Synthesis of α-[5-(5-amino-1,3,4-thiadiazol-2-yl)-2-imidazolylthio] acetic acids

Article abstract of DOI:10.1002/jhet.5570450537

(Chemical Equation Presented) The paper describes synthesis and antituberculosis activity of α-[5-(5-amino-1,3,4-thiadiazol-2-yl)- imidazol-2-ylthio]acetic acids (5a,b). The compounds were tested against Mycobacterium tuberculosis strain H37Rv in comparis

Full text of DOI:10.1002/jhet.5570450537

Sep-Oct 2008
1477
Synthesis of ꢀ-[5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-
imidazolylthio]acetic acids
Farzin Hadizadeh1,2* , Rahil Vosooghi1
1Department of Medicinal Chemistry, Pharmacy Faculty, Mashhad University of Medical Sciences, Mashhad,
P.O.Box 91775-1365, Iran; 2Biotechnology and Pharmaceutical Research Center, Mashhad University of
Medical sciences, Mashhad, Iran
hadizadehf@mums.ac.ir
Received September 15, 2007
R
HOOCH2CS
N
CH
N
NH
C
S
NH2
N
4a,b
NH4Fe(SO4).12H2O
R
HOOCH2CS
NH2
S
N
N
N
N
5a,b
R = (a) CH3 , (b) CH2C6H5
The paper describes synthesis and antituberculosis activity of ꢀ-[5-(5-amino-1,3,4-thiadiazol-2-yl)-
imidazol-2-ylthio]acetic acids (5a,b). The compounds were tested against Mycobacterium tuberculosis
strain H37Rv in comparison to rifampicin. Compounds exhibited low activity (MIC ꢀ 6.25 μg/ml, %
inhibition ꢁ 24).
J. Heterocyclic Chem., 45, 1477 (2008).
INTRODUCTION
1,3,4-thiadiazol-2-yl)imidazol-2-ylthio]acetic acids (5a,b).
1-Alkyl-2-mercapto-5-hydroxymethylimidazoles (1a,b)
were synthesized from dihydroxyacetone, potassium
thiocyanate and alkylamine hydrochloride as described
previously [9]. Treatment of the latter with ethyl
bromoacetate gave ꢀ-[1-alkyl-5-hydroxymethyl-2-
imidazolylthio]acetic acid (2a,b).
The treatment of mycobacterial infections has become
an important and challenging problem because of the
emergence of multiple-drug-resistance organisms and
because of the acquired immunodeficiency syndrome
(AIDS) pandemic [1]. The high rates of drug – resistant
tuberculosis currently reported in many countries are
alarming, science among this phenomenon rapid drug
susceptibility tests are needed and effective chemotherapy
regimens with newly developed drugs are urgently being
sought [2].
Recently the synthesis of some alkyl ꢀ-(5-aryl-1,3,4 -
thiadiazol-2-ylthio)acetates and 2-(5-nitro-2-furyl)- and
2-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,3,4-thiadiazole
derivatives as potential antituberculosis agents has been
reported [3,4]. The 1,3,4-thiadiazole ring system have
incorporated in many substances with antibacterial,
amoebicide, parasiticide and antifungal activity [5,6]. In
addition imidazole derivatives are known to posses
antimicrobial activity [7,8]. Accordingly we designed and
synthesized ꢀ-[5-(5-amino-1,3,4-thiadiazol-2-yl)-2-imida-
zolylthio]acetic acids (5a,b). The compounds were tested
for antituberculosis activity.
Scheme 1
R
R
HOOCH2CS
BrCH2COOEt
HS
N
N
MnO2
CH2OH
CH2OH
N
N
MeOH, NaOH
1a,b
2a,b
R
N
R
HOOCH2CS
HOOCH2CS
N
CHO
CH
N
NH
C
S
NH2
N
H2NNH CNH2
S
N
4a,b
3a,b
R
HOOCH2CS
NH4Fe(SO4).12H2O
NH2
N
S
N
R = (a) CH3 , (b) CH2C6H5
N
N
5a,b
RESULTS AND DISCUSSION
Oxidation of 2a,b with manganese dioxide afforded ꢀ-
[1-alkyl-5-formyl-2-imidazolylthio]acetic acid (3a,b).
Condensation of the 3a,b with thiosemicarbazide gave the
Scheme 1 outline the synthetic sequences employed in
our laboratories for preparation of the ꢀ-[5-(5-amino-

1478
F. Hadizadeh, R. Vosooghi
Vol 45
2-(5-Formyl-1-benzyl-2-imidazolylthio)acetic acid (3b).
This compound was obtained in 95% yield as an oil; ir (CHCl3):
1700 (CO acid), 1645 cm-1 (CO aldehyde); 1H nmr
(CDCl3): ꢂ 3.73 (s, 2H, CH2S), 5.42 (s, 2H, CH2N), 6.81-7.23
(m, 5H, arom), 7.64 (s, 1H, H-C4 imidazole), 9.53 ppm (s, 1H,
CHO); Anal. Calcd. for C13H12N2O3S: C, 56.51; H, 4.38; N,
10.14. Found: C, 56.59; H, 4.48; N, 10.23.
intermediate thiosemicarbazones (4a,b). Oxidative ring
closure of the latter with iron (III) ammonium
sulfate.12H2O produced ꢀ-[5-(5-amino-1,3,4-thiadiazol-
2-yl)-1-alkyl-2-imidazolylthio] acetic acid (5a,b).
Title compounds 5a,b were evaluated in vitro for anti
tuberculosis activity against Mycobacterium tuberculosis
strain H37Rv in comparison to rifampicin as part of
TAACF TB screening program under direction of the
U.S. National institute of Health, NIAID division.
Compounds exhibited low activity (MIC ꢀ 6.25μg/ml, %
inhibition ꢁ 24)
General Procedure for preparation of 2-carboxy-
methylthio-1-alkylimidazol-5-thiosemicarbazone (4a,b). To a
stirring mixture of compound 3a, b (11.95 mmoles) in ethanol
(168 mL), conc. hydrochloric acid (0.16 mL) was added. The
reaction mixture was heated for 10 minutes and the reaction
progress followed by TLC. After cooling, the white precipitate
was collected by filtration, washed with H2O and dried to give
compound 4a,b, which were used directly at the next step.
General Procedure for preparation of ꢀ-[5-(5-Amino-
EXPERIMENTAL
1,3,4-thiadiazol-2-yl)-1-alkyl-2-imidazolylthio]acetic
acid
Melting points were determined on Electrothermal Capillary
apparatus and are uncorrected. The ir spectra were obtained
using a Perkin-Elmer Model 1000. H nmr were obtained on
Bruker Ac-80 spectrophotometer and chemical shifts (ꢂ) are in
ppm relative to internal tetramethylsilane. Errors of elemental
analyses were within ±0.4% of theoretical values. Compounds
1a, b were prepared as described previously [9].
(5a,b). A stirring solution of compound 4 (1.82 mmoles) and
iron (III) ammonium sulfate.12H2O (1 g, 2.07 mmoles) in
distilled water (15 mL) was refluxed for 4 hours. Again iron (III)
ammonium sulfate.12H2O (1 g, 2.07 mmoles) and distilled water
(30 mL) was added and the reflux continued for 4 hours. After
cooling the precipitate was collected by filtration and washed
with distilled water to give compounds 5a, b.
1
General Procedure for preparation of 2-(5-hydroxy-
methyl-1-alkyl-2-imidazolylthio)acetic acid (2a,b). To a
stirring suspension of compound 1a, b (22.7 mmoles) in
methanol (370 ml) was added dropwise sodium hydroxide (1.0
N, 24 mL) at room temperature. The clear pale yellow
suspension was stirred for 10 minutes. Ethyl bromoacetate (66
mmoles, 5.5 mL) was added dropwise and stirring was
continued overnight. After evaporation of the methanol, the
residue was suspended in water (250 mL) and extracted with
chloroform (3 x 100 mL). The solvent was evaporated to give
compounds 2a,b.
ꢀ-[5-(5-Amino-1,3,4-thiadiazol-2-yl)-1-methyl-2-imidazol-
ylthio]acetic acid (5a). This compound was obtained in 80%
yield; as an oil; 1H nmr (D2O+CF3COOH)): ꢂ 3.72 (s, 2H,
CH2S), 3.93 (s, 3H, NCH3), 7.82 (s, 1H, H-C4 imidazole); Anal.
Calcd. for C8H9N5O2S2: C, 35.41; H, 3.34; N, 25.81. Found: C,
35.29; H, 3.23; N, 25.79.
ꢀ-[5-(5-Amino-1,3,4-thiadiazol-2-yl)-1-benzyl-2-imidazol-
ylthio]acetic acid (5b). ). This compound was obtained in 86%
yield; mp 215-214°; ir (potassium bromide): 3400 cm-1 (NH). 1H
nmr (DMSO-d6): ꢂ 3.73 (s, 2H, CH2S), 5.62 (s, 2H, CH2N),
6.81-7.53 (m, 7H, arom, NH2), 7.99(s, 1H, H-C4 imidazole),
11.33 ppm (br-s, 1H, COOH); Anal. Calcd. for C14H13N5O2S2:
C, 48.40; H, 3.77; N, 20.16. Found: C, 48.35; H, 3.89; N, 20.29.
Biological assay. The compounds were screened for
antituberculosis activity under direction of the US National
Institute of Health, NIAID division. All compounds were
2-(5-Hydroxymethyl-1-methyl-2-imidazolylthio)acetic acid
(2a). This compound was obtained in 66% yield as an oil; ir
1
(CHCl3): 3100 (OH), 1650 cm-1 (CO); H nmr (CDCl3): ꢂ 3.52-
3.73 (m, 6H, CH2S, NCH3, OH), 4.65 (s, 2H, CH2O), 7.14 ppm
(s, 1H, H-C4 imidazole); Anal. Calcd. for C7H10N2O3S: C,
41.57; H, 4.98; N, 13.85. Found: C, 41.47; H, 4.78; N, 13.96.
2-(5-Hydroxymethyl-1-benzyl-2-imidazolylthio)acetic acid
(2b). This compound was obtained in 56% yield; mp 110-111°;
initially screened against Mycobacterium tuberculosis strain
-1
H Rv at single concentration of 6.25 μg.ml in BACTEC 12B
m3e7dium using
a broth microdilution assay. Compounds
1
ir (potassium bromide): 3100 (OH), 1700 cm-1 (CO); H nmr
demonstrating growth inhibition ꢀ 90% in the primary screening
were considered active. None of the compounds 5a and 5b were
found to be active. They exhibited only low activity (MIC ꢀ
6.25μg/ml, % inhibition ꢁ 24). Rifampicin (MIC= 0.025- 0.125
μg/ml) was used as positive control drug.
(CDCl3): ꢂ 3.73 (s, 2H, CH2S), 4.42 (s, 2H, CH2O), 5.25 (s, 2H,
CH2N), 6.82-7.31 ppm (m, 6H, arom); Anal. Calcd. for
C13H14N2O3S: C, 56.10; H, 5.07; N, 10.06. Found: C, 56.15; H,
5.17; N, 10.14.
General Procedure for preparation of 2-(5-formyl-1-alkyl-
2-imidazolylthio)acetic acid (3a,b). A stirring suspension of
compound 2 (12.8 mmoles) and manganese dioxide (82.2
mmoles) in chloroform (50 mL) was refluxed overnight. The
reaction mixture was cooled to room temperature and filtered on
diatomaceous earth. The chloroform was evaporated to give
compound 3a, b.
Acknowledgement. This work was supported by a grant
from Research Council of Mashhad University of Medical
Sciences. Antimicrobial data were provided by the Tuberculosis
Antimicrobial Acquisition Coordinate Facility (TAACF)
through a research and development contact with U.S. National
Institute of Allergy and Infectious Diseases.
2-(5-Formyl-1-methyl-2-imidazolylthio)acetic acid (3a).
This compound was obtained in 93% yield as an oil; ir (CHCl3):
1700 (CO acid), 1655 cm-1 (CO aldehyde); 1H nmr
(CDCl3): ꢂ 3.73 (s, 2H, CH2S), 3.92 (s, 3H, NCH3), 7.84 (s, 1H,
H-C4 imidazole), 9.53 ppm (s, 1H, CHO); Anal. Calcd. for
C7H8N2O3S: C, 41.99; H, 4.03; N, 13.99. Found: C, 41.76; H,
3.99; N, 14.20.
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Synthesis of ꢀ-[5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-imidazolylthio]acetic acids
1479
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