers (a) being downfield
(6 4.61) and the protons of isomers (b) being upfield (6 3.61).
Furthermore the I3C NMR spectrum of compound 14a shows
a peak at 6 185.79 (C=S) while the presence of a C=N group
in compound 14b is evidenced by the presence of a characteristic resonance at 165.54 ppm.
We have observed (by HPLC and NMR analysis) that pure
compound 14a rapidly establishes an equilibrium with 14b
upon dissolution in polar solvents (DMSO or acetone/water)
commonly employed in biological tests. The same behaviour
has been observed for pure 14b that rapidly interconverted
with 14a (HPLC tR 13.22 and 8.28 min). As a consequence
of these observations mixtures (a,b) were not separated as
single pure isomers.
Anti-Mycobacterium Avium Activity
Table 1. In vitro anti-M. U
Compound MAC
ATCC
15769
V ~ activity
U ~
(MIC in Fg/ml).
MAC
ISS
486
MAC
AN 1
MAC
AN2
MAC
AN3
2
32
32
32
>32
32
3
>32
>32
16
>32
16
4
>32
16
16
>32
16
5
16
16
16
>32
16
6
16
16
16
>32
16
7
>32
>32
>32
>32
>32
9a,b
8
4
2
8
2
10a,b
4
4
4
8
4
lla,b
4
4
4
16
4
12a,b
8
4
2
4
2
13a,h
4
4
i
7
4
2
Four M. aviurn strains (ISS 486 and AN 1-3) isolated from
14a,b
8
4
2
4
2
blood of AIDS patients and identified to the species level by
Ethambutol 2
I
0.5
2
RNA-DNA hybridization (Gen-Probe, San Diego, USA), and
the type strain ATCC 15769 were evaluated in this study. The
in vitro anti-M. avium activities of the N-(2-hydroxyethyl)1,2-benzisothiazol-3(2H)-onecarbamic esters 3-7 and of the Experimental
N-(2-hydroxyethyl)-l,2-benzisothiazole-3(2H)-thione10aChemistry. Reactions were monitored by thin layer chromatography on
14a and N-(2-hydroxyethyl)-3-imino-3H-l,2-benzodithiole 0.25 mm Merck silica gel (60 F m ) and visualised by UV light (h = 254 or
lob-14b carbamic esters as isomeric mixtures are reported 365 nm); flash chromatography was done using silica gel 60 (60-200 pm,
in Table 1. Biological results illustrate the good anti-M. avium Merck). Melting points were measured using a Kofler hot-stage apparatus
activity obtained with mixtures (a,b) (MIC between 2 and 8 and are uncorrected. 'H and I3C NMR were recorded at 300 MHz and
pg/ml). Activity of compounds 3-7 was generally poor, al- 75.46 MHr using a Bruker ACE-300 spectrometer, in CDC13. 'H chemical
shifts (6) were reported with MejSi (6 = 0.00 ppm) as internal standard. 13C
though several compounds have some anti-M. avium activity
chemical shifts (6) were reported with CHCI3 (central peak, 6 = 77.00 ppm)
(MIC = 16 pg/ml).
as internal standard. The following abbreviations are used: br = broad,
The substitution of sulphur for oxygen in the ketobenziso- s = singlet, d = doublet, dd = double doublet, t = triplet, dt = double triplet
thiazole system effects important modifications on the elec- and m = multiplet. Mass spectra were obtained on a Finnigan MAT 8222
tronic structure and increases the lypophilicity of the spectrometer using the direct inlet. Electron ionisation was performed at
molecule, suggesting a possible relationships between this 70 eV and 0.5 mA with a source temperature of 250 "C. Elemental analyses
Arch. Pham. Pham. Med. Chein. 329,421425 (1996)
423
In Vitro Anti-Mycobacterium avium Activity
Table 2. Physicochemical data of compounds 3-7.
Compd.
3
Mass d z (% ra)
'H NMR (CDC13)
C12H14N203S
266(M+,Il), 177 (loo), 164 (16),
151 (15), 136 (16)
61.13 (t. 3H, CH3), 3.21 (m, 2H, NH-CHd,
4.15 (t, 2H, N-CHz), 4.35 (t, 2H, 0-CHZ), 4.80 (bs,
1H, NH), 7.35-7.70 (m, 3H, Ar), 8.04 (d, 1H, H-4)
C13H16N203S
280 (Mf,12), 177 (100). 164 (13),
151 (8), 136 (20)
6 0.90 (t,3H, CH,), 1.50 (m, 2H, CH,),
3.13 (9, 2H, NH-CH2), 4.15 (t, 2H, N-CHZ),
4.35 (t, 2H, O-CHz), 4.80 (bs, IH, NH),
7.35-7.70 (m, 3H, Ar),8.02 (d, IH, H-4)
92
c I 3H16N203S
280 (M',12), 177 (loo), 164 (13),
151 (8), 136 (22)
6 1.10 (d, 6H, CH3), 3,79 (m, IH, NH-CH),
4.15 (t, 2H, N-CHz), 4.35 (t, 2H, 0-CH,),
4,80 (bs, lH, NH), 7.20-7.60 (m. 3H, Ar),
8.06 (d, IH, H-4)
78
14Hl 8N203S
294 (M+,10), 177 (loo), 164 (13),
151 (8), 136(18)
6 0.90 (t, 3H, CH3), 1,32 (m, 2H, CH2-CH3),
mp "C
Yield
(solvents) (%)
Analyses
86-88
85
100-102 82
(C, H, N)
(A)
4
(A)
5
105-107
(A)
6
82-84
(A)
7
136-138
90
14H1XN203S
(A)
294 (M',lO), 177 (IOO), 164 (13),
151 (8), 136 (16)
1.46 (m, 2H, 2 CH2), 3.16 ( q, H, NH-CH2),
4.15 (t, 2H, N-CHz), 4.35 (t, 2H, 0-CHZ),
4.80 (bs, IH, NH),7.40-7.65 (m, 3H,Ar),
8.04 (d, IH, H-4)
6 1.25 (s, 9H, CH3), 4.15 (t, 2H, N-CHz),
4.35 (t. 2H, O-CH2), 4.80 (bs, IH, NH),
7.35-7.70 (m, 3H, Ar), 8.04 (d, IH, H-4)
(A): Ethyl acetate /petroleum ether
Table 3. Physicochemical data of compounds lOa,b-l4a,b.
Compd
mp "C
Yield
(solvents) %
Analyses
Mass d
z (% ra)
'H NMR (CDCl,)
(C, H, N)
-
10a,b
-
70
C12H14N202S2
282 (Mf,30), 193 (loo), 167 (go),
149 (23), 134 (12), 116 (65), 72 (18)
6 1.15 (t, lOa,b: 6H, CH3), 3.23 (m, 10a,b: 4H,
CHzNH), 3.62 (t, lob: 2H, N-CHz), 4.49 (t, lob: 2H,
0-CHz), 4.70 (t, 10a: 2H, N-CH2and bs, 2H, NH),
7.26-7.35 (m, 10a,b: 4H, H5 and H-6),
7.46 (d, 10a,b: 2H, H-7), 8.02 (d, lob: 2H, H-4),
8.40 (d, 1Oa: 2H, H-4).
lla,b
-
68
C13H16N202S2
296 (M', 7), 193 (loo), 167 (18),
149 (lo), 130 (71), 108 (20), 88 (17)
6 0.90 (t. lla,b: 6H, CH& 1.40-1.60 (m, lla,b: 4H,
CH,), 3.12 (m, lla,b: 2H, CH2NH), 3.61 (t, llb: 2H,
N-CHz), 4.48 (t. lla,b: 4H, 0-CH2), 4.68 (t, lla: 2H,
N-CHz), 4.93 (bs, 2H, NH),7.10-7.40 (m, lla,b:
8H, H5-7), 8.02 (d, llb: 2H, H-4),
8.38 (d, l l a : 2H, H-4).
12a,b
-
75
C13H16N202S2
238 (M', 3 , 1 9 3 (loo), 180 (13),
166 (15), 130 (42), 88 (51), 64 (8)
6 1.15 (d, 12a,b: 9H, N-CH2), 3.58 (t, 12b: 2H, N-CH2),
13a,b
-
65
C14H1 XNZ0ZS2
310 (M', 4), 193 (loo), 180 (15),
167 (17), 144 (74), 88 (31), 57 (18)
(m, 12a,b: 2H, N-CH), 3.80 4.52 (t, 12a,b: 4H, 0-CH2),
4.63 (bs, 2H, NH), 4.69 (t. 12a: 2H, N-CH2),
7.23-7.50 (m, lla,b: 8H, H5-7), 8.00 (d, 12b: 2H, H-4),
8.39 (d, 12a: 2H, H-4).
6 0.90 (t. 13a,b: 6H, CH3). 1.32 and 1.48 (m, 13a,b:
4H each, CH2), 3.19 (m, 13a,b: 2H,CH2NH),
3.62 (t. 13b: 2H, N-CHz), 4.49 (t, 13a,b: 4H, 0-CH2),
3 68 (t. 13a: 2H, N-CH2), 4.75 (bs, 2H, NH),
7.27-7.33 (m, 13a,b: 4H, H5 and H-6), 7.43-7.52
(m. 13a,b: 2H, H-7), 8.04 (d, 13b: 2H, H-4),
8.36 (d, 13a: 2H, H-4).
14a
15540
(A)
310 (M', 24), 193 (IOO), 180 (22),
167 (30), 135 (13), 108 (15), 88 (go),
57 (29)
6 1.32 (s, 9H, CH3), 4.45 (t, 2H, 0-CHz),
4.68 (t. 2H, N-CHz), 4.78 (bs, IH, NH),
7.49 (m, 2H, H5 and H-6), 7.69 (d, lH, H-7),
8.38 (d, lH, H-4).
14b
69-72
(A)
310 (M', 8), 295 (5), 238 (7),
193 (IOO), 180 (lo), 167 (12), 144 (9),
88 (37).
6 1.32 (s, 9H, CH,), 3.60 (t. 2H, N-CH,), 4.43
(A): Ethyl acetate /petroleum ether.
Arch. Pharm. Pharm. Med. Chem. 329,421425 (19%)
(t, 2H, 0-CHz), 4.78 (bs, lH, NH), 7.30-7.48
(m, 3H, H-5, H-6, H-7), 8.05 (d, 1H, H-4).
424
indicated by the symbols were within 0.35% of the theoretical values and
were performed on a Carlo Erba 1106 Elemental Analyser. Retention times
(tR) were assessed by analytical RP-HPLC with a Hewlett Packard 1050
equipped with a 79853C multiwavelength detector, on a RP-18 LiChroCART 250-4 (Merk).
The operational conditions were: CH3CN/H20 (70:30) as solvent, flow
rate 0.8 mL/min. UV detection at h = 254 nm.
N-(2-Hydroxyethyl)-I , 2-benzisothiazol-3(2H)-one(2)
This compound was prepared as reported in reference [19]. Yield 82 9%.
~p 110-13 T (ethyl acetate). HPLC tR 4.64 min. 'H NMR: 6 3.95 (t, 2 ~ 1 ,
N-CH2), 4.05 (t, 2H, 0-CHz), 7.41 (dt, IH, H-5, J4.5 = J5.6 = 8.0 Hz. J5.7 =
1.0 Hs), 7.55 (dt, IH, H-7, J6.7 = 8.0 Hz, J5.7 = 1.0 Hz), 7.62 (dt, lH, H-6.
J7.6 = J5.6 = 8.0 Hz, J4,6 = 1.0 Hz, 1H), 8.03 (dt, 1H, H-4, J s , =
~ 8.0 HZ, J6,4
= 1.0 Hz). MS dz,(% ra): 195 (M+, 28), 164 (90), 152 (38), 151 (loo), 136
(41). Anal. ( C Y H ~ N O ~ ) .
Syn/hesis of Compounds 3 , 4 , 6
A solution of N-hydroxyethyl- 1,2-benzisothiazol-3(2H)-one(2) (3 mmol)
in 15 in1 of dry xylene was added dropped to a suspension of Dabco
(0.3 mmol) and the appropriate isocyanate (4 mmol) in the same solvent
(15 ml), with stirring. The reaction mixture was refluxed for 4-5 h, the
solvent was removed under reduced pressure and the residue purified by flash
chromatography (eluting system n-hexanelethyl acetate). Physicochemical
data are reported in Table 2.
Synthesis o j Compounds 5, 7
A solution of N-hydroxyethyl-l,2-benzisothiazol-3(2H)-one
(2) (3 mmol)
in 15 ml of dry CC14 was added dropwise to a suspension of Fe(acac)i
(0.3 mmol) and the appropriate isocyanate (4.5 mmol) in the same solvent
( I 5 ml) with stirring, at 50 "C and under nitrogen. The reaction mixture was
refluxed for 1 h, the solvent was removed under reduced pressure and the
residue purified through flash chromatography (eluting system n-hexane/ethyl acetate). Physicochemical data are reported in Table 2.
i~-12-Hydroxyethgl)-l,2-benzi~othiazole-3(2H)-thione
and N-(2-Hydroxyethyl)-3-irnino-3H-l,2-benzodithiole
(9a,b)
Ethanolamine (81 mmol) was added to a solution of 3H-1,2-benzodithiole3-thione 12'] (54 mmol) in 40 ml of ethanol. The mixture was refluxed for
3 h, the solvent was removed under reduced pressure and the residue purified
through flash chromatography (63 % yields, eluting system n-hexanelethyl
acetate (1:l)). HPLC tR 5.41 and 7.64 min. 'H NMR: 6 3.51 (t, 9b: 2H,
N-CHz), 4.00 (t, 9b: 2H, O-CH2), 4.11 (t, 9a: 2H, O-CHz), 4.51 (t, 9a: 2H,
N-CHz), 7.22-7.70 (m, 6H, Ar), 8.01 (d,9b: IH, H-4), 8.34 (d, 9a: IH, H-4).
MS m/z (% ra): 21 I (M+, 47), 180 (loo), 178 (78), 167 (43), 152 (8), 134
(18). Anal. (CgHgNOS2).
Synthesis of Compounds 1Oa,b, lla,b, 13a,b
Pregnolato and co-workers
Microbiology
Stock solutions were made in methanol (derivatives 3-7) and in dimethyl
sulfoxide (derivatives lOa,b-l4a,b). Working solutions, whose concentrations were 40-fold greater than the desired concentrations, were made from
stock solutions in sterile distilled water, except for derivatives lOa,b-l4a,b
which were diluted in DMSO. We verified that methanol in a 50% acqueous
solution (final concentration 1.25%) did not suppress or delay M. avium
strains growth. In the same way, the alternative solvent, DMSO, did not
suppress growth when added undiluted (producing 5% concentration in the
medium).
Ethambutol, as reference drug, was employed in the screening.
Radiometric Method
The growth of bacteria was recorded radiometrically by using the BACTEC 460-TB system (Becton Dickinson, Sparks, USA). Growth in 7H12
liquid medium (Becton Dickinson) containing 14C-labeled palmitic acid
leads to the consumption of this substrate, with subsequent release of I4CO2
in the confined atmos here above the medium.'2h1The BACTEC instrument
detects the amount of 4C02 and records it as a Growth Index (GI) on a scale
from 0 to 999.
?
MIC Determination in 7H12 Broth
For broth-determined MIC all substances were added to respective 7H12
vials in a volume of0. 1 ml per vial to achieve serial doubling concentrations.
A 7H12 broth seed vial was cultivated and recorded daily until it reached the
maximum GI, then the culture was diluted 1:100 and 0.1 ml of this dilution
was inoculated in the test vials and in one of the substance-free control vials.
The colony counts on agar plates were used to calculate the number of colony
forming units (CFU) per one ml, such an inoculum provides an initial
bacterial concentration of lo4 to lo5 CFU/ml.
Another substance-free control vial, the 1: I00 control, was inoculated with
a bacterial suspension I00 times lower to provide 10' 10' CFU/ml, representing 1% of the bacterial population. The vials were incubated at 37"C, and
the GI readings were recorded daily in the BACTEC 460 instrument.
According to previous studies by Heifet~,'~'-~*'
the broth-determined MIC
by the BACTEC system was defined as the lowest substance concentration
in presence of which the final GI reading was no greater than 50 after 8 days
of incubation. During the same period the GI of 1:100 diluted control was
greater than 20 for three consecutive days, while the growth in the undiluted
control reached the maximum GI reading of 999 no earlier than the fourth
day of cultivation.
MIC validation. To verify that the MIC was the lowest concentration
inhibiting the growth of more than 99% of the bacterial population, we
decided to perform the CFU/ml counts sampling from the broth vials and
plating on 7H10 agar only for the type strain ATCC 15769.
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(3 mmol) and Dabco (0.3 mmol) in dry benzene (50 mL) under stirring. The
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solvent was removed under reduced pressure and the residue purified through
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In Vitro Anti-Mycobacterium avium Activity
425
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Received: May 31, 1996 [FP127]
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hydroxyethyl, avium, one, esters, 32h, mycobacterium, thione, activity, carbamic, anti, vitro, benzisothiazol
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