Synthesis and root growth activity of some new acetylhydrazinecarbothioamides and 1,2,4-triazoles substituted with the 5H-dibenzo[a,d][7]annulene moiety

Article abstract of DOI:10.2298/JSC120120068S

New hydrazinecarbothioamides 5a-d bearing 5H-dibenzo[a,d][7]annulene moiety were synthesized using classical procedures. 1H-NMR analysis indicated the existence of two conformational isomers, a major axial (about 75 %) and a minor equatorial one (25 %), which are interconvertible by middle ring inversion. Cyclization of compounds 5a-d in NaOH solution produced the corresponding 4H-1,2,4-triazole-3-thiols (6a-d) that proved to be pure axial isomers. All the new compounds were extensively characterized by elemental analysis, IR, UV, 1H-NMR and 13C-NMR spectroscopy and were biologically investigated using phytobiological tests. Copyright

Full text of DOI:10.2298/JSC120120068S

J. Serb. Chem. Soc. 77 (11) 1541–1549 (2012)
UDC 547.497.1+547.79:611.018.1+615.9
JSCS–4369
Original scientific paper
Synthesis and root growth activity of some new
acetylhydrazinecarbothioamides and 1,2,4-triazoles
substituted with the 5H-dibenzo[a,d][7]annulene moiety
1
1
1
*
LAURA I. SOCEA , THEODORA V. APOSTOL , GABRIEL ŞARAMET , ŞTEFANIA F.
BĂRBUCEANU1, CONSTANTIN DRAGHICI2 and MIHAELA DINU1
1Carol Davila University of Medicine and Pharmacy, Faculty of Pharmacy, Organic
Chemistry Department, Traian Vuia Street 6, 020956, Bucharest, Romania and
2C. D. Neniţescu Institute of Organic Chemistry, Romanian Academy,
Splaiul Independenţei 202B, 060023, Bucharest, Romania
(Received 20 January, revised 20 June 2012)
Abstract: New hydrazinecarbothioamides 5a–d bearing 5H-dibenzo[a,d][7]an-
1
nulene moiety were synthesized using classical procedures. H-NMR analysis
indicated the existence of two conformational isomers, a major axial (about 75
%) and a minor equatorial one (25 %), which are interconvertible by middle
ring inversion. Cyclization of compounds 5a–d in NaOH solution produced the
corresponding 4H-1,2,4-triazole-3-thiols (6a–d) that proved to be pure axial
isomers. All the new compounds were extensively characterized by elemental
1
analysis, IR, UV, H-NMR and 13C-NMR spectroscopy and were biologically
investigated using phytobiological tests.
Keywords: carbothioamide; 1,2,4-triazole; 5H-dibenzo[a,d][7]annulene; plant
growth regulation activity.
INTRODUCTION
The 5H-dibenzo[a,d][7]annulene ring is present in the structure of many
compounds used in therapeutics as antibacterial, anticonvulsive, anticholinergic,
myorelaxant, antihistaminic, antifungal, carbonic anhydrase inhibitors, anti-in-
flammatory, analgesic, anti-arrhythmia, antiparasitic agents, but mostly they are
1–4
used as antidepressant drugs.
Hydrazinecarbothioamides are compounds with various pharmacological acti-
vities: anti-inflammatory, antimicrobial, tuberculostatic, anticonvulsive and anti-
5–8
viral.
The synthesis of compounds containing the 1,2,4-triazole ring in their struc-
ture has attracted widespread attention, mainly in connection with their wide
range of pharmacological properties. It is well documented that 1,2,4-triazole
*Corresponding author. E-mail: laurasocea@gmail.com
doi: 10.2298/JSC120120068S
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SOCEA et al.
derivatives possess antimicrobial, antifungal, tuberculostatic, analgesic and car-
9–13
bonic anhydrase inhibitor activities.
2,14–18
Motivated by these facts and as a continuation of previous work,
the
synthesis, characterization and action on vegetal cell division of new hydrazine-
carbothioamides and 1,2,4-triazole derivatives containing the 5H-dibenzo[a,d]-
[7]annulene moiety are presented herein.
The structures of these new compounds were elucidated by elemental anal-
1
13
ysis and IR, UV, H-NMR and C-NMR spectroscopy. The newly synthesized
19–21
products were tested using phytobiological tests.
19,21
The Triticum bioassay (Constantinescu method)
revealed concentration-
dependent mitoinhibitory effects for the investigated substances.
EXPERIMENTAL
Materials, methods and instruments
All chemicals used in this study were supplied by Sigma–Aldrich and Merck.
The melting points were determined using a Böetius apparatus and are uncorrected.
Elemental analyses were realized using a Perkin–Elmer CHNS/O Analyzer Series II 2400 ins-
trument and the results were within ±0.4 % of theoretical values. The infrared spectra were
recorded on a Vertex 70 Bruker spectrometer using the KBr pellet technique and the results
are expressed in wave number (cm-1). The 1H-NMR and 13C-NMR spectra were registered on
a Varian Gemini 300 BB spectrometer working at 300 MHz for 1H and 75 MHz for 13C, using
DMSO-d6 as the solvent for hydrazinecarbothioamides and CDCl3 for 1,2,4-triazole com-
pounds. The chemical shifts are expressed in δ (ppm) using TMS as the internal standard. The
UV–Vis spectra were recorded on a SPECORD 40 Analytik Jena spectrometer in methanol
(2.5×10-5 M) in the wavelength range 200–600 nm.
The plant bioassay (Triticum bioassay) used embryonic roots from Triticum vulgare
Mill. as the biological reagent. A Labophot II Nikon microscope (ob. 10× and 100×) was
used.20,21
Procedure for the preparation of 2-(5H-dibenzo[a,d][7]annulen-5-ylacetyl)hydrazinecarbo-
thioamide 5a
The mixture of 2-(5H-dibenzo[a,d][7]annulen-5-yl)acetohydrazide (3, 0.004 mol), and
KSCN (0.008mol) in 40 mL water was refluxed in the presence of 1 mL of concentrated HCl
for 10 h. On cooling the reaction mixture to room temperature, a white solid appeared. This
was filtered off and recrystallized from methanol–water (1:3, v:v) to obtain the desired
compound.
General procedure for the preparation of 2-(5H-dibenzo[a,d][7]annulen-5-ylacetyl)-N-alkyl-
(aryl)hydrazinecarbothioamides 5b–d
The mixture of 2-(5H-dibenzo[a,d][7]annulen-5-yl)acetohydrazide (3, 0.004 mol) and
the corresponding isothiocyanate 4b–d (0.004 mol) in absolute ethanol (30–50 mL) was
refluxed for 6–12 h. On cooling the reaction mixture to room temperature, a solid appeared.
This was filtered off and recrystallized from ethanol to obtain the desired compound.
General procedure for the preparation of compounds 6a–d
A solution of the corresponding carbothioamide 5a–d (1 mmol) in 8 mL of 8 % NaOH
solution was refluxed for 3–9 h and then filtered. After cooling, the filtrate was neutralized
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ROOT GROWTH ACTIVITY OF ACETYLHYDRAZINECARBOTHIOAMIDES
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with acetic acid. The obtained white precipitate was filtered and recrystallized from CHCl3:pet-
roleum ether (1:2, v/v).
Triticum bioassay – Constantinescu method
The effects of the title compounds on root growth of wheat were determined according to
the bioassay – Triticum test. The method is based on the study of the influence of substances
at various dilutions on root elongation and mitotic film, depending on their duration of action
on wheat (Triticum sp., Poaceae) caryopses germinated under well-defined laboratory con-
ditions.
All the compounds were tested at 0.5, 0.25 and 0.05 mM concentrations. The solutions
were placed in 10 cm diameter Petri dishes and then the wheat caryopses with a main root of
1 cm were introduced.
The dishes were covered with their lids and the caryopses were left in contact with the
solutions for 5 days. In parallel, a control sample was prepared, in which the test solutions
were replaced by distilled water. Root elongation was evaluated at the same time for 5 days.
Observations were made on the morphological changes, as well as on the aspect, the number
of radicles and the length of the main radicle.
For the microscopic study, after 24 h, the embryonic root of two caryopses from each
Petri dish was sectioned at a distance of 5 mm from the tip and stained with dilute acetic
orcein, a dye with a great affinity for chromatin in acetic medium (an acid pH is required for
the hydrolysis of the chromatin) which will be stained red. The stained sections were micro-
scopically examined using a LaboPhot II Nikon microscope (ocular 10×, object-glass 100×)
by immersion in cedar oil.
The data represent the average values from two independent experiments and the results
were processed statistically by the Student’s t-test (Table I).
TABLE I. Plant growth regulation activities of compounds 5a–d and 6a–d (the root length is
the mean value of measurements made on day five of the treatment)
Compd.
Concentration, mM
Root length SDa, mm
p-Valueb
Effect, %
M
–
0.5
108.4 3.3
33.2 3.0
42.0 4.1
64.0 6.0
68.7 5.8
85.5 7.0
92.0 8.7
52.0 5.2
75.3 7.0
82.1 8.7
102.8 1.9
96.5 9.1
89.6 9.0
56.5 5.6
61.3 4.0
103.7 2.1
70.7 7.7
79.1 8.0
92.5 8.2
–
–
5a
5a
5a
5b
5b
5b
5c
5c
5c
5d
5d
5d
6a
6a
6a
6b
6b
6b
<0.00001
<0.00001
<0.00001
<0.0001
<0.001
<0.001
<0.00001
<0.001
<0.001
NSd
<0.001
<0.001
<0.00001
<0.0001
NS
76.42c
67.48
45.12
40.34
23.27
16.66
57.31
33.63
26.72
5.69
0.25
0.05
0.5
0.25
0.05
0.5
0.25
0.05
0.5
0.25
0.05
0.5
0.25
0.05
0.5
0.25
0.05
12.09
19.10
52.74
47.86
4.77
38.31
29.77
16.15
0.0001
0.001
<0.001
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SOCEA et al.
TABLE I. Continued
Compd.
Concentration, mM
Root length SDa, mm
p-Valueb
Effect, %
6c
6c
6c
6d
6d
6d
0.5
0.25
0.05
0.5
0.25
0.05
63.3 6.1
65.3 5.9
98.8 3.9
63.0 5.8
83.2 7.9
109.7 3.9
<0.00001
<0.0001
0.004
<0.00001
<0.001
NS
45.83
40.75
9.75
46.13
25.60
–1.32e
astandard deviation; bsignificant level (statistical significance in the two-population (independent) Student’s t-
-test); positive value of effect = inhibition effect on wheat root growth; dthe two means are not significantly
c
different; enegative value of effect = stimulating effect on wheat root growth
RESULTS AND DISCUSSION
Chemistry
The synthesis pathway used for the preparation of the title compounds is
shown in Scheme 1.
Scheme 1. Reaction pathway to the target compounds 5a–d and 6a–d.
The synthesis of the new compounds was realized in several steps, starting
from 5H-dibenzo[a,d][7]annulen-5-ylacetic acid (1) that was transformed into the
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ROOT GROWTH ACTIVITY OF ACETYLHYDRAZINECARBOTHIOAMIDES
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ethyl ester 2. Ethyl 5H-dibenzo[a,d][7]annulen-5-ylacetate (2) was reacted with
14,22,23
hydrazine hydrate according to a literature method
affording 2-(5H-di-
benzo[a,d][7]annulen-5-yl)acetohydrazide (3).
2-(5H-Dibenzo[a,d][7]annulen-5-ylacetyl)hydrazinecarbothioamide (5a) was
obtained by refluxing 3 with KSCN and concentrated HCl.
The new 2-(5H-dibenzo[a,d][7]annulen-5-ylacetyl)-N-alkyl/arylhydrazine-
carbothioamides 5b–d were obtained by nucleophilic addition of 3 to different
14,15,24,25
alkyl or aryl isothiocyanates 4b–d.
The new 5-(5H-dibenzo[a,d][7]annulen-5-ylmethyl)-4-alkyl/aryl-4H-1,2,4-tri-
azole-3-thiols 6a–d were synthesized by subjecting 5a–d to intramolecular cycli-
14–16,26,27
zation in 8 % sodium hydroxide solution under reflux.
Analytical and spectral data of the newly prepared compounds
The spectral data of all the newly synthesized hydrazinecarbothioamides and
1,2,4-triazoles are given in the Supplementary Material to this paper. The data
are in accordance with the proposed structures. The general structure of 5 with
atom numbering is given Fig. 1.
Fig. 1. The general structure of 5 with atom numbering.
The nucleophilic addition of 2-(5H-dibenzo[a,d][7]annulen-5-yl)acetohydra-
zide to KSCN and various isothiocyanates was confirmed in the infrared spectra
of the new acylhydrazinecarbothioamides 5a–d by the appearance of new ab-
–1
sorption bands due to the stretching vibration of the C=S group (1256–1259 cm ),
–1
the NO group (1566, 1350 cm ) and the stretching vibration of the CH group.
2
3
The C=O and N–H stretching bands were present at 1686–1674 and 3419–3184
–1
cm , respectively.
The structures of the 1,2,4-triazole-3-thiols 6a–d were also proved based on
their spectral data. The IR spectra confirmed the cyclization of 5a–d to 6a–d by
the disappearance of the ν
band. Moreover, instead of two or three NH bands
C=O
–1
of compound 5, compound 6 exhibited only one band in KBr at 3419–3092 cm ,
characteristic for the –NH–CS group. It seems that in KBr, the mercaptotriazole 6
existed in the form of their thionic tautomers (Scheme 2).
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SOCEA et al.
Scheme 2. Tautomeric forms of the mercaptotriazoles 6a–d.
1
The H-NMR spectra of carbothioamides 5a–d indicated the presence of two
isomers, 5′-axial and 5′-equatorial in a ratio of about 3:1, interconvertible by
middle ring inversion (Scheme 3).
Scheme 3. Interconversion of the acylcarbothioamides 5a–d between the 5′-axial and
5′-equatorial isomers by middle ring inversion.
The NH protons signals appear as singlets between 8.13–10.30 ppm, the
10′
11′
double bond protons H and H appear as singlets at 7.01–7.07 ppm. The ali-
phatic side chains protons also exhibited normal δ values.
13
In the C-NMR spectra of 5a–d, the dibenzo[a,d][7]annulene moiety ap-
10′
11′
pears in a narrow δ domain (123–140 ppm), with C and C easily recogniz-
able at δ 130.9–131.7 ppm. The signal at δ ≈ 181 ppm could be attributed to the
C=S carbon atom. The remaining carbon atoms afforded signals that partially
overlapped with those of the side chains. However, the assignments of these sig-
nals could be made using incremental calculations for the substituents and the re-
sults were very similar to those of the triazoles 6a–d.
1
The H-NMR spectra of triazoles 6a–d indicated the presence of a single
conformational isomer, namely the axial one.
Surprisingly, cyclization of 5 to 6 and the subsequent work-up were accom-
panied by the loss of the minor equatorial isomer, probably because of its higher
solubility in the acidic water.
5′
12′
The H (eq.) appears at δ 4.35–4.61 ppm (triplet, J = 7.7 Hz) and CH
2
protons as a doublet at 2.89–3.01 ppm in 6a–d. Interestingly, the NH signals of
5b–d totally disappeared being replaced by a singlet at δ 10.85–11.70 ppm, attri-
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ROOT GROWTH ACTIVITY OF ACETYLHYDRAZINECARBOTHIOAMIDES
1547
butable to the SH proton. In the case of triazole 6a, a singlet appears at 9.04 ppm
attributed to the NH group and another one at 10.85 ppm attributed to the SH
group.
Thus, in solution, the equilibrium is shifted towards the thiolic form.
Conversion of carbothioamides 5 to triazoles 6 is also nicely supported by
13
C-NMR spectra in which a new quaternary carbon signal (for C ) appears at δ
3
165.69–168.37 ppm simultaneously with the disappearance of the C=S signal
from 5 (δ 181 ppm). Moreover, instead of C=O signal from 5 at 169–170 ppm, a
new signal appears for C of 6 at about 150–151 ppm.
5
Triticum bioassay
The effects of the title compounds 5a–d and 6a–d on the sprouting of wheat
were investigated. After treating with solutions of 0.5, 0.25 and 0.05 mM concen-
trations of compounds 5a–d and 6a–d for 5 days, from the difference in length
between the main root of caryopses treated with the title compounds and those
treated with distilled water (last day), the plant growth regulating activities of the
compounds were determined from the formula:
length of sample radicle −10 mm
length of reference radicle −10 mm
Effect (%) = 100 –
×100
where 10 mm represents the initial length of the main root. A positive result re-
presents inhibition, whereas a negative result implies growth stimulation.
The results of the Triticum bioassay – the Constantinescu method (the root
elongation values for each sample tested in the day) are presented in Table I.
The compounds 5a–d and 6a–c inhibited root growth at all concentrations,
without cytotoxicity (Table I). The inhibitory activity declined with decreasing
applied concentration.
The microscopic examination of the wheat embryonic roots showed mitode-
pressive and mitostatic effects for 0.50 and 0.25 mM concentrations: the shape of
the cell was irregular and nuclei with a hypertrophied nucleolus were observed.
At 0.05 mM concentration (except for compound 5a), phases of normal division
were noticed, the aspect being generally similar to that observed for the control.
CONCLUSIONS
In this paper, the synthesis and characterization of four new acetylhydrazine-
carbothioamides and four 4H-1,2,4-triazole-3-thiol derivatives containing 5H-di-
benzo[a,d][7]annulene moiety were presented. The structures of new compounds
1
13
were confirmed by spectral data (IR-, UV-, H-NMR and C-NMR).
All the compounds were investigated for their biological activities concer-
ning regulation of the growth of wheat using the phytobiological method – the
Triticum test. A microscopic study demonstrated mitosis inhibition activity for
compounds 5a–d and 6a–d, without cytotoxicity.
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SOCEA et al.
SUPPLEMENTARY MATERIAL
Analytical and spectral data of the synthesized compounds are available electronically
from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgements. This paper is supported by the Sectoral Operational Programme
Human Resources Development, financed from the European Social Fund and by the
Romanian Government under the contract number POSDRU/89/1.5/S/64109.
И З В О Д
СИНТЕЗА И БИОЛОШКА АКТИВНОСТ НОВИХ АЦЕТИЛХИДРАЗИН-
КАРБОТИОАМИДА И 1,2,4-ТРИАЗОЛА СУПСТИТУИСАНИХ
5H-ДИБЕНЗО[a,d][7]АНУЛЕНИМА
LAURA I. SOCEA1, THEODORA V. APOSTOL1, GABRIEL ŞARAMET1, ŞTEFANIA F. BĂRBUCEANU1,
CONSTANTIN DRAGHICI2 и MIHAELA DINU1
1Carol Davila University of Medicine and Pharmacy, Faculty of Pharmacy, Organic Chemistry Department,
Traian Vuia Street 6, 020956, Bucharest, Romania и 2C. D. Neniţescu Institute of Organic Chemistry,
Romanian Academy, Splaiul Independenţei 202B, 060023, Bucharest, Romania
Описана је синтеза нових деривата 5a–d 5H-dибензо[a,d][7]анулена. Анализа 1H-
-NMR спектара указује на присуство два конформациона изомера, доминантниог (око
75%) аксијалног и споредног екваторијалног (око 25 %), који подлежу конформационој
измени инверзијом средњег прстена. Циклизацијом dеривата 5a–d у раствору натријум-
хидроксида добијају се одговарајући деривати 6a–d, 4H-1,2,4-триазол-3-тиоли, који су
добијени као чисти аксијални изомери. Сва нова једињења окарактерисана су елемен-
1
талном анализом, IR, UV, H-NMR и 13C-NMR спектроскопијом и испитана им је био-
лошка активност фитобиолошким тестом.
(Примљено 20. фебруара, ревиdирано 20. јуна 2012)
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