Synthesis and antimycobacterial activity of (3,4-diaryl-3H-thiazol-2-ylidene)-hydrazide derivatives

Article abstract of DOI:10.1016/S0014-827X(03)00103-4

[5-(Pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid (3,4-diaryl-3H-thiazol-2-ylidene)-hydrazide derivatives were synthesized and tested for their in vitro antimycobacterial activity. Some compounds showed an interesting activity against a strain of Mycobacterium tuberculosis H ₃₇Rv and three clinical isolates of M. tuberculosis.

Full text of DOI:10.1016/S0014-827X(03)00103-4

Il Farmaco 58 (2003) 631ꢀ637
/
www.elsevier.com/locate/farmac
Synthesis and antimycobacterial activity of (3,4-diaryl-3H-thiazol-2-
ylidene)-hydrazide derivativesꢀ
Maria Grazia Mamolo a,*, Valeria Falagiani a, Daniele Zampieri a, Luciano Vio a,
Elena Banfi b, Giuditta Scialino b
a Dipartimento di Scienze Farmaceutiche, Universita` di Trieste, Piazzale Europa 1, I-34127 Trieste, Italy
b Dipartimento di Scienze Biomediche (Sez.Microbiologia), Universita` di Trieste, Via Fleming 22, I-34127 Trieste, Italy
Received 5 August 2002; accepted 28 December 2002
Abstract
[5-(Pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid (3,4-diaryl-3H-thiazol-2-ylidene)-hydrazide derivatives were synthesized and
tested for their in vitro antimycobacterial activity. Some compounds showed an interesting activity against a strain of
Mycobacterium tuberculosis H37Rv and three clinical isolates of M. tuberculosis.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: 2-[5-(Pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid (3,4-diaryl-3H-thiazol-2-ylidene)-hydrazide derivatives; Antimycobacterial
activity
1. Introduction
dene)-hydrazide derivatives 1aꢀw (Scheme 1) in which
/
the arylidene moiety of the previously described com-
pounds was replaced by the 3,4-diaryl-3H-thiazol-2-
ylidene one.
In our search for new antimycobacterial agents we
already synthesized a series of [5-pyridin-2-yl)-1,3,4-
thiadiazol-2-ylthio]acetic acid arylidene-hydrazide deri-
vatives [1], some of which exhibited a moderate in vitro
antimycobacterial activity against a strain of Mycobac-
terium tuberculosis H37Rv sensitive to isoniazid and
rifampicin and a strain of Mycobacterium avium resis-
tant to ciprofloxacin and rifampicin. None of the
synthesized compounds showed activity against the
tested strains of Staphylococcus aureus, Escherichia
coli and Candida albicans. With the aim to obtain
more active and selective antimycobacterial compounds
we sinthesized a series of [5-(pyridin-2-yl)-1,3,4-thiadia-
zol-2-ylthio]acetic acid (3,4-diaryl-3H-thiazol-2-yli-
Actually, 3,4-disubstituted 3H-thiazol-2-ylidene-hy-
drazide derivatives have been described for their anti-
bacterial and antifungal properties [2,3]. Moreover, the
thioacetyl hydrazone moiety, linked to the 2 position of
the 1,3,4-thiadiazole derivatives 1aꢀw, was present in
other compounds characterized by antibacterial [4],
antimicotic [4,5] and antimycobacterial [1] activity and
/
ꢀ A preliminary account of this work was presented at Italianꢀ
HungarianꢀPolish Joint Meeting on Medicinal Chemistry Giardini
Naxos, Ramada Hotel, 28 Septemberꢀ1 October 1999.
* Corresponding author.
/
/
/
hydrazidoꢀ
/
hydrazone derivatives have been described
E-mail address: mamolo@univ.trieste.it (M.G. Mamolo).
for their antimycobacterial properties [6].
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(03)00103-4

632
M.G. Mamolo et al. / Il Farmaco 58 (2003) 631ꢀ637
/
The new synthesized compounds have been tested for
hydrazide 4 was treated with substituted arylisothiocia-
nates to obtain the thiosemicarbazide derivatives 5aꢀ
(Table 2) which were cyclized with variously substituted
their in vitro antimycobacterial activity toward a strain
of M. tuberculosis H37Rv and three clinical isolates of
M. tuberculosis.
/l
2-bromoacetophenones to yield the corresponding deri-
vatives 1aꢀ
hydrobromides. IR spectra of thiosemicarbazide deriva-
tives 5aꢀl exhibited characteristic broad stretching
bands in the 3250ꢀ3115 and 3350ꢀ
3257 cmꢁ1 regions.
The CÄO bands were observed in the 1702ꢀ
1659 cmꢁ1
range. Their H NMR spectra exhibited N4ꢀH, N2ꢀ
and N1ꢀ
H in the 9.27ꢀ9.89, 9.72ꢀ10.16 and 10.42ꢀ
10.61 ppm regions, respectively [8]. The methylene Sꢀ
CH2 protons resonated as a singlet in the 4.05ꢀ4.25 ppm
region. The IR spectra of thiazoline derivatives 1aꢀ
/
w, isolated as free bases or in the form of
/
2. Chemistry
/
/
/
/
The synthesis of [5-(pyridin-2-yl)-1,3,4-thiadiazol-2-
ylthio]acetic acid (3,4-diaryl-3H-thiazol-2-ylidene)-hy-
drazide derivatives 1aꢀw (Table 1) was carried out
(Scheme 1) by treating pyridine-2-carboxamidrazone
with carbon disulfide to obtain 5-(pyridin-2-yl)-3H-
1,3,4-thiadiazole-2-thione 2 [7]. Compound 2 was
made to react with ethyl bromoacetate to afford the
1
/
/H
/
/
/
/
/
/
/
/w
exhibited NH and CÄ
/
O bands in the 3471ꢀ3279 and
/
1690ꢀ
/
1625 cmꢁ1 regions, respectively, attributed to the
[5-(pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic
acid
1
function. H NMR spectra displayed a
COꢀ
/
NHꢀ
/
NÄ
/
ethylester (3) [1] from which the [5-(pyridin-2-yl)-1,3,4-
thiadiazol-2-ylthio] acetic acid hydrazide (4) [1] was
obtained by treatment with hydrazine hydrate. The
single NH resonance at 10.32ꢀ
/
12.39 ppm. The absence
H and N4ꢀ
H
of the thiosemicarbazide moiety N2ꢀ
/
/
Scheme 1.

Table 1
Spectral data of compounds 5aꢀ
/l
Comp.
R
H
Yield
(%)
M.p.
(8C)
IR (nujol,
cmꢁ1
1H-NMR (CDCl3) (d)
Mass m/z
[Mꢂ
Formula
(C,H,N)
)
]
5a
5b
5c
5d
5e
5f
79
192ꢀ
196ꢀ
181ꢀ
197ꢀ
203ꢀ
176ꢀ
190ꢀ
203ꢀ
/
4
8
3
9
5
8
2
5
3270, 3158, 4.23 (s, 2H, Sꢀ
1683
/
CH2), 7.01ꢀ
/
8.80 (m, 9H, arom. and pyr.), 9.56 (1H, NH, disappearing on deuteration, N4H), 9.81 402
(1H, NH, disappearing on deuteration, N2H), 10.42 (1H, NH, disappearing on deuteration, N1H)
3305, 3250, 4.22 (s, 2H, SꢀCH2), 7.12ꢀ
8.72 (m, 8H, arom. and pyr.), 9.44 (1H, NH, disappearing on deuteration, N4H), 10.00 436, 438
1671
(1H, NH, disappearing on deuteration, N2H), 10.61 (1H, NH, disappearing on deuteration, N1H)
3257, 3150, 4.22 (s, 2H, Sꢀ
1682
3297, 3140, 4.22 (s, 2H, Sꢀ
1698
3330, 3230, 4.19 (s, 2H, Sꢀ
1702
3300, 3160, 4.22 (s, 2H, Sꢀ
1680
3320, 3233, 4.23 (s, 2H, Sꢀ
1699
(1H, NH, disappearing on deuteration, N2H), 10.46 (1H, NH, disappearing on deuteration, N1H)
3278, 3165, 2.09 (s, 3H, CH3), 4.23 (s, 2H, SꢀCH2), 6.94ꢀ8.82 (m, 8H, arom. and pyr.), 9.35 (1H, NH, disappearing on
1682
deuteration, N4H), 9.72 (1H, NH, disappearing on deuteration, N2H), 10.51 (1H, NH, disappearing on deuteration,
N1H)
3280, 3130, 2.17 (s, 3H, CH3), 4.21 (s, 2H, Sꢀ
1680
deuteration, N4H), 9.78 (1H, NH, disappearing on deuteration, N2H), 10.45 (1H, NH, disappearing on deuteration,
N1H)
80 3350, 3250, 2.23 (s, 3H, CH3), 4.22 (s, 2H, Sꢀ
1660
deuteration, N4H), 9.72 (1H, NH, disappearing on deuteration, N2H), 10.44 (1H, NH, disappearing on deuteration,
C16H14N6OS3
2ꢀ
/
Cl 61
/
/
/
C16H13N6S3OCl
C16H13N6S3OCl
C16H13N6S3OCl
C16H13N6OS3Br
C16H13N6OS3Br
C16H13N6OS3Br
C17H16N6OS3
3-Cl 81
4-Cl 79
2-Br 83
3-Br 71
4-Br 82
/
/
CH2), 7.06ꢀ
/
8.84 (m, 8H, arom. and pyr.), 9.61 (1H, NH, disappearing on deuteration, N4H), 9.96 436, 438
8.75 (m, 8H, arom. and pyr.), 9.60 (1H, NH, disappearing on deuteration, N4H), 9.90 436, 438
(1H, NH, disappearing on deuteration, N2H), 10.49 (1H, NH, disappearing on deuteration, N1H)
/
/
CH2), 7.26ꢀ
/
(1H, NH, disappearing on deuteration, N2H), 10.49 (1H, NH, disappearing on deuteration, N1H)
/
/
CH2), 7.05ꢀ
/
8.70 (m, 8H, arom. and pyr.), 9.41 (1H, NH, disappearing on deuteration, N4H), 9.91 480, 482
(1H, NH, disappearing on deuteration, N2H), 10.56 (1H, NH, disappearing on deuteration, N1H)
/
/
CH2), 7.16ꢀ
/
8.74 (m, 8H, arom. and pyr.), 9.60 (1H, NH, disappearing on deuteration, N4H), 9.96 480, 482
(1H, NH, disappearing on deuteration, N2H), 10.46 (1H, NH, disappearing on deuteration, N1H)
CH2), 7.29ꢀ
8.75 (m, 8H, arom. and pyr.), 9.59 (1H, NH, disappearing on deuteration, N4H), 9.87 480, 482
5g
5h
/
/
/
2-
CH3
89
59
68
/
/
/
416
5i
5j
3-
CH3
177ꢀ
/
9
/
CH2), 7.15ꢀ/8.92 (m, 8H, arom. and pyr.), 9.27 (1H, NH, disappearing on
416
C17H16N6OS3
C17H16N6OS3
4-
CH3
179ꢀ
/
/
CH2), 7.00-8.79 (m, 8H, arom. and pyr.), 9.47 (1H, NH, disappearing on
416
N1H)
98 3290, 3130, 4.25 (s, 2H, Sꢀ
1697
3312, 3115, 4.04 (s, 2H, Sꢀ
1659
(1H, NH, disappearing on deuteration, N2H), 10.57 (1H, NH, disappearing on deuteration, N1H)
5k
5l
3-
79
77
196ꢀ
/
/
CH2), 7.37ꢀ
/
8.75 (m, 8H, arom. and pyr.), 9.89 (1H, NH, disappearing on deuteration, N4H), 10.16 446
C16H13N7O2S3
C16H13N7O2S3
NO2
4-
(1H, NH, disappearing on deuteration, N2H), 10.57 (1H, NH, disappearing on deuteration, N1H)
214ꢀ
/
6
/
CH2), 7.46ꢀ
8.75 (m, 8H, arom. and pyr.), 9.47 (1H, NH, disappearing on deuteration, N4H), 9.87 446
/
NO2

Table 2
Spectral data of compounds 1aꢀ
/w
Comp.
R
R?
Yield
(%)
M.p.
(8C)
IR (nujol,
cmꢁ1
1H-NMR (CDCl3) (d)
Mass m/z Formula (C,H,N)
[Mꢂ
)
]
1a
1b
1c
1d
1e
1f
H
H
48
192
210
226
235
290
250
245
215
178
255
162
210
252
250
275
244
3383,1702
3378, 1664
3471,1721
3342, 1678
3342,1663
3390, 1674
3279, 1651
3393, 1657
3389, 1677
3382, 1692
3421, 1718
3445, 1638
3384, 1708
3381,1698
3392, 1701
3386,1706
4.27 (s, 2H, CH2), 6.82 (s, 1H, CH thiazoline), 7.18ꢀ
disappearing on deuteration)
/
8.77 (m, 14H, arom. and pyr.), 11.92 (1H, NH,
8.77 (m, 13H, arom. and pyr.), 10.41 (1H, NH,
8.80 (m, 13H, arom. and pyr.), 10.41 (1H, NH,
8.84 (m, 13H, arom. and pyr.), 11.54 (1H, NH,
8.85 (m, 13H, arom. and pyr.), 10.39 (1H, NH,
502
C24H18N6OS3
H
2-Cl 46
3-Cl 52
4-Cl 50
2-Br 55
3-Br 57
4-Br 50
4.12 (s, 2H, CH2), 6.50 (s, 1H, CH thiazoline), 6.95ꢀ
/
536ꢀ
536ꢀ
536ꢀ
580ꢀ
580ꢀ
580ꢀ
8.78 (m, 13H, arom. and pyr.), 516
/
538
538
538
582
582
582
C24H17N6OS3Cl
C24H17N6OS3Cl
C24H17N6OS3Cl
C24H17N6OS3Br
C24H17N6OS3Br
C24H17N6OS3Br
C25H20N6OS3
disappearing on deuteration)
H
4.15 (s, 2H, CH2), 6.63 (s, 1H, CH thiazoline), 6.92ꢀ
/
/
disappearing on deuteration)
H
4.24 (s, 2H, CH2), 6.52 (s, 1H, CH thiazoline), 6.74ꢀ
/
/
disappearing on deuteration)
H
4.28 (s, 2H, CH2), 6.96 (s, 1H, CH thiazoline), 7.10ꢀ
/
/
disappearing on deuteration)
H
4.21 (s, 2H, CH2), 6.67ꢀ
deuteration)
4.15 (s, 2H, CH2), 6.65 (s, 1H, CH thiazoline), 6.86ꢀ
disappearing on deuteration)
2.08 (s, 3H, CH3), 4.12 (s, 2H, CH2), 6.33 (s, 1H, CH thiazoline), 6.95ꢀ
10.32 (1H, NH, disappearing on deuteration)
/
8.82 (m, 14H, thiaz., arom. and pyr.), 10.85 (1H, NH, disappearing on
/
1g
1h
1i
H
/
8.79 (m, 13H, arom. and pyr.), 10.53 (1H, NH,
/
H
2-
55
61
64
54
45
50
53
49
56
/
CH3
3-
H
2.11 (s, 3H, CH3), 4.15 (s, 2H, CH2), 6.61 (s, 1H, CH thiazoline), 6.74ꢀ
10.57 (1H, NH, disappearing on deuteration)
/
8.77 (m, 13H, arom. and pyr.), 516
8.75 (m, 13H, arom. and pyr.), 516
C25H20N6OS3
CH3
4-
1j
H
2.17 (s, 3H, CH3), 4.13 (s, 2H, CH2), 6.50 (s, 1H, CH thiazoline), 6.91ꢀ
10.47 (1H, NH, disappearing on deuteration)
/
C25H20N6OS3
CH3
3-
1k
1l
H
4.19 (s, 2H, CH2), 6.65 (s, 1H, CH thiazoline), 6.86ꢀ
/
8.79 (m, 13H, arom. and pyr. and 1H, NꢂH,
547
547
C24H17N7O3S.3HBr
C24H17N7O3S3
NO2
4-
disappearing on deuteration), 10.53 (1H, NH, disappearing on deuteration)
H
4.15 (s, 2H, CH2), 6.65 (s, 1H, CH thiazoline), 6.86ꢀ
disappearing on deuteration)
4.26 (s, 2H, CH2), 6.79 (s, 1H, CH thiazoline), 7.20ꢀ
/
8.79 (m, 13H, arom. and pyr.), 10.53 (1H, NH,
8.68 (m, 13H, arom. and pyr.), 8.46 (1H, NꢂH,
NO2
H
1m
1n
1o
1p
2-Cl
3-Cl
4-Cl
2-Br
/
536ꢀ
/
538
538
538
582
C24H17N6OS3Cl.HBr
C24H17N6OS3Cl.HBr
C24H17N6OS3Cl.HBr
C24H17N6OS3Br.HBr
disappearing on deuteration) 12.01 (1H, NH, disappearing on deuteration)
4.32 (s, 2H, CH2), 6.89 (s, 1H, CH thiazoline), 7.19ꢀ
8.71 (m, 13H, arom. and pyr. and 1H, NꢂH,
disappearing on deuteration), 12.22 (1H, NH, disappearing on deuteration)
4.29 (s, 2H, CH2), 6.94 (s, 1H, CH thiazoline), 7.15ꢀ
8.84 (m, 13H, arom. and pyr. and 1H, NꢂH,
disappearing on deuteration), 12.10 (1H, NH, disappearing on deuteration)
4.30 (s, 2H, CH2), 6.91 (s, 1H, CH thiazoline), 7.12ꢀ
8.75 (m, 13H, arom. and pyr.), 11.13 (1H, NꢂH, 580ꢀ
disappearing on deuteration), 12.18 (1H, NH, disappearing on deuteration)
H
H
H
/
536ꢀ
/
/
536ꢀ
/
/
/

M.G. Mamolo et al. / Il Farmaco 58 (2003) 631ꢀ
/
637
635
signals, the Ä
SꢀCH2ꢀ resonance at 4.11ꢀ
cyclization to the thiazoline derivatives 1aꢀ
/
CHꢀ
/
resonance at 6.29ꢀ/7.11 ppm and the
ꢀ
/
/
/
/
4.35 ppm confirmed the
w. The
w, isolated as hydro-
/
thiazoline derivatives 1k and 1mꢀ
/
bromides, presented an additional NHꢂ signal.
3. Experimental
ꢂ
3.1. Chemistry
Melting points were determined with a Buchi 510
¨
capillary apparatus, and are uncorrected. Infrared
spectra in nujol mulls were recorded on a Jasco FT
200 spectrophotometer. Proton nuclear magnetic reso-
nance (1H NMR) spectra were determined on a Varian
Gemini 200 spectrometer; chemical shifts are reported as
d (ppm) relative to tetramethylsilane as internal stan-
dard, deuterochloroform as solvent. Reaction courses
and product mixtures were routinely monitored by thin-
layer chromatography (TLC) on silica gel precoated
F
254 Merck plates. EI MS spectra (70 eV) were taken on
a VG 7070 spectrometer. Elemental analyses (C, H, N)
were performed on a Carlo Erba analyzer and were
within90.3 of the theoretical value.
/
3.1.1. 4-Phenyl-1-[[(5-pyridin-2-yl)-1,3,4-thiadiazol-2-
ylthio]acetyl]thiosemicarbazide (5a)
A solution of 1.95 g (7.29 mmol) of [5-(pyridin-2-yl)-
1,3,4-thiadiazol-2-ylthio]acetic acid hydrazide 4 and 0.99
g (7.29 mmol) of phenylisothiocyanate was refluxed for
3 h. The solution was concentrated at reduced pressure
and the solid formed was filtered off and crystallized
from absolute ethanol to obtain 2.31 g (78.7%) of 5a;
m.p. 192ꢀ
IR (Nujol, cmꢁ1): 3270, 3158, 1683. 1H NMR
(CDCl3ꢀTMS): d 4.23 (s, 2H, SꢀCH2), 7.01ꢀ8.80 (m,
/
194 8C.
/
/
/
9H, arom. and pyr.), 9.56 (1H, NH, disappearing on
deuteration, N4H), 9.81 (1H, NH, disappearing on
deuteration, N2H), 10.42 (1H, NH, disappearing on
deuteration, N1H) MS: m/z 402 [Mꢂ].
In an analogous way compounds 5bꢀl have been
/
prepared. Yields, melting points and spectral data are
recorded in Table 1.
3.1.2. [5-(Pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic
acid (3,4-diphenyl-3H-thiazol-2-ylidene)-hydrazide (1a)
A mixture of 1.5 g (3.73 mmol) of 4-phenyl-1-[[(5-
(pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetyl]thiosemi-
carbazide 5a and 0.74 (3.73 mmol) of 2-bromoaceto-
phenone in 80 ml of absolute ethanol was refluxed for 4
h. The obtained solution was evaporated under reduced
pressure and the residue was treated with saturated
NaHCO3 solution. The obtained precipitate was fil-
tered, washed with cold water, dried and recrystallized
from ethanol to obtain 0.88g (47.3%) of 1a; m.p. 192 8C.

636
M.G. Mamolo et al. / Il Farmaco 58 (2003) 631ꢀ637
/
IR (Nujol, cmꢁ1): 3383, 1702. 1H NMR (CDCl3ꢀ
TMS): d 4.27 (s, 2H, CH2), 6.82 (s, 1H, CH thiazole),
7.18ꢀ8.77 (m, 14H, arom. and pyr.), 11.92 (1H, NH,
disappearing on deuteration) MS: m/z 502 [Mꢂ].
Analogously, the compounds 1aꢀj and 1l were pre-
pared. With the same procedure compounds 1k and
1mꢀw were obtained as HBr salts. Yields, melting points
and spectral data of compounds 1aꢀw are reported in
/
Table 3
Activity of the (3,4-diaryl-3H-thiazol-2-ylidene) hydrazides derivatives
1aꢀw against M. tuberculosis H37Rv and three clinical isolates of M.
/
/
tuberculosis
/
/
/
Table 2.
3.2. Microbiology
Comp.
H37Rv
180
190
331
3.2.1. Antimycobacterial activity
The antimycobacterial activity has been evaluated on
M. tuberculosis reference strain H37Rv, on two sensitive
M. tuberculosis clinical strains and on one multiresistant
M. tuberculosis clinical isolate, all strains belonging to
our collection. The inhibiting activity of the new
molecules was tested by means of a standard agar
dilution technique [9] with viable counts performed in
quadrant petri plates containing Middlebrook and Cohn
7H11 agar, supplemented with Middlebrook OADC
enrichment. Serial dimethylsulfoxide twofold dilutions
of the different chemicals tested were placed in each
quadrant; control plates were included with known
antitubercular drugs and no drug. A 20-ml sample of
each reference strain or clinical strain suspension,
containing 104/ml mycobacteria in sterile saline with
the addition of 0.02% polysorbate 80, was inoculated
onto each chemical containing quadrant. All plates were
INH
RIF
1a
1b
1c
0.5
n.t.
0.05
0.5
16
0.05
0.5
ꢀ
/
128
80
ꢀ
/
80
80
80
40
80
40
40
80
40
40
40
40
80
80
80
80
80
80
80
80
80
80
40
ꢀ
/
80
80
ꢀ
/
20
80
40
80
40
40
80
20
80
80
80
40
80
40
80
40
40
80
40
40
80
20
ꢀ
ꢀ
/
80
80
40
80
80
80
80
80
40
80
40
80
80
40
80
80
40
20
80
40
80
80
ꢀ
ꢀ/
/
80
80
80
80
10
80
80
40
40
80
80
80
80
40
80
80
80
40
80
40
80
80
ꢀ/
/
1d
1e
ꢀ
ꢀ
/
ꢀ/
1f
/
1g
1h
1i
ꢀ/
ꢀ/
ꢀ
ꢀ
/
/
1j
1k
1l
ꢀ
/
ꢀ
/
ꢀ/
ꢀ
/
1m
1n
1o
1p
1q
1r
ꢀ
/
ꢀ
ꢀ
/
ꢀ
/
ꢀ/
/
ꢀ/
ꢀ
/
ꢀ
ꢀ
/
ꢀ
/
ꢀ
/
/
ꢀ
/
ꢀ
/
ꢀ/
1s
ꢀ
/
ꢀ/
incubated at 37 8C in 5% CO2 for 3ꢀ4 weeks. Minimal
/
1t
ꢀ
/
ꢀ
/
ꢀ/
inhibiting concentration (MIC) of each compound was
defined as the lowest chemical dilution associated with
at least a 99% reduction in the number of visible
colonies.
1u
1v
ꢀ
/
ꢀ/
ꢀ
ꢀ
/
ꢀ
/
1w
/
ꢀ/
against the strain of M. tuberculosis H37Rv. These
compounds are characterized by the presence of a
substituent in the para or meta position of the phenyl
ring but their activity does not depend from electronic
effects, since electron-donating and electron-withdraw-
ing substituents produce the same level of activity.
4. Results and discussion
A
series of 2-[5-(pyridin-2yl)-1,3,4-thiadiazol-2-
ylthio]acetic acid (3,4-diaryl-3H-thiazol-2-ylidene)-hy-
drazide derivatives 1aꢀw (Table 1) have been synthe-
/
sized with the aim to evaluating their antimycobacterial
activity (Table 3) toward a strain of M. tuberculosis
H37Rv and three strains of M. tuberculosis 180, M.
tuberculosis 190 and M. tuberculosis 331, isolated from
human bronchial aspirates. The clinical isolate of M.
tuberculosis 190 was resistant to isoniazid and rifampi-
cin. With the exception of 1w, which explicated a weak
However, both the series of compounds 1aꢀ
/
l and 1mꢀ
/
w, substituted only at one of the phenyl residues, include
compounds exhibiting a moderate in vitro antimyco-
bacterial activity against the tested strains of clinical
isolates of M. tuberculosis, their MIC values reaching 20
mg/ml against the strains of M. tuberculosis 180 (com-
pounds 1b, 1i and 1w) and M. tuberculosis 190
(compounds 1s) and 10 mg/ml against the strain of M.
tuberculosis 331 (compound 1f). Interestingly, com-
pounds 1d, 1j, 1l, 1o, 1r, 1s, 1u exhibited a moderate
antimycobacterial activity against the strain of M.
tuberculosis 190, resistant to isoniazid and rifampicin.
Only the para-substituted compounds 1o and 1u were
activity (MICꢃ
/
40 mg/ml), compounds 1mꢀ
/w, substi-
tuted at the phenyl residue linked to the 3-position of the
thiazoline cycle, were inactive against the tested strain of
M. tuberculosis H37Rv. However, compounds 1d, 1f, 1g,
1iꢀ
position of the thiazoline ring, exhibited a moderate in
vitro antimycobacterial activity (MICꢃ40 mg/ml)
/
l, substituted at the phenyl residue linked to the 4-
/

M.G. Mamolo et al. / Il Farmaco 58 (2003) 631ꢀ
/
637
637
moderately active toward all the clinical isolates of M.
tuberculosis.
The obtained results are not suitable for an evaluation
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/
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The Authors would like to thank dott. M. Cebulec for
the microanalyses. This research was carried out with
the financial support of the Italian M.U.R.S.T. (60%).
Medicine, William & Wilkins, Baltimore, MD, 1986, pp. 181ꢀ222.
/