Synthesis and antibacterial evaluation of new sulfanyltetrazole derivatives bearing piperidine dithiocarbamate moiety

Article abstract of DOI:10.1080/00397911.2017.1401639

A series of new alkyl or aryl sulfanyltetrazole derivatives containing dithiocarbamate moiety (5a–6e) were synthesized. The structures of the compounds were characterized by IR, ¹H NMR, ¹³C NMR spectra, and elemental analysis data. The present study examines the antibacterial potential of novel synthetic sulfanyltetrazole compounds against clinically important gram-positive and -negative strains. The results of screening showed that attachment of dithiocarbamate to sulfanyltetrazole derivatives results in enhancement of antibacterial activity. The compound 6d showed the best activity among the tested compounds. Also, the less polar 2,5-disubstituted sulfanyltetrazole regioisomers showed an increased antibacterial activity compared with the corresponding more polar regioisomers.

Full text of DOI:10.1080/00397911.2017.1401639

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis and antibacterial evaluation of new
sulfanyltetrazole derivatives bearing piperidine
dithiocarbamate moiety
Mahrokh Baghershiroudi, Kazem D. Safa, Khosro Adibkia & Farzaneh
Lotfipour
To cite this article: Mahrokh Baghershiroudi, Kazem D. Safa, Khosro Adibkia &
Farzaneh Lotfipour (2018): Synthesis and antibacterial evaluation of new sulfanyltetrazole
derivatives bearing piperidine dithiocarbamate moiety, Synthetic Communications, DOI:
10.1080/00397911.2017.1401639
To link to this article: https://doi.org/10.1080/00397911.2017.1401639
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Date: 08 January 2018, At: 09:47

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1401639
Synthesis and antibacterial evaluation of new
sulfanyltetrazole derivatives bearing piperidine
dithiocarbamate moiety
Mahrokh Baghershiroudia, Kazem D. Safaa, Khosro Adibkiab, and Farzaneh Lotfipourb
aOrganosilicon Research Laboratory, Faculty of Chemistry, University of Tabriz, Tabriz, Iran; bFaculty of
Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
ABSTRACT
ARTICLE HISTORY
Received 8 October 2017
A series of new alkyl or aryl sulfanyltetrazole derivatives containing
dithiocarbamate moiety (5a–6e) were synthesized. The structures of
the compounds were characterized by IR, 1H NMR, 13C NMR spectra,
and elemental analysis data. The present study examines the
antibacterial potential of novel synthetic sulfanyltetrazole compounds
against clinically important gram-positive and -negative strains. The
results of screening showed that attachment of dithiocarbamate to
sulfanyltetrazole derivatives results in enhancement of antibacterial
activity. The compound 6d showed the best activity among the tested
compounds. Also, the less polar 2,5-disubstituted sulfanyltetrazole
regioisomers showed an increased antibacterial activity compared
with the corresponding more polar regioisomers.
KEYWORDS
Antibacterial activity;
carbodithioate; polarity;
regioisomer;
sulfanyltetrazole
GRAPHICAL ABSTRACT
Introduction
Tetrazoles are a class of important heterocycles with a wide range of applications in
organic chemistry,[1] coordination chemistry,[2] agriculture,[3] photography industry,[4]
energetic materials,[5] and drug development.[6] Among the compounds containing
tetrazole moieties, 5-substituted-1H-tetrazoles are the most interesting materials. The
compounds have applications as an isosteric replacement of carboxylic acids to improve
the potency, solubility, and cell permeability of this class of compounds.[7] Various
methods for the synthesis of tetrazoles have been reported. Among these families,
CONTACT Kazem D. Safa
dsafa@tabrizu.ac.ir
Organosilicon Research Laboratory, Faculty of Chemistry, University of
Tabriz, Tabriz, 5166614766, Iran.
Supplemental data (full experimental detail, IR, 1H and 13C NMR spectra and elemental analysis data) can be accessed on
the publisher’s website.
© 2017 Taylor & Francis

2
M. BAGHERSHIROUDI ET AL.
sulfanyltetrazoles are one of the most important classes of favored scaffolds in the field of
pharmaceuticals. We are currently performing synthetic studies on sulfanyltetrazole deri-
vatives. Sulfanyltetrazole compounds have many biological applications including
antimycobacterial,[8–10] anti HIV,[11–14] and activator in RNA synthesis[15]; but their
potential use as antibacterial has been less investigated.[16,17] On the other hand,
dithiocarbamate scaffolds are covering a wide range of applications, such as in
fungicides,[18] pesticides,[19] as linkers in solid-phase organic synthesis,[20] synthesis of
ionic liquids,[21] antibacterial,[22] antifungal activity,[23] and possible application in cancer
treatment.[24]
In the last decade, due to increased resistance to antibacterial agents, the researches in
this regard are rapidly growing. Hence, the need for new drugs for resistant strains will
form an important part of medical research. In view of these facts, it was assumed that
the combined effects of dithiocarbamate moiety and sulfanyltetrazole pharmacophores
can result in an interesting biological activity. To the best of our knowledge, antibacterial
properties of dithiocarbamate derivatives of sulfanyltetrazole have not been investigated.
Hence, we report herein the synthesis and antibacterial evaluation of new heterocyclic
compounds such as sulfanyltetrazoles containing dithiocarbamate. This combination was
proposed in an effort to study the influence of such structure variation on the assumed
biological activities, with the aim of adding some synergistic biological significance to
the target molecules. The present study examined the antibacterial activities of prepared
alkyl, aryl sulfanyltetrazoles and sulfanyltetrazole compounds containing dithiocarbamate
moiety against some pathologically important bacteria, including Staphylococcus aureus,
Escherichia coli, Salmonella typhi, and Pseudomonas aeruginosa. We also examined the
effect of alkyl or aryl groups on the biological properties of the sulfanyltetrazole
compounds. These results pave the way for further investigations for the combination of
these compounds with other groups.
Results and discussion
Chemistry
Synthesis of sulfanyltetrazole derivatives was performed according to Scheme 1. As
depicted in Scheme 1, alkyl and aryl thiocyanates were converted to the corresponding
sulfanyltetrazoles by the reaction with sodium azide and tetrabutylammonium chloride
(TBAC) in toluene at 90 °C in good yields.
The synthesis of the sulfanyltetrazole derivatives containing dithiocarbamate was
achieved through the synthetic pathways as presented in Scheme 1. Bromoalkylation of
sulfanyltetrazole derivatives was performed by reacting sulfanyltetrazoles with 1,4-
dibromobutane with anhydrous K2CO3 in dry acetone. The reaction gave a mixture of
the two regioisomers (3 and 4). The reaction between brominated sulfanyltetrazoles,
piperidine, and CS2 in an ice bath, led to the formation of sulfanyltetrazole derivatives
containing dithiocarbamate as a mixture of regioisomers (5, 6).[25] The obtained
1,5- and 2,5-regioisomers were separated by preparative column chromatography in a ratio
of 1:1 to 1:1.5 and unambiguously identified by the 1H and 13C NMR. The tetrazole carbon
atom and N–CH2 protons of the more polar 1,5-regioisomers are more shielded than the
less polar 2,5-regioisomers.[26,27]

SYNTHETIC COMMUNICATIONS®
3
Scheme 1. Synthesis of the target compounds 2a–6e. Reagents and conditions: (i) NaN3, TBAC, toluene,
90 °C, 2–6 h; (ii) K2CO3, acetone, Br(CH2)4Br, 25 °C, 24 h; (iii) CS2, 0 °C, piperidine, 1–2 h. Note: TBAC,
tetrabutylammonium chloride.
Biological evaluation
Determination of antibacterial activities
The minimum inhibitory concentration (MIC) values for the synthetic compounds as
compared with the standard drug ciprofloxacin are shown in Table 1. The study of
antibacterial screening compounds revealed that the synthesized compounds (2a–6e)
showed an inhibition in the range of 200–0.78 µg mL−1 against bacterial tested strains.
Among the sulfanyltetrazole compounds containing dithiocarbamate moiety, compound
6d displayed excellent activity against S. aureus (0.78 µg mL−1). Compound 5d exhibited
high activity against S. aureus (1.56 µg mL−1). Compounds 6e and 5e are the next impor-
tant compounds. Among the sulfanyltetrazole derivatives, compound 2d exhibited good
activity against S. aureus (6.25 µg mL−1), whereas it moderately acted against E. coli
(MIC: 12.5 µg mL−1) and S. typhi, and P. aeruginosa (25 µg mL−1). Compounds 2a and
Table 1. In vitro MIC values (µg mL−1) of compounds (2a-6e).
MIC (µ g mL−1
)
Compounds
S. aureus
E. coli
100
S. typhi
P. aeruginosa
2a
50
200
200
100
25
200
200
100
25
2b
50
100
50
2c
25
2d
6.25
12.5
25
12.5
2e
25
50
50
5a
50
100
100
25
200
100
25
5b
25
50
5c
12.5
1.56
6.25
12.5
12.5
6.25
0.78
3.12
0.195
12.5
5d
3.12
6.25
12.5
50
6.25
25
100
50
12.5
6.25
12.5
0.39
5e
12.5
25
25
12.5
6a
6b
50
6c
12.5
3.12
6.25
0.098
6d
1.56
6.25
0.024
6e
Ciprofloxacin
MIC, minimum inhibitory concentration.

4
M. BAGHERSHIROUDI ET AL.
2b showed moderate activities against S. aureus (MIC: 50 µg mL−1) and E. coli (MIC:
100 µg mL−1).
Structure activity relationship
The results revealed that the replacement of H atom of sulfanyltetrazole ring by
carbodithioate moiety leads to a significant change in antibacterial activity. As shown in
Table 1, replacing the –NH group in compound 2d with a carbodithioate moiety as
in 6d, resulted in an obvious improvement in the antibacterial spectrum against both
gram-positive and gram-negative bacteria with special high activity against S. aureus
(MIC: 0.78 µg mL−1) and E. coli (MIC ¼ 1.56 µg mL−1). As depicted in Table 1, among
the synthesized compounds, sulfanyltetrazoles having a free-NH group showed moderate
inhibitory behavior. Also, compounds 2a, 2b, 5a, 5b, 6a, and 6b with 5 and 6 carbon alkyl
side chains revealed relatively similar activities against tested bacteria. Generally, the
results showed that aromatic substituents lead to better biological activity than aliphatic
substituents. The compounds were effective, especially on gram-positive bacteria.
According to the Table 1, 2,5-regioisomers were more potent than the corresponding
1,5-regioisomers. In this view, the MIC value of 6d against S. aureus was 0.78 µg mL−1,
whereas for the analog 5d was 1.56 µg mL−1. Moreover, 1,5-regioisomers of compounds
5a–6e mostly showed 50% of the activity of 2,5-analogues against the same organism.
Experimental
Chemicals were either purchased from Merck or synthesized in our laboratory.
Commercial reagents and solvents were used without further purification. The IR spectra
1
were recorded on a Bruker Tensor 270 spectrometer using KBr discs. H and 13C NMR
spectra were recorded on a Bruker FT-400 MHz spectrometer at room temperature with
DMSO-d6 and CDCl3 as solvents. Elemental analyses were performed on an Elementar
Vario EL III instrument. The optical density was quantified at 600 nm by an enzyme linked
immunoabsorbent assay reader (Bioteck, Winooski, USA).
General procedure for the synthesis of 5-(pentylsulfanyl)-1H-tetrazole (2a)
5-(Pentylsulfanyl)-1H-tetrazole compound was prepared according to the procedure
described in the literature[28] with some modification. 1-thiocyanatopentane 1a
(1.0 mmol) was added to a suspension of sodium azide (1.3 mmol) and TBAC (1.3 mmol)
in toluene (3 mL). The reaction mixture was stirred at 90 °C for 4 h until completion, as
determined by thin layer chromatography. After cooling, the reaction mixture was
extracted with water (5 mL). To the aqueous layer, concd HCl was added dropwise to
precipitate the tetrazole product. After filtration, the solid was washed with HCl 4 M
and after drying, recrystallized from appropriate solvent.
Colorless solid; Yield 90%, mp 64–66 °C (CCl4) (Lit.[29] 65–67 °C). IR (KBr, cm−1): 3068,
2962, 2929, 2859, 2811, 2702, 2550, 2498, 2363, 1525, 1463, 1431, 1360, 1308, 1262,
1
1213, 1039, 984, 893, 825, 781, 726, 687, 644. H NMR (400 MHz, DMSO-d6): δ 0.84
(t, J ¼ 7.0 Hz, 3 H, CH3), 1.24–1.35 (m, 4H, CH2CH2), 1.64 (t, J ¼ 7.0 Hz, 2H, CH2),
3.19 (t, J ¼ 7.0 Hz, 2H, S-CH2). 13C NMR (100 MHz, DMSO-d6): δ 13.92, 21.68, 28.88,
30.13, 32.08, 154.43. Anal. Calcd. for C6H12N4S: C 41.84, H 7.02, N 32.53, S 18.61%. Found:
C 41.91, H 7.19, N 32.45, S 18.53%.

SYNTHETIC COMMUNICATIONS®
5
General procedure for the synthesis of 4-(5-(pentylsulfanyl)-1H-tetrazole-1-yl)butyl
piperidine-1-carbodithioate (5a) and 4-(5-(pentylsulfanyl)-2H-tetrazole-2-yl)butyl
piperidine-1-carbodithioate (6a)
According to the reference[25] to a mixture of bromoalkyl sulfanyltetrazole derivatives 3a
and 4a (2 mmol) and carbon disulfide (CS2) (4 mmol) in an ice bath, piperidine (4 mmol)
was added and stirred at 0 °C for 30 min, then warmed to room temperature and stirring
was continued until the reaction was complete. Water was added and the reaction
product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, and
the solvent was concentrated in vacuum. The residue was purified by preparative column
chromatography eluting with n-hexane–ethyl acetate to afford pure regioisomers (5a, 6a).
(5a): Yellow solid; Yield 22%, mp 88–90 °C. The product was purified by column
chromatography (n-hexane/EtOAc, 3:1), FTIR (KBr, cm−1): 3062, 2959, 2933, 2861,
2698, 2552, 2496, 1528, 1460, 1433, 1362, 1308, 1261, 1211, 1223, 1022, 984, 890, 824.
1H NMR (400 MHz, CDCl3, ppm): δ 0.88 (t, 3H, J ¼ 7.1 Hz, CH3), 1.31–1.44
(m, 4H, 2CH2), 1.70–1.81 (m, 10H, 2CH2), 2.11–2.17 (m, 2H, CH2), 2.55 (t, 2H, J ¼ 6.9 Hz,
S-CH2), 3.17 (t, 2H, J ¼ 7.4 Hz, S-CH2), 3.82, 4.26 (s, 4H, N-CH2), 4.18 (t, 2H, J ¼ 6.9 Hz,
N-CH2). 13C NMR (100 MHz, CDCl3, ppm): δ 12.81, 21.14, 23.21, 24.45, 24.91, 26.51,
28.22, 29.76, 31.10, 36.63, 45.39, 50.50, 51.76, 152.13, 195.27. Anal. Calcd. for
C16H29N5S3: C 49.58, H 7.54, N 18.07, S 24.81%. Found: C 49.43, H 7.63, N 18.04, S 24.84%.
(6a): Yellow solid; Yield 28%, mp 95–97 °C. The product was purified by column
chromatography (n-hexane/EtOAc, 5:1), FTIR (KBr, cm−1): 3058, 2961, 2934, 2857,
2688, 2550, 2494, 1533, 1462, 1430, 1361, 1309, 1265, 1209, 1222, 1024, 986, 892, 826.
1H NMR (400 MHz, CDCl3, ppm): δ 0.90 (t, 3H, J ¼ 7.1 Hz, CH3), 1.30–1.43 (m, 4H,
2CH2), 1.71–0.79 (m, 10H, 2CH2), 2.11–2.18 (m, 2H, CH2), 2.75 (t, 2H, J ¼ 6.9 Hz,
S-CH2), 3.18 (t, 2H, J ¼ 7.4 Hz, S-CH2), 3.61, 4.17 (s, 4H, N-CH2), 4.60 (t, 2H, J ¼ 6.9 Hz,
N-CH2). 13C NMR (100 MHz, CDCl3, ppm): δ 12.91, 21.13, 23.28, 24.45, 24.92, 26.56,
28.21, 29.76, 31.11, 35.73, 50.21, 51.52, 51.71, 162.27, 195.34. Anal. Calcd. for
C16H29N5S3: C 49.58, H 7.54, N 18.07, S 24.81%. Found: C 49.45, H 7.61, N 18.07, S 24.82%.
Conclusion
The present work involves the synthesis of novel alkyl or aryl sulfanyltetrazole derivatives
containing carbodithioate moieties to explore their antibacterial activity. The synthesized
compounds, including the sulfanyltetrazoles (2a–2e), carbodithioate moieties (5a–6e) were
evaluated and tested against bacterial strains. The obtained results indicated that sulfanyl-
tetrazole compounds containing carbodithioate moiety have strong antibacterial properties
in comparison to the corresponding sulfanyltetrazoles. Of the synthesized compounds, 6d
showed the best activity against all the tested microorganisms (0.78–6.25 µg mL−1).
The antibacterial activity results and structure activity relationship indicated that the inser-
tion of carbodithioate moiety to its corresponding sulfanyltetrazole analogues results in
increasing the antibacterial activity of the target compounds. Also, most 2,5-regioisomers
are more potent than the corresponding 1,5-regioisomers.
References
[1] He, Y.; Cai, C. Catal. Lett. 2010, 140, 153–159.
[2] Łodyga-Chruścińska, E. Coord. Chem. Rev. 2011, 255, 1824–1833.

6
M. BAGHERSHIROUDI ET AL.
[3] Lim, S. J.; Sunohara, Y.; Matsumoto, H. J. Pestic. Sci. 2007, 32, 249–254.
[4] Boff, J. S.; Clark, B. A.; Friedrich, L. E.; Singer, S. P. Google Patents US6190848, 2001.
[5] Gao, H.; Shreeve, J. N. M. Chem. Rev. 2011, 111, 7377–7436.
[6] Zhan, P.; Liu, H.; Liu, X.; Wang, Y.; Pannecouque, C.; Witvrouw, M.; De Clercq, E. Med. Chem.
Res. 2010, 19, 652–663.
[7] Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379–3393.
[8] Karabanovich, G.; Roh, J.; Soukup, O.; Pávková, I.; Pasdiorová, M.; Tambor, V.; Stolaříková, J.;
Vejsová, M.; Vávrová, K.; Klimešová, V. Med. Chem. Commun. 2015, 6, 174–181.
[9] Adamec, J.; Waisser, K.; Kuneš, J.; Kaustová, J. Arch. Pharm. 2005, 338, 385–389.
[10] Karabanovich, G.; Roh, J.; Smutný, T.; Němeček, J.; Vicherek, P.; Stolaříková, J.; Vejsová, M.;
Dufková, I., Vávrová, K.; Pávek, P. Eur. J. Med. Chem. 2014, 82, 324–340.
[11] Zhan, P.; Li, Z.; Liu, X.; De Clercq, E. Mini. Rev. Med. Chem. 2009, 9, 1014–1023.
[12] Adamec, J.; Beckert, R.; Weiss, D.; Klimešová, V.; Waisser, K.; Möllmann, U.; Kaustova, J.;
Buchta, V. Bioorg. Med. Chem. 2007, 15, 2898–2906.
[13] Gagnon, A.; Ma’an, H. A.; Bonneau, P. R.; Coulombe, R.; DeRoy, P. L.; Doyon, L.; Duan, J.;
Garneau, M.; Guse, I.; Jakalian, A. Bioorg. Med. Chem. Lett. 2007, 17, 4437–4441.
[14] Wang, Z.; Wu, B.; Kuhen, K. L.; Bursulaya, B.; Nguyen, T. N.; Nguyen, D. G.; He, Y. Bioorg.
Med. Chem. Lett. 2006, 16, 4174–4177.
[15] Welz, R.; Müller, S. Tetrahedron Lett. 2002, 43, 795–797.
[16] Celik, G. D.; Disli, A.; Oner, Y.; Acik, L. Med. Chem. Res. 2013, 22, 1470–1479.
[17] Dhayanithi, V.; Shafi, S. S.; Kumaran, K.; Jai, S. K.; Ragavan, V. R.; Goud, K. S. P. N.; Kumari,
S.; Pati, H. N. J. Serb. Chem. Soc. 2011, 76, 165–175.
[18] Marinovich, M.; Viviani, B.; Capra, V.; Corsini, E.; Anselmi, L.; D’Agostino, G.; Di Nucci, A.;
Binaglia, M.; Tonini, M.; Galli, C. L. Chem. Res. Toxicol. 2002, 15, 26–32.
[19] Bergendorff, O.; Hansson, C. J. Agric. Food. Chem. 2002, 50, 1092–1096.
[20] Morf, P.; Raimondi, F.; Nothofer, H.-G.; Schnyder, B.; Yasuda, A.; Wessels, J. M.; Jung, T. A.
Langmuir. 2006, 22, 658–663.
[21] Zhang, D.; Chen, J.; Liang, Y.; Zhou, H. Synth. Commun. 2005, 35, 521–526.
[22] Günay, N. S.; Çapan, G.; Ulusoy, N.; Ergenç, N.; Ötük, G.; Kaya, D. Farmaco. 1999, 54,
826–831.
[23] Imamura, H.; Ohtake, N.; Jona, H.; Shimizu, A.; Moriya, M.; Sato, H.; Sugimoto, Y.; Ikeura, C.;
Kiyonaga, H.; Nakano, M. Bioorg. Med. Chem. 2001, 9, 1571–1578.
[24] Güzel, Ö.; Salman, A. Bioorg. Med. Chem. 2006, 14, 7804–7815.
[25] Azizi, N.; Aryanasab, F.; Saidi, M. R. Org. Lett. 2006, 8, 5275–5277.
[26] Ortar, G.; Cascio, M. G.; Moriello, A. S.; Camalli, M.; Morera, E.; Nalli, M.; Di Marzo, V. Eur. J.
Med. Chem. 2008, 43, 62–72.
[27] Bethel, P.; Hill, M.; Mahon, M.; Molloy, K. J. Chem. Soc. Perkin Trans. 1999, 1, 3507–3514.
[28] Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis. 1998, 1998, 910–914.
[29] Myznikov, L.; Vorona, S.; Artamonova, T. E.; Zevatskii, Y. Russ. J. Gen. Chem. 2017, 87,
1313–1316.