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K. K. Roy et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5589–5593
Scheme 2. Synthesis of compounds of prototype-2. Reagents and conditions: (i)
triethylamine, benzoyl isothiocynate, THF; (ii) 10% NaOH, 100 °C; (iii) THF, RT.
freshly synthesized
a-bromo-acetophenones afforded the corre-
sponding 4-arylthiazole-2-yl derivatives (11, 12a–c, 13a–d) using
the condition of Hantzsch reaction.9
A total of 15 novel compounds was synthesized and evaluated
for their anti-TB activity against the replicating Mtb H37Rv (lab
strain) in agar dilution assay11 containing isoniazid (INH) and
rifampicin (RMP) as positive control. Table 1 summarizes the
anti-TB activity (minimum inhibitory concentration: MIC) of the
synthesized compounds 7a–d, 8a–c, 11, 12a–c and 13a–d along
with isoniazid and rifampicin (positive controls) obtained from
agar dilution assay.
Figure 1. Rational design of modified analogues of nitazoxanide (NTZ).
Among the synthesized compounds, six compounds, namely
7a–d, 8b and 11 effectively inhibited the growth of replicating
Mtb over a long period (4 weeks) with micromolar MIC values.
Structurally, all the above six active compounds except 7d are
non-nitro derivatives unlike NTZ and still have 2–3 times better
anti-TB activity than the drug NTZ. Therefore, above data suggests
that the presence of nitro group is not mandatory for potential
inhibition of the growth of Mtb and hence, for promising anti-TB
activity. Also, looking at the structure of NTZ, TIZ and identified ac-
tive compounds (7a–d, 8b and 11), it is also evident that the pres-
ence of a nitro group at the position 5 of the aminothiazole is not
essential for anti-TB activity, although it may be necessary for anti-
protozoal activity. In the recent past, many researchers have
looked for the importance of nitro group in different antimicrobial
agents. Pankuch and Appelbaum showed that only compounds
that carried a nitro-thiazole were active in vitro against protozo-
ans, while non-nitro derivatives were not.12 Other studies13,14 in
G. lamblia also demonstrated that only nitro-thiazolides exhibited
profound antigiardial activity in vitro, and identified a novel G.
lamblia nitroreductase (GLNR1) as a potential target. In contrast,
Stadelmann et al.15 revealed that not only nitro-thiazolides, but
also halogenated thiazolides, were effective against metacestodes.
Scheme 1. Synthesis of compounds of prototype-1. Reagents and conditions: (i)
thisemicarbazide, AcOH, THF, reflux; (ii) Br2, AlCl3, THF, RT; (iii) THF, RT.
compound may furnish more potent candidate compounds for the
development of anti-TB agents. Recently, Ballard et al reported var-
ious head group analogues of NTZ with improved antibacterial
activities and demonstrated that modification of head group is a
viable route for the synthesis of NTZ-related antibacterial
analogues.7
In view of above and in continuation of our previous research
efforts8 toward the identification of potent anti-TB agents, we de-
scribe here synthesis and biological evaluation of substituted 4-
arylthiazol-2-amine class as growth inhibitors of M. tuberculosis
H37Rv. Figure 1 outlines the rational design of modified analogues
of nitazoxanide (NTZ). Some of these novel derivatives have shown
2–3 times better activity over the anti-protozoal drug NTZ (1) to-
ward the inhibition of the growth of replicating M. tuberculosis
(Mtb) H37Rv.
The synthesis of prototype 1 compounds is outlined in Scheme
1. The thiosemicarbazone intermediates (4a–b) were obtained by
the reaction between the ketones (3a–b) and thiosemicarbazide
in absolute ethanol with catalytic amount of acetic acid (Scheme
1). The condensation of thiosemicarbazone intermediates (4a–b)
In comparison to the observed anti-TB MIC value of 52.12
lM
(16 g/mL) for the drug NTZ, the compound 7a, comprising (5-
l
methoxy-3, 4-dihydronaphthalen-1(2H)-ylidene)hydrazine and 3,
4-dimethoxyphenyl groups linked to position 2 and 4 of thiazole
respectively, exhibited about 3 times better anti-TB activity with
MIC value of 15.28 lM in agar dilution assay. In the same series,
another compound 7c, bearing 4-fuorophenyl group at position 4
of thiazole, also exhibited about 3 times better Mtb growth inhib-
with different freshly prepared
a-bromo-acetophenones (6a–d)
itory activity with MIC value of 17.03 lM than the drug NTZ.
essentially using the recommended condition of Hantzsch reac-
Another two compounds 7b and 7d in the same series, bearing 2,
4-dicholoro and 3-nitrophenyl groups respectively at position 4
of thiazole, also exhibited good Mtb growth inhibitory activity with
tion9 afforded the corresponding 4-arylthiazol-2-yl derivatives
(7a–d, 8a–c) in high yields (80–90%). The different substituted a-
bromo-acetophenones were synthesized using bromine (Br2) in
MIC of 29.90 and 31.73
pounds were less potent than compounds 7a and 7c, they were still
lM respectively. Although, these two com-
the presence of aluminium chloride (AlCl3) as catalyst.10
The Scheme 2 outlines the synthesis of prototype 2 compounds.
The reaction of substituted anilines with benzoyl isothiocyanate
afforded the corresponding N-(substituted phenylcarbamothio
yl)benzamide intermediates (9a–c), which upon debenzoylation
reaction yielded the corresponding phenylthioureas (10a–c). The
condensation of these phenylthioureas (10a–c) with different
about 2 times more potent than the drug NTZ (MIC = 52.12 lM)
toward the growth inhibition of replicating Mtb H37Rv.
The compound 8b, having 1-(2, 4-dichlorobenzyl)-3-(hydrazo-
nomethyl)-1H-indole and 2, 4-dichlorophenyl group linked to the
position 2 and 4 respectively, did not show any improved anti-TB
activity (MIC = 22.89 lM) over compounds 7a (MIC = 15.28 lM)