Preparation and properties of antitubercular 1-piperidino-3-arylthioureas [1]

Article abstract of DOI:10.1002/jhet.5570420632

1-Piperidino-3-arylthioureas, of interest in the investigation of novel heterocyclic structures for their antitubercular activity, may be conveniently prepared in good yield and purity by the reaction of 1-aminopiperidine with aryl isothiocyanates in etha

Full text of DOI:10.1002/jhet.5570420632

Sep-Oct 2005
1225
Preparation and Properties of Antitubercular
1-Piperidino-3-Arylthioureas [1]
Michael J. Hearn* and Eleanor R. Webster
Department of Chemistry, Wellesley College
Wellesley, Massachusetts 02481
Michael H. Cynamon
Veterans Affairs Medical Center, 800 Irving Avenue
Syracuse, New York 13210
Received March 18, 2005
1-Piperidino-3-arylthioureas, of interest in the investigation of novel heterocyclic structures for their anti-
tubercular activity, may be conveniently prepared in good yield and purity by the reaction of 1-aminopiperi-
dine with aryl isothiocyanates in ethanol. The reaction takes place readily without the complication of
thiourethane contaminants, and the products may be suitably identified by significant characteristics in the
infrared spectra and the hydrogen and carbon magnetic resonance spectra.
J. Heterocyclic Chem., 42, 1225 (2005).
In spite of the fact that certain heterocyclic compounds
We have found that the compounds are readily formed
from 1-aminopiperidine (I) and isothiocyanates (II) in
good yield and purity as stable highly-crystalline solids.
The reactions take place cleanly without formation of by-
products (see Scheme). The resulting thioureas may be
characterized in straightforward ways by standard spectro-
metric techniques and show activity against both labora-
tory strains and drug-resistant clinical isolates of M. tuber-
culosis.
have been among the most effective antitubercular med-
ications prescribed for patients for some fifty years [2-4],
much remains unknown about the scope of heterocyclic
structures that will possess this important anti-infective
activity [5]. Since the designation of tuberculosis as a
global public health crisis by the World Health
Organization in the last decade [6], new strains have
appeared of Mycobacterium tuberculosis characterized by
increased virulence or strong resistance to drugs com-
monly used in the past in treatment [7-10]. With a third of
the world’s population now infected with the bacillus and
as many as three million deaths per year attributed to the
disease [11,12], the medical and research communities
have been faced with a declining number of antimycobac-
terials appropriate for an effective therapeutic regimen
against this ancient killer [13-15]. There is an urgent need
for advances in the design of antitubercular agents that will
lead to newer and more powerful drugs [16]. The chem-
istry of heterocyclic compounds is likely to serve as a well-
spring for the discovery of such drugs [17-21].
In a typical example, compound I was treated with m-
tolyl isothiocyanate (IIe, Ar = 3-CH Ph, 1.09 equivalents)
3
in refluxing absolute ethanol for two hours. At the end of
this time, hot filtration of the reaction mixture induced
immediate crystallization of the product within the filtrate.
The white needles were isolated and rinsed with absolute
ethanol to give IIIe (Ar = 3-CH Ph, 84%) in analytically
3
pure form. In each case examined, the reaction could be
tested for completion through the distinguishing spectro-
metric features of the 1-piperidino-3-arylthioureas.
Among the more noteworthy of these were 1) N-H bands
consistent with the thiourea moiety near 3280 and 3160
wavenumbers in the infrared spectrum, 2) N-H peaks near
δ 9.5 and 9.2 ppm in the hydrogen nmr spectrum, each
integrating for one hydrogen, and 3) a signal near δ 177
ppm for the thiocarbonyl unit in the carbon nmr spectrum
(see Experimental). Conspicuously absent in the isolated
products were the exceptionally intense infrared bands
Recent disclosures from our laboratory [22] and others
[23-25] have noted the role of the thiourea moiety in novel
structures bearing antitubercular characteristics, but not
much work has been done to date to extend this observa-
tion to heterocyclic systems. As part of our ongoing explo-
ration of this issue, we now report on the preparation and
properties of a series of 1-piperidino-3-arylthioureas (III).
-1
belonging to the parent mustard oils II in the 2000 cm
region. Our results on the preparation of these materials
are summarized in the Table.
We would like to comment briefly on the choice of sol-
vent. In general, the selection of a solvent for the reaction
of a nitrogenous base with an isothiocyanate should be
made carefully. Alcohols have sometimes been used for
this purpose [26,27], but we have observed that some

1226
M. J. Hearn and E. R. Webster
Vol. 42
Table
Thioureas III
max
-1
1
13
Entry
Compound
Ar
Ph
% Yield
mp °C
ν
N-H, cm
H-NMR
C-NMR
1.
2.
3.
4.
5.
6.
7.
8.
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
74
76
72
78
84
76
62
81
80
55
60
68
158-9
140-1
164-5
183-4
173
3289, 3177
3292, 3143
3284, 3160
3276, 3136
3246, 3135
3314, 3146
3267, 3135
3292, 3148
3276, 3174
3243, 3130
3260, 3172
3283, 3144
δ9.60, 9.28
9.44, 9.10
9.32, 9.00
9.47, 9.23
9.53, 9.22
9.51, 9.13
9.49, 9.18
9.42, 9.16
9.87, 9.53
9.95, 9.71
9.59, 9.30
9.49, 9.17
δ 177
178
178
177
177
177
177
177
177
177
177
180
4-CH OPh
3
4-(CH ) NPh
3 2
2-CH Ph
3
3-CH Ph
3
4-CH Ph
158
3
4-(CH ) CHPh
148-50
141-3
169-70
161
158-9
177
3 2
4-PhCH OPh
4-CH CH OCOPh
3 2
2
9.
10.
11.
12.
IIIj
IIIk
IIIl
2,4-Cl Ph
4-FPh
2,4,6-F Ph
2
3
amino compounds are not sufficiently nucleophilic to react
with isothiocyanates rapidly. In such cases, reaction of the
mustard oil with an alcohol solvent (ROH) may lead to
substantial contamination of the product with the related
thiourethane (ArNHCSOR) [28]. The thiourethane is fre-
quently removed from the desired thiourea only with some
difficulty. Heteroaromatic amines and other aromatic
amines typically fall into this less nucleophilic category,
especially when they are substituted, and are more oppor-
tunely reacted in non-hydroxylic solvents, including
toluene and tetrahydrofuran. Although we explored the use
of both toluene and ethanol in the preparations described in
this paper (see Experimental), 1-aminopiperidine was suf-
ficiently reactive in all cases examined to permit the use of
ethanol, frequently resulting in analytically pure thioureas.
In terms of biological assessment of the 1-piperidino-
3-arylthioureas, the evaluation of compound IIIa (Ar =
Ph) is representative. The substance was assayed in vitro
in several strains of M. tuberculosis. The compound
appears to have similar levels of activity against both sus-
ceptible and drug-resistant organisms. Thus in strain
Erdman, a fully drug-susceptible strain, the minimum
inhibitory concentration (MIC) was 32 µg/mL. In a panel
of strains isolated from the clinic showing resistance to
the current frontline medication isoniazid, the following
MIC data were obtained: strain 1889, 32 µg/mL; strain
303, 8 µg/mL; strain 35829, 16 µg/mL. Concerning over-
all effectiveness, these MIC data are of the same order of
magnitude as those for antitubercular thioureas that have
recently been reported, but not so potent as some individ-
ual examples from the thiourea class [22,23]. A full
account of the biological evaluation of these materials
will appear in due course.
contaminants, and the products may be reliably identified by
their salient spectrometric characteristics.
EXPERIMENTAL
General methods were as previously described in detail [9,22],
including safety notes and information on instrumentation, com-
mercial suppliers of analytical services, solvents and reagents.
Although compounds IIIa and IIIb had been alluded to in the lit-
erature some time ago [29], they have now been fully character-
ized by up-to-date methods as shown below.
1-Piperidino-3-phenylthiourea (IIIa).
The reaction of 1.41 g (10.4 mmoles) of phenyl isothiocyanate
(IIa) to 1.02 g (10.2 mmoles) of N-aminopiperidine I in absolute
ethanol was completed during 30 minutes of reflux. The mixture
was cooled slowly to room temperature and the resulting solid fil-
tered. On concentration of the mother liquor using a Dean Stark
trap, a second crop was obtained. The total crude yield was 1.79
g (74 %). Three ether washes of the combined crops gave analyt-
ically pure material with a recovery of 83%, mp 158-9º, lit mp
159-160º [29]; ir: 3289 (w), 3177 (m), 3045 (w), 2950 (w), 2930
(m), 2855 (w), 2822 (w), 1600 (w), 1589 (w), 1536 (s), 1493 (s),
1443 (s), 1378 (w), 1316 (w), 1289 (m), 1272 (s), 1255 (m), 1201
(s), 1152 (m), 1088 (m), 1036 (m), 991 (m), 933 (m), 909 (w),
1
866 (m), 803 (m), 762 (m), 735 (s), 680 (s); H nmr (DMSO-d ):
6
δ 9.60 (1H, s), 9.28 (1H, s), 7.60 (2H, d, J = 9 cps), 7.30 (2H, m),
7.10 (1H, m), 2.91 (2H, m), 2.51 (2H, m), 1.66 (5H, m), 1.10 (1H,
13
m); C (DMSO-d ): δ 177.4, 139.3, 128.2, 124.8, 56.3, 25.5,
6
+
23.1; HR-MS (fast atom bombardment, MH ) calculated for
C H N S 236.1221, found 236.1222.
12 18
3
Anal. Calcd. for C H N S: C, 61.24; H, 7.28. Found: C,
12 17
3
60.95; H, 7.41.
1-Piperidino-3-(4-methoxyphenyl)thiourea (IIIb). Solvent
Studies.
Method A, Ethanol. In a manner similar to that noted above,
1.0 g (10 mmoles) of N-aminopiperidine (I) and 1.7 g (10.3
mmoles) of p-methoxyphenyl isothiocyanate (IIb) gave a first
crop of silky white needles 1.76 g (66%). Concentration of the
mother liquor gave additional product, overall yield (78%) mp
140° (corr.); ir as below, Method C.
In summary, we have found that 1-piperidino-3-arylth-
ioureas, prepared in the exploration of novel heterocyclic
structures for antitubercular activity, may be conveniently
formed in good yield and purity by the reaction of 1-amino-
piperidine with aryl isothiocyanates in ethanol. The reaction
takes place readily without the formation of thiourethane
Method B, Toluene, Two Crops. With the same quantities as

Sep-Oct 2005
Preparation and Properties of Antitubercular 1-Piperidino-3-Arylthioureas
1227
above in Method A, save for the substitution of toluene for
ethanol, a first crop of 48% was obtained. Concentration of the
mother liquor using a Dean Stark trap gave a second crop, total
yield 76%. Three ether washes followed by recrystallization
from ethanol gave analytically pure material, melting point 140-
1º (corr.); ir as below, Method C.
13
m), 1.08 (1H; m broad); C nmr (DMSO-d ): δ 177.1, 136.4,
6
128.7, 124.4. 56.0, 25.1, 22.8, 20.48; HR-MS (fast atom bom-
bardment, MH ) calculated for C
+
H N S 250.1378, found
13 20 3
250.1380.
Anal. Calcd. for C H N S: C, 62.61; H, 7.68. Found: C,
13 19
3
62.97; H, 7.92.
Anal. Calcd. for C H N OS: C, 58.84; H, 7.22. Found: C,
13 19
3
1-Piperidino-3-(m-tolyl)thiourea (IIIe).
59.11; H, 7.34.
Method C, Toluene, One Crop. With the same quantities as
above in Method A, save for the substitution of toluene for
ethanol, the yield of analytically pure white, flaky crystals was
1.76 g (48%), mp 140-1° (corr), lit mp 140-1° [29]; ir: 3292 (w),
3143 (w), 2935 (w), 2826 (w), 1538 (s), 1509 (s), 1493 (s), 1466
(w), 1439 (w), 1293 (w), 1273 (w), 1232 (s), 1212 (s), 1177 (m),
1163 (m), 1147 (m), 1091 (m), 1033 (s), 991 (w), 928 (w), 865
In a manner similar to that for IIId, 1.00 g (10.0 mmoles) of N-
aminopiperidine (I) and 1.63 g (10.9 mmoles) of m-tolyl isothio-
cyanate (IIe) gave analytically pure white needles, 2.09 g (84%)
mp 173°; ir: 3246 (w), 3135 (m), 3038 (w), 2988 (w), 2940 (m),
2858 (w), 2828 (w), 1609 (w), 1590 (m), 1536 (s), 1505 (s), 1478
(m), 1440 (m), 1380 (w), 1346 (w), 1308 (w). 1291 (m), 1272
(m), 1257 (m), 1228 (w), 1213 (s), 1152 (w), 1148 (m), 1089 (m),
1034 (m), 994 (m), 968 (w), 909 (w), 901 (w), 877 (m), 869 (w),
1
(m), 838 (m), 808 (m), 740 (m), 698 (w); H nmr (DMSO-d ): δ
6
1
9.44 (1H, s), 9.10 (1H, s), 7.40 (2H, d, J = 9), 6.86 (2H, d, J = 9),
3.74 (3H, s), 2.93 (2H, m), 2.52 (2H, m), 1.65 (5H, m), 1.08 (1H,
855 (w), 838 (w), 791 (s), 782 (s), 719 (s), 688 (s); H nmr
(DMSO-d ): δ 9.53 (1H, s), 9.22 (1H, s), 7.48 (1H, d, J = 9 cps),
6
13
s (broad)); C (DMSO-d ): δ 177.9, 156.8, 132.2, 126.8, 113.4,
7.42 (1H, s), 7.15 (1H, m), 6.93 (1H, d, J = 9 cps), 2.92 (2H, m),
6
+
13
55.5, 25.5, 23.1; HR-MS (fast atom bombardment, MH ) calcu-
2.52 (2H, m), 2.31 (3H, s), 1.69 (5H, s), 1.08 (1H, s); C nmr
lated for C H N OS 266.1327, found 266.1333.
(DMSO-d ): δ 177.0, 138.8, 137.2, 127.7, 125.1, 124.6, 121.3,
13 20
3
6
Anal. Calcd. for C H N OS: C, 58.84; H, 7.22. Found: C,
55.2, 25.1, 22.7, 20.9; HR-MS (fast atom bombardment) calcu-
13 19
3
58.88; H, 7.38.
lated for C H N S 250.1378, found 250.1377.
13 19
3
Anal. Calcd. for C H N S: C, 62.61; H, 7.68. Found: C,
62.48; H, 7.92.
13 19
3
1-Piperidino-3-(4-dimethylaminophenyl)thiourea (IIIc).
Since the 4-dimethylaminophenyl isothiocyanate (IIc) as
received from the commercial source is typically non-granular,
2.34 g (13.1 mmoles) was first dissolved in 25 mL of absolute
ethanol with warming. The warm solution was added by pipet to
a stirred solution at room temperature of 1.00 g (10 mmoles) of
N-aminopiperidine (I) in 5 mL of absolute ethanol over a period
of about 5 minutes. The homogeneous mixture was refluxed for
80 minutes and filtered hot. White needles appeared almost
immediately. After standing, the product (IIIc) was collected by
filtration; 1.99 g (72%), mp 164-5°; ir: 3284 (w), 3160 (w), 2932
(w), 2823 (w), 1612 (w) 1520 (s), 1494 (s), 1439 (m), 1382 (w),
1344 (m), 1274 (m), 1243 (m), 1205 (s), 1186 (s), 1160 (m), 1149
(m), 1126 (m), 1087 (m), 1060 (w), 1034 (m), 990 (m), 946 (w),
1-Piperidino-3-(p-tolyl)thiourea (IIIf).
By a method analogous to that for IIIc, p-tolyl isothiocyanate
(IIf, 1.63 g, 10.9 mmoles) was reacted with 1.00 g (10.0 mmoles)
of N-aminopiperidine (I) for two hours to give 1.90 g of analyti-
cally pure product (76%), mp 158°; ir: 3314 (w), 3146 (w), 2935
(m), 1539 (s), 1512 (s), 1491 (s), 1381 (w), 1306 (w), 1290 (m),
1275 (s), 1205 (m), 1170 (m), 1144 (m), 1086 (m), 988 (m), 929
(w), 864 (m), 843 (w), 825 (s), 806 (m), 785 (s), 733 (s), 695 (w);
1
H nmr (DMSO-d ): δ 9.51 (1H, s), 9.13 (1H, s), 7.47 (2H, d, J =
6
9), 7.08 (2H, d, J = 9), 2.92 (2H, m), 2.51 (2H, m), 2.25 (3H, m),
1.62 (5H, m), 1.08 (1H, m);
136.4, 133.5, 128.3, 124.4, 55.6, 25.1, 22.8, 20.4; HR-MS (fast
atom bombardment) calculated for C H N S 250.1378, found
13
C nmr (DMSO-d ): δ 177.1,
6
1
908 (w), 866 (w), 816 (s), 801 (s), 767 (s), 732 (m), 688 (w); H
13 19
3
nmr (DMSO-d ): δ 9.32 (1H,s), 9.00 (1H,s), 7.30 (2H, d, J = 9
250.1380.
Anal. Calcd. for C H N S: C, 62.61; H, 7.68. Found: C,
6
cps), 6.69 (2H, d, J = 9 cps), 2.88 (8H, m), 2.52 (2H, broad m),
13 19
3
13
1.62 (5H, m), 1.08 (1H, m); C nmr (DMSO-d ): δ 177.7, 147.9,
62.78; H, 7.72.
6
128.4, 126.2, 111.8, 55.1, 25.3, 22.5; HR-MS (fast atom bom-
bardment, MH ) calculated for C
278.1566.
+
1-Piperidino-3-(4-i-propylphenyl)thiourea (IIIg).
H N S 278.1565, found
14 23 4
In a manner similar to that for IIId, 0.78 g (4.4 mmoles) of 4-
i-propylphenyl isothiocyanate (IIg) and 4.1 g (4.1 mmoles) of N-
aminopiperidine (I) gave 0.73 g of glistening white crystals
(62%), mp 148-150°; ir: 3267 (w), 3135 (m), 3033 (w), 2954
(m), 2935 (m), 2859 (w), 2830 (w), 1584 (w), 1537 (s), 1514 (s),
1493 (s), 1466 (m), 1442 (m), 1417 (m), 1381 (w), 1361 (w),
1338 (w), 1302 (w), 1270 (s), 1255 (s), 1205 (s), 1149 (m), 1103
(w), 1087 (w), 1060 (w), 1049 (m), 1037 (m), 1018 (w), 996 (w),
928 (m), 909 (w), 871 (m), 861 (w), 835 (s), 809 (w), 799 (m),
Anal. Calcd. for C H N S: C, 60.39; H, 7.96. Found: C,
14 22
4
60.60; H, 8.09.
1-Piperidino-3-(o-tolyl)thiourea (IIId).
The addition of 1.63 g (10.9 mmoles) of o-tolyl isothiocyanate
(IId) in 5 mL of absolute ethanol by pipet in small portions to a
stirred solution of 1.00 g (10 mmoles) of N-aminopiperidine (I) in
10 mL of absolute ethanol was followed by refluxing for two
hours and hot filtration. White crystals appeared immediately in
the filtrate. After cooling, filtration and drying, the yield was
1.95 g (78%), mp 183-4°; ir: 3276 (w), 3136 (w), 2943 (w), 2853
(w), 2808 (w), 1583 (w), 1533 (s), 1499 (s), 1479 (s), 1457 (s),
1252 (m), 1221 (s), 1146 (w), 1088 (w), 1062 (w), 1032 (m), 992
1
768 (m), 743 (w), 702 (m); H nmr (DMSO-d ): δ 9.49 (1H, s),
6
9.18 (1H, s), 7.50 (2H, d, J = 9), 7.20 (2H, d, J = 9), 2.92 (3H,
m), 2.54 (2H, m), 1.64 (5H, m), 1.19 (6H, d, J = 6), 1.08 (1H, m);
13
C nmr (DMSO-d ): δ 177.1, 144.6, 136.7, 125.6, 125.1, 124.4,
6
55.2, 32.9, 25.1, 23.9, 22.7; HR-MS (fast atom bombardment)
1
(m), 925 (w), 857 (m), 810 (m), 792 (m), 770 (w), 733(s); H nmr
calculated for C H N S 278.1691, found 278.1688.
15 23 3
(DMSO-d ): δ 9.47 (1H, s), 9.23 (1H, s), 7.59 (1H d, J = 9), 7.18
Anal. Calcd. for C H N S: C, 64.94; H, 8.36. Found: C,
15 23 3
65.05; H, 8.47.
6
(3H, m), 2.94 (2H, d , J = 9), 2.53 (2H, m), 2.24 (3H, s), 1.65 (5H,

1228
M. J. Hearn and E. R. Webster
Vol. 42
1-Piperidino-3-(4-benzyloxyphenyl)thiourea (IIIh).
1498 (s), 1413 (w), 1256 (m), 1212 (s), 1151 (m), 1100 (m),
1038 (m), 999 (m), 937 (w), 871 (m), 840 (s), 818 (s), 733 (s);
In a manner similar to that for IIId, 2.68 g (11.1 mmoles) of 4-
benzyloxyphenyl isothiocyanate (IIh) and 1.00 g (10.0 mmoles)
of N-aminopiperidine (I) gave the title compound in 81% yield,
mp 141-3°; ir: 3292 (w), 3148 (m), 3031 (w), 2935 (m), 2916
(w), 2828 (w), 1542 (s), 1507 (s), 1492 (s), 1467 (m), 1452 (m),
1413 (w), 1377 (m), 1294 (m), 1275 (m), 1234 (s), 1208 (s), 1163
(s), 1146 (m), 1104 (m), 1091 (m), 1061 (w), 1035 (m), 1000 (s),
946 (w), 935 (w), 913 (m), 864 (m), 857 (m), 828 (s), 805 (m),
1
H nmr (DMSO-d6): δ 9.59 (1H, s), 9.30 (1H, s), 7.60 (2H, m),
7.18 (2H, m), 2.92 (2H, m), 2.50 (2H, s), 1.64 (5H, s); 1.09 (1H,
13
m); C nmr (DMSO-d ): δ 177.4, 160.7, 157.5, 135.3, 126.8,
6
114.5, 114.3, 55.2, 25.0, 22.7; HR-MS (fast atom bombard-
ment) calculated for C H N SF 254.1127, found 254.1128.
12 16
3
Anal. Calcd. for C H N SF: C, 56.89; H, 6.36. Found: C,
12 16
3
56.91; H, 6.45.
1
752 (s), 737 (s), 695 (s); H nmr (DMSO-d ): δ 9.42 (1H, s), 9.16
1-Piperidino-3-(2,4,6-trifluorophenyl)thiourea (IIIl).
6
(1H, s), 7.41 (7H, m), 7.00 (2H, m), 5.09 (2H, s), 2.92 (2H, m),
In a manner similar to that for IIId, 2,4,6-trifluorophenyl isothio-
cyanate (IIl) (1.56 g, 6.11 mmoles) was reacted with 0.751 g (7.51
mmoles) of N-aminopiperidine (I) to give IIIl (68%), mp 177°; ir:
3283 (w), 3144 (w), 2953 (w), 1604 (w), 1536 (s), 1513 (s), 1476
(s), 1450 (s), 1366 (w), 1255 (m), 1214 (m), 1172 (w), 1149 (w),
1121 (s), 1063 (w), 1041 (s), 994 (s), 923 (w), 851 (s), 834 (m), 801
13
2.49 (2H, m), 1.69 (5H, s), 1.09 (1H, m); C nmr (DMSO-d ): δ
177.4, 155.4, 137.1, 132.1, 128.3, 127.7, 127.6, 126.4, 114.0,
69.2, 55.2, 25.14, 22.8; HR-MS (fast atom bombardment) calcu-
6
lated for C H N OS 342.1640, found 342.1641.
19 23
3
Anal. Calcd. for C H N OS, C, 66.83; H, 6.79. Found: C,
19 23
3
66.67; H, 6.83.
1
(w), 764 (w); H nmr (DMSO-d ): δ 9.49 (1H, s), 9.17 (1H, s), 7.21
6
(2H, m), 2.92 (2H, m), 2.47 (2H, m), 1.58 (5 H, s), 1.10 (1H, m);
C nmr (DMSO-d ): δ 179.7, 161.9, 160.6, 158.6, 157.5, 114.2,
100.3, 55.1, 25.0, 22.8; HR-MS (fast atom bombardment) calcu-
1-Piperidino-3-(4-ethoxycarbonylphenyl)thiourea (IIIi).
13
6
By a method analogous to that for IIIc, 4-ethoxycar-
bonylphenyl isothiocyanate (IIi, 2.28 g, 11.3 mmoles) reacted
with 1.00 g (10 mmoles) of N-aminopiperidine (I) to produce
analytically pure material, 2.46 g (80%), mp 169-170°; ir: 3276
(w), 3174 (w), 2956 (w), 2932 (w), 2827 (w), 1715 (s), 1605
(m), 1583 (w), 1534 (s), 1482 (s), 1464 (m), 1442 (m), 1406 (s),
1365 (w), 1295 (w), 1265 (s), 1201 (s), 1173 (s), 1150 (m), 1099
(s), 1037 (m), 1023 (m to s), 1013 (m to s), 993 (m), 929 (w),
911 (w), 873 (m), 857 (m), 803 (s), 775 (m), 748 (s), 710 (s), 660
lated for C H N SF 290.0939, found 290.0940.
12 14
3
3
Anal. Calcd. for C H N SF : C, 49.82; H, 4.88. Found: C,
12 14
3
3
49.87; H, 4.90.
Biological Assessments in vitro.
Detailed accounts have appeared of the methods used for these
evaluations [9,30]. In brief, the minimum inhibitory concentra-
tions of the antimicrobial agents were determined by a broth dilu-
tion method. M. tuberculosis strain Erdman (ATCC 35801) was
obtained from the American Type Culture Collection, Manassas,
Virginia. Other strains were clinical isolates. The minimum
inhibitory concentrations of all antimicrobial agents were deter-
mined in modified 7H10 broth (7H10 agar formulation with agar
and malachite green omitted; pH 6.6) supplemented with 10%
Middlebrook oleic acid-albumin-dextrose-catalase (OADC)
enrichment (Difco Laboratories, Detroit, Michigan) and 0.05%
Tween 80.
1
(m); H nmr (DMSO-d ): δ 9.87 (1H, s), 9.53 (1H, s), 7.91 (4H,
6
s), 4.30 (2H, m), 2.92 (2H, m), 2.56 (2H, m), 1.69 (5H, s), 1.31
(3H, m);
125.1, 122.9, 60.4, 55.2, 25.0, 22.7, 14.1; HR-MS (fast atom
13
C nmr (DMSO-d ): δ 176.6, 165.3, 143.4, 129.1,
6
bombardment) calculated for C
308.1434.
H N O S 308.1433, found
15 21 3 2
Anal. Calcd. for C H N O S: C, 58.61; H, 6.89. Found: C,
15 21
3 2
58.61; H, 7.00.
1-Piperidino-3-(2,4-dichlorophenyl)thiourea (IIIj).
N-Aminopiperidine (I, 1.00 g, 10.0 mmoles) in toluene reacted
with 2,4-dichlorophenyl isothiocyanate (IIj, 2.04 g, 10.0
mmoles) to deposit a voluminous white solid, which was col-
lected by filtration and dried to give IIIj, 1.68 g (55%), mp 161°;
ir: 3243 (w), 3130 (m), 2982 (w), 2947 (m), 2852 (w), 2815 (w),
1570 (m), 1536 (s), 1497 (s), 1448 (m), 1439 (m), 1376 (m), 1300
(m), 1272 (m), 1248 (s), 1205 (m), 1137 (m), 1092 (s), 1062 (w),
1053 (m), 1030 (m), 993 (m), 939 (w), 865 (m), 854 (s), 825 (m),
Acknowledgments.
This work was supported by the Global Alliance for
Tuberculosis Drug Development and by grant 1 R15 AI48397-01
from the Division of AIDS, NIAID, NIH. We thank Dr. Sheldon
Morris, United States Food and Drug Administration, for the
clinical isolates of drug-resistant M. tuberculosis. High resolution
mass spectra (HR-MS) and low resolution mass spectra were
determined at the National Institutes of Health Mass
Spectrometry Facility at Michigan State University, East
Lansing, Michigan.
1
811 (s), 787 (m), 745 (m), 684 (m), 668 (m); H nmr (DMSO-
d ): δ 9.95 (1H, s), 9.71 (1H, s), 8.35 (1H, d, J = 9 cps), 7.69 (1H,
6
d, J = 1 cps), 7.42 (1H, dd, J = 9, 1 cps), 2.95 (2H, m), 2.60 (2H,
13
m), 1.65 (5H, m), 1.12 (1H, m); C nmr (DMSO-d ): δ 177.4,
6
REFERENCES AND NOTES
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[1] Respectfully dedicated to the memory of Jean V. Crawford of
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