Some 3-Thioxo/Alkylthio-1,2,4-triazoles with a Substituted Thiourea Moiety as Possible Antimycobacterials

Article abstract of DOI:10.1016/S0960-894X(01)00283-9

A series of novel N-alkyl/aryl-N'-[4-(4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione-5-yl)phenyl]thioureas 1-19 and three S-alkylated representatives of the former, N-alkyl/aryl-N'-[4-(3-aralkylthio-4-alkyl/aryl-4H-1,2,4-triazole-5-yl)phenyl]thioureas 20-22, were synthesized and tested for antimycobacterial activity against Mycobacterium tuberculosis H37Rv as well as Mycobacterium fortuitum ATCC 6841 which is a rapid growing opportunistic pathogen. Compounds 4 and 9-11 were found to possess the same MIC value with that of Tobramycin against M. fortuitum ATCC 6841 whereas 1-3 and 21 had positive response against M. tuberculosis H37Rv at varying degrees. Compound 21 was identified as the most potent derivative of the 1-22 series by an MIC value of 6.25 μg/ml and selectivity index of 1.6

Full text of DOI:10.1016/S0960-894X(01)00283-9

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1703–1707
Some 3-Thioxo/Alkylthio-1,2,4-triazoles with a Substituted
Thiourea Moiety as Possible Antimycobacterials
Ilkay Kuc u kguzel,a,* S. Guniz Kuc u kguzel,a Sevim Rollasa and Muammer Kirazb
aDepartment of Pharmaceutical Chemistry, Marmara University, Faculty of Pharmacy, Haydarpasa 81010 Istanbul, Turkey
bCenter for Research and Application of Culture Collections of Microorganisms, University of Istanbul,
Faculty of Medicine, C¸ apa, Istanbul, Turkey
Received 22 December 2000; revised 6 March 2001; accepted 18 April 2001
Abstract—A series of novel N-alkyl/aryl-N0-[4-(4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione-5-yl)phenyl]thioureas 1–19 and
three S-alkylated representatives of the former, N-alkyl/aryl-N0-[4-(3-aralkylthio-4-alkyl/aryl-4H-1,2,4-triazole-5-yl)phenyl]thiour-
eas 20–22, were synthesized and tested for antimycobacterial activity against Mycobacterium tuberculosis H37Rv as well as Myco-
bacterium fortuitum ATCC 6841 which is a rapid growing opportunistic pathogen. Compounds 4 and 9–11 were found to possess
the same MIC value with that of Tobramycin against M. fortuitum ATCC 6841 whereas 1–3 and 21 had positive response against
M. tuberculosis H37Rv at varying degrees. Compound 21 was identified as the most potent derivative of the 1–22 series by an MIC
value of 6.25 mg/mL and selectivity index of 1.6. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
tuberculosis agents led us to investigate the anti-
mycobacterial effects of these compounds (Fig. 1).
There has been an increasing demand for new anti-
tuberculosis agents, as the fast development of myco-
bacterial resistance to conventional drugs is one of the
major difficulties in the treatment of tuberculosis.
Among azoles, 1,2,4-triazoles have been reported to
exhibit antibacterial,1À5 antifungal,3À7 antiviral8 and
tuberculostatic9 activities. Earlier reports also indicated
similar biological properties such as antibacterial10 and
anti-HIV11,12 effects associated with substituted thiour-
eas. Thiacetazone [A] which possesses a thiosemicarba-
zone structure, has been reported as a tuberculostatic
agent. In a previous work, Doub and co-workers
revealed antituberculosis properties of a wide number of
phenylthioureas [B].13 Glasser and Dougthy also repor-
ted similarly the same type of activity associated with a
number of thiourea derivatives substituted with a het-
erocyclic ring at one nitrogen.14 Based on these obser-
vations we have prepared a number of N-substituted-N0-
[4-(4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione-5-
yl)phenyl]thioureas 1–19 as well as three S-alkylated
derivatives 20–22. The similarity of pharmacophores
present in our structures with those of reported anti-
Chemistry
Synthesis of 1–22 required stepwise reactions including
benzoylation of benzocaine15 at the first step which
provided protection of the amino function during the
following two reactions (Scheme 1) and allowed to
introduce different groups at R1 and R2 positions.
Hydrazinolysis of
I then gave 4-(benzoylamino)-
benzoylhydrazine II15 which was then reacted with
alkyl/aryl isothiocyanates to give 1-aroyl-4-alkyl/aryl
thiosemicarbazides III16 as described. Cyclocondensa-
tion of the latter to give 5-(4-aminophenyl)-4-alkyl/aryl-
2,4-dihydro-3H-1,2,4-triazole-3-thiones IV was per-
formed by refluxing III in alkaline medium.6 3-Ben-
zylthio-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2,4-triazoles
V were obtained as previously described by the reac-
tions of IV with appropriate benzylchlorides in etha-
nolic sodium hydroxide.17,18
The final step comprised of the reaction of the amines
IV or V with various alkyl or aryl isothiocyanates
yielding the corresponding title compounds 1–22. This
kind of reaction was reported to be performed in certain
dry solvents or mixtures.10,17,19À22 In the present study,
*Corresponding author. Tel.: +90-216-414-2962; fax: +90-216-345-
2952; e-mail: kucukguzel@usa.net
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00283-9

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I. Kuc¸ukguzel et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1703–1707
¨ ¨ ¨
Figure 1.
.
Scheme 1. Synthetic route to 1–22. Reagents and conditions: (a) C6H5COCl/(C2H5)2O; (b) H2N–NH2 H2O/EtOH, reflux; (c) R1-NCS/EtOH, reflux;
(d) NaOH (2 N), reflux; (e) Ar-CH2Cl/NaOH–EtOH; (f) R2-NCS/dioxane–MeOH (2:1, v/v), reflux.
dioxane–methanol (1:2, v/v) was tried and found to be
useful.23,24 The yields of title compounds seemed, how-
ever, to be affected by the possible formation of several
byproducts such as urethans.13 Another yield-limiting fac-
tor might be the side reaction of isothiocyanates with het-
erocyclic nitrogen at the second position of 1,2,4-triazoline
ring present in IV series.22 In spite of these probabilities,
spectral findings such as the 1H NMR resonances at 13–14
ppm due to heterocyclic NH–CS function and the lack of
resonances attributable to NH2 function supports the
regioselectivity of this reaction. Of these compounds, 8,25
20,26 2127 and 2228 were originally synthesized in the pre-
1
sent study and were characterized by UV, IR and H
NMR spectroscopy data as well as elemental analysis.

I. Kuc¸ukguzel et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1703–1707
¨
1705
¨
¨
Results and Discussion
effecting a reduction in fluorescence of 90% relative to
controls. Only the re-test of 21 was performed using the
BACTEC 460radiometric system as it could not be
achieved using MABA because of the fluorescent nature
of this compound.33
Antimycobacterial activity of the synthesized com-
pounds were investigated against M. fortuitum ATCC
6841, a rapidly growing strain, by the use of microdilu-
tion broth susceptibility method.29À32 As shown in
Table 1, most of the thiourea derivatives showed activ-
ity against M. fortuitum ATCC 6841 whilst six com-
pounds, 8, 12, 18 and 20–22 were found completely
inactive. Of the screened compounds, 4, 9, 10 and 11
were observed to have the same MIC with that of
tobramycin, the standard used, by 32 mg/mL. However,
it was also observed that the substituents at the terminal
nitrogen of thiourea function had no determining influ-
ence on the antimycobacterial activity towards M. for-
tuitum ATCC 6841.
As illustrated in Table 2, only one 3-alklythio derivative
(21) of 1–22 demonstrated potent inhibitory activity
against M. tuberculosis H37Rv by an MIC value of 6.25
mg/mL, whereas remaining compounds 1–3, which were
selected for level 2 screening, did not possess an MIC
less than 12.5 mg/mL.
Compound 21 was also screened to assess toxicity to a
VERO cell line at concentrations equal to and greater
than the MIC for M. tuberculosis H37Rv.34 The IC50
value was found at a concentration level of >10 mg/mL
for compound 21 and the resulting selectivity index
(SI=IC50/MIC) was calculated as >1.6 (Table 2). Hav-
ing the SI<10, this compound was not considered to be
evaluated further due to its remarkable cytotoxicity.
Compounds 1–22 were also tested for in vitro anti-
tuberculosis activity against M. tuberculosis H37Rv
using the BACTEC 12B medium using a broth micro-
dilution assay, the Microplate Alamar Blue Assay
(MABA).33,34 Rifampicin was used as the standard in
the antimycobacterial assays. As shown in Table 1,
compounds 8 and 10 were completely inactive against
M. tuberculosis H37Rv at 12.5 mg/mL, whereas remain-
ing compounds exhibited varying degrees of inhibition
in the primary screen. Of these compounds, the ones
which exhibited < 90% inhibition in the primary screen
(MIC>12.5 mg/mL) were not considered for further
evaluation.
Three representatives of 1–19 series, namely compounds
1–3 were tested in vitro for killing of M. tuberculosis
Erdman (ATCC 35801) in monolayers of mouse bone
marrow macrophages by determining EC90 and EC99,
lowest concentration effecting a 90and 99% reduction,
respectively, in colony forming units at 7 days compared
to drug-free controls.35 As shown in Table 2, compounds
1–3 were observed to effect 90% reduction in myco-
bacterial growth at concentration levels 18–34-fold lower
than those of their MIC values whilst EC99 of the above
were extremely high to compare to that of standard used.
Compounds 1–3 effecting ꢀ90% inhibition in the pri-
mary screen at 12.5 mg/mL were re-tested at lower con-
centrations against M. tuberculosis H37Rv to determine
the actual MIC in a broth microdilution assay using
MABA. The MIC is defined as the lowest concentration
In many cases, it has been demonstrated that sub-
stituted thioureas may be of interest as antibacterial,
Table 1. Antimycobacterial activity versus M. fortuitum ATCC 6841 and primary antituberculosis activity screening results of 1–22
Compound
R1
R2
R3
R4
MICa
(mg/mL)
MICb
(mg/mL)
Inhibitionc
(%)
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH2CH¼CH2
C6H11
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
H
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
H
64
64
64
32
64
64
64
<12.5
<12.5
<12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
<12.5
>12.5
93
90
94
10
29
89
10
0
71
0
35
12
6
27
17
12
13
13
11
85
94
63
CH3
C6H5
CH2CH¼CH2
CH2CH3
CH2CH3
CH2CH¼CH2
CH2CH¼CH2
CH2CH¼CH2
C6H11
C6H11
CH3
>128
32
32
9
CH2CH¼CH2
10
11
12
13
14
15
16
17
18
19
20
21
22
C6H5
CH2CH¼CH2
C6H11
32
C6H11
>128
64
64
64
64
64
>128
64
CH2CH2C6H5
C6H5
C6H5
CH2CH¼CH2
CH3
CH2CH3
CH2CH¼CH2
C6H11
C6H5
C6H4Cl(4)
CH3
C6H5
C6H5
C6H5
C6H5
CH3
CH3
C6H5
>128
>128
>128
CH2CH¼CH2
Cl
Cl
Cl
Cl
CH2CH¼CH2
aMIC effecting M. fortuitum ATCC6841; MIC of tobramycin=32 mg/mL.
bMIC effecting M. tuberculosis H37Rv; MIC of rifampicin=0.25 mg/mL.
cReduction of mycobacterial growth using M. tuberculosis H37Rv at 12.5 mg/mL.

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I. Kuc¸ukguzel et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1703–1707
¨ ¨ ¨
Table 2. Level 2 antituberculosis activity assay results of 1–3 and 21
Compound
Level 2 assay
IC50a (mg/mL)
Level 3 assay
b
c
MIC (mg/mL)
SI
EC90
EC99
EC90/MIC
1
2
3
21
>12.5
>12.5
>12.5
6.25d
—
—
—
>10
—
—
—
>1.6
0.371
0.303
0.698
—
>100
48.65
>100
—
<0.02968
<0.02424
<0.05584
—
aIC50 of RMP=147.
bEC90 of RMP=0.007.
cEC99 of RMP=0.451.
dThe assay was performed using BACTEC in which MIC of RMP was found as 0.125 mg/mL.
References and Notes
antiviral or antituberculosis agents. As 1,2,4-triazoles
have also been reported as possible antimicrobials,
incorporation of these two moieties in a single molecule
was aimed to enhance possible antituberculosis activity
which might arise from each side.
1. Aboul Wafa, O. M.; Berto, F. A. G. Arch. Pharm. (Wein-
heim) 1992, 325, 123.
2. Holla, B. S.; Shivananda, M. K.; Shenoy, S.; Antony, G.
Boll. Chim. Farmaceutico 1998, 137, 233.
In contrast to the results obtained from M. fortuitum
ATCC 6841, in vitro antituberculosis assay results of 1–
22 using M. tuberculosis H37Rv revealed that either
substituents at the N-4 position of the triazole ring (R1)
or the ones at the terminal nitrogen of thioureas (R2)
influenced the antituberculosis activity. As shown in
Tables 1 and 2, optimal activity was achieved with the
derivatives possessing a methyl group at the R1 position
whilst a linear decrease in antituberculosis activity was
observed in the direction of methyl>ethyl>allyl>
heavier groups. On the other hand, functionalities
bulkier than an allyl group at the R2 position also gave
rise to almost complete loss of inhibition of myco-
bacterial growth. The fact that highest antituberculosis
activity in phenylthioureas could be reached by deriva-
tives with the terminal nitrogen substituted by a single
short chain alkyl group, was also in accordance with
previous reports.13,14
3. Kuc u kguzel, S. G.; Rollas, S.; Erdeniz, H.; Kiraz, M. Eur.
J. Med. Chem. 1999, 34, 153.
4. Rollas, S.; Yılmaz, N.; Erdeniz, H.; Kiraz, M. Med. Sci.
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Ekinci, A. C.; Vidin, A. Eur. J. Med. Chem. 2000, 35, 761.
6. Rollas, S.; Kalyoncuoglu, N.; Sur-Altıner, D.; Yegenoglu,
Y. Pharmazie 1993, 48, 308.
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Metab. Drug Interact. 1995, 12, 161.
8. Jones, A. S.; Sayers, J. R.; Walker, R. T.; De Clercq, E. J.
Med. Chem. 1988, 31, 268.
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11. Hogberg, M.; Engelhardt, P.; Vrang, L.; Zhang, H.
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V. N.; Sudbeck, E. A.; Uckun, F. M. Bioorg. Med. Chem.
Lett. 2000, 10, 87.
From the above data one can conclude that both 1,2,4-
triazole or thiourea components of the structures 1–22
contributed to antituberculosis activity. Moreover,
bulky groups introduced at either R1 and R2 positions
led to a dramatic decrease in activity most probably due
to a steric hindrance which does not allow the com-
pounds to reach the active site. In addition, S-alkylation
products of three derivatives selected from the 1–19
series have been prepared not only to mask the –NH–
CS– function present in 1,2,4-triazoline-3-thiones but
also to provide them an increased lipophilicity. This
modification led to the most active derivative, com-
pound 21, which still needs to be improved from the
toxicological point of view.
13. Doub, L.; Richardson, L. M.; Herbst, D. R.; Black, M. L.;
Stevenson, O. L.; Bambas, L. L.; Youmans, G. P.; Youmans,
A. S. J. Am. Chem. Soc. 1958, 80, 2205.
14. Glasser, A. C.; Doughty, R. M. J. Pharm. Sci. 1962, 51,
1031.
15. Durgun, B. B.; Rollas, S. J. Pharm. Uni. Mar. 1991, 7, 107.
16. Kalyoncuoglu, N.; Rollas, S.; Sur-Altıner, D.; Yegenoglu,
Y.; Ang, O. Pharmazie 1992, 47, 796.
17. Ram, V. J.; Vidyottama, D.; Pieters, L. A. C.; Vlietinck,
A. J. J. Heterocycl. Chem. 1989, 26, 625.
18. Kuc u kguzel, I.; Komurcu, S. G.; Rollas, S. Sympo-
sium Abstracts Book, 4th International Symposium on
Pharmaceutical Sciences, June 27–30, 1995, Ankara, Tur-
key; O-13.
19. Hazzaa, A. A. B.; Labouta, I. M.; Kassem, M. G. Arch.
Pharm. Chem. Sci. Ed. 1983, 11, 43.
20. Emilsson, H.; Selander, H. Acta Pharm. Suec. 1983, 20,
419.
21. Emilsson, H.; Selander, H.; Gaarder, J. Acta. Pharm.
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Acknowledgements
The authors thank Dr. Joseph A. Maddry from the
Tuberculosis Antimicrobial Acquisition and Coordinat-
ing Facility (TAACF), National Institute of Allergy and
Infections Diseases Southern Research Institute, GWL
Hansen’s Disease Center, Colorado State University,
Birmingham, AL, USA, for the in vitro evaluation of
antimycobacterial activity using M. tuberculosis H37Rv.
22. Kubota, S.; Horie, K.; Misra, H. K.; Toyooka, K.; Uda,
M.; Shibuya, M.; Terada, H. Chem. Pharm. Bull. 1985, 33,
662.
23. Kuc u kguzel, I.; Rollas, S.; Ulgen, M. J. Pharm. Uni. Mar.
1994, 10, 17.
24. Kuc u kguzel, I.; Rollas, S.; Cevikbas, A. Drug Metab.
Drug Interact. 1995, 12, 151.

I. Kuc¸ukguzel et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1703–1707
¨
1707
¨
¨
25. N-Methyl-N0-[4-(4-allyl-2,4-dihydro-3H-1,2,4-triazole-3-
thione-5-yl)phenyl]thiourea 8: Mr 305.42; mp 197–199 ꢁC;
Yield 45%; UV lmax (e) 260(28832), 285 (26724) nm; IR nmax
3436, 3342, 3107, 2931, 1601, 1578, 1513, 1443, 1319, 1313,
28. N-Allyl-N0-{4-[3-[(2,4-dichlorobenzyl)thio]-4-phenyl-4H-
1,2,4-triazole-5-yl]phenyl}thiourea 22: Mr 526.51; mp. 195–
198 ꢁC; yield 60%; UV lmax (e) 232 (14264), 262 (11966), 298
(15699) nm; IR nmax 3648, 3237, 1595, 1560, 1543, 1319, 1272,
726 cmÀ1 ; 1H NMR (DMSO-d6) d 4.11 (s, 2H, NH–CH2), 4.43
(s, 2H, S-CH2), 5.08–5.11 (d, 1H, J=10.3 Hz, CH¼CH2 cis),
5.15–5.20(d, 1H, J=17.3 Hz, CH¼CH2 trans), 5.84–5.91 (m,
1H, –CH¼), 7.26–7.61 (m, 12H, Ar–H), 8.01 (b, 1H, NH–CH2),
9.67 (b, 1H, Ar–NH). Anal. for C25H21Cl2N5S2 (%, calcd/
found): 57.03/57.45 (C), 4.02/4.09 (H), 13.30/13.14 (N).
29. Hawkins, J. E.; Wallace, R. J., Jr.; Brown, B. A. Anti-
microbial Susceptibility Tests: Mycobacteria. In Manual of
Clinical Microbiology, 5th ed.; Balows, A., Hausler, W. J., Jr.,
Herrmann, K. L., Isenberg, H. O., Shadami, H. J., Eds.;
American Society for Microbiology. Washington, DC, 1991;
pp 1138–1152
30. NCCLS. Methods for Dilution Susceptibility Tests for
Bacteria That Grow Aerobically, 2nd ed. Approved Standard.
NCCLS document M7-A2.NCCLS, Villanova, PA, 1990.
31. NCCLS. Performance Standards for Antimicrobial Sus-
ceptibility Testing, 3rd Informational Supplement. M 100-S3.
NCCLS, Villanova, PA, 1991.
32. Swenson, J. M.; Thornsberry, C.; Silcox, V. A. Anti-
microb. Agents Chemother. 1982, 22, 186.
33. Collins, L.; Franzblau, S. G. Antimicrob. Agents Che-
mother. 1997, 41, 1004.
1
1262, 1190cm À1; H NMR (DMSO-d6) d 2.94 (d, 3H, CH3),
4.64–4.71 (d, 2H, N-CH2), 4.86 (d, 1H, J=17.3 Hz, CH¼CH2
trans), 5.15 (d, 1H, J=10.5 Hz, CH¼CH2 cis), 5.81–5.89 (m,
1H, ÀCH¼), 7.58–7.64 (m, 4H), 7.78–8.16 (b, 1H, NH-CH3),
9.08–10.31 (b, 1H, Ar–NH), 13.75 (b, 1H, NH–triazoline);
.
anal. for C13H15N5S2 1=2 H2O (%, calcd/found): 49.68/50.33
(C), 5.09/4.89 (H), 22.29/21.49 (N).
26. N-Methyl-N0-[4-(3-benzylthio-4-methyl-4H-1,2,4-triazole-5-
yl)phenyl]thiourea 20: Mr 369.51; mp 200–202 ꢁC; yield 74%;
UV lmax (e) 231.3 (18549), 256.4 (24794), 289.4 (28822) nm;
IR nmax 3283, 3248, 3060, 1607, 1548, 1478, 1419, 1319, 1313,
1272, 714 cmÀ1 ; 1H NMR (DMSO-d6) d 2.95 (d, 3H, J=4 Hz,
CS–NH–CH3), 3.41 (s, 3H, >N–CH3), 4.36 (s, 2H, S-CH2),
7.26–7.61 (m, 9H, Ar-H), 7.92 (b, 1H, NH-CH3), 9.84 (b, 1H,
Ar-NH). Anal. for C18H19N5S2 (%, calcd/found): 58.51/58.16
(C), 5.18/4.96 (H), 18.95/18.68 (N).
27. N-Allyl-N0-{4-[3-[(2,4-dichlorobenzyl)thio]-4-methyl-4H-
1,2,4-triazole-5-yl]phenyl}thiourea 21: Mr 464.43; mp 186–
189 ꢁC; yield 65%; UV lmax (e) 234 (33857), 257 (37108), 291
(37805) nm; IR nmax 3260, 3060, 1608, 1590, 1543, 1472, 1320,
1261, 732 cmÀ1
;
1H NMR (DMSO-d6) d 3.52 (s, 3H, >N–
CH3), 4.16 (s, 2H, N-CH2), 4.41 (s, 2H, S-CH2), 5.11–5.14 (d,
1H, J=9.3Hz, CH¼CH2 cis), 5.19–5.24 (d, 1H, J=9.3 Hz,
CH¼CH2 trans), 5.88–5.92 (m, 1H, –CH¼), 7.37–7.68 (m, 7H,
Ar–H), 7.86–8.31 (b, 1H, NH–CH2), 9.41–10.01 (b, 1H, Ar–
NH). Anal. for C20H19Cl2N5S2 (%, calcd/found): 51.72/51.81
(C), 4.12/4.01 (H), 15.08/14.92 (N).
34. Kuc u kguzel, S. G.; Rollas, S.; Kuc u kguzel, I.; Kiraz, M.
Eur. J. Med. Chem. 1999, 34, 1093.
35. Skinner, P. S.; Furney, S. K.; Jacobs, M. R.; Klopman,
G.; Ellner, J. J.; Orme, I. M. Antimicrob. Agents Chemother.
1996, 40, 2809.