Synthesis and antimicrobial evaluation of novel 3-(arylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-diones and their 2-thioxo analogues

Article abstract of DOI:10.1080/00397911.2017.1316407

The preparation of some novel 3-(arylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-diones 8(i–xiv) and 3-(arylideneamino)-3a,8a-dihydroxy-2-thioxo-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazol-8(2H)-ones 9(i–xiv) have been reported through one-pot catalyst-free reaction of aldehydes, semicarbazide hydrochloride/thiosemicarbazide with ninhydrin. All the synthesized compounds have been screened for antimicrobial activity and some of them were observed to possess broad spectrum antibacterial potential as well as significant antagonistic potential against fungal pathogens.

Full text of DOI:10.1080/00397911.2017.1316407

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis and anti-microbial evaluation of novel
3-(arylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-
tetrahydroindeno[1,2-d]imidazole-2,8-diones and
their 2-thioxo analogues
Yeshwinder Saini, Rajni Khajuria, Ramneet Kaur, Sanjana Kaul, Tanwi
Sharma, Suruchi Gupta, Vivek K. Gupta, Rajni Kant & Kamal K. Kapoor
To cite this article: Yeshwinder Saini, Rajni Khajuria, Ramneet Kaur, Sanjana Kaul, Tanwi
Sharma, Suruchi Gupta, Vivek K. Gupta, Rajni Kant & Kamal K. Kapoor (2017): Synthesis and anti-
microbial evaluation of novel 3-(arylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2-
d]imidazole-2,8-diones and their 2-thioxo analogues, Synthetic Communications, DOI:
10.1080/00397911.2017.1316407
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1316407
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Date: 17 April 2017, At: 10:33

Synthesis and anti-microbial evaluation of novel 3-(arylideneamino)-3a,8a-
dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-diones and their 2-thioxo
analogues
Yeshwinder Saini1, Rajni Khajuria1, Ramneet Kaur1, Sanjana Kaul2, Tanwi Sharma2,
Suruchi Gupta2, Vivek K. Gupta3, Rajni Kant3, Kamal K. Kapoor1
1Department of Chemistry, University of Jammu, Jammu, India, 2School of
Biotechnology, University of Jammu, Jammu, India, 3Department of Physics &
Electronics, University of Jammu(X-ray crystallography group), Jammu, India
Corresponding Author: Kamal K. Kapoor, Email: k2kapoor@yahoo.com; Sanjana Kaul,
Email: sanrozie@rediffmail.com
Abstract
The preparation of some novel 3-(arylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-
tetrahydroindeno[1,2-d]imidazole-2,8-diones 8(i-xiv) and 3-(arylideneamino)-3a,8a-
dihydroxy-2-thioxo-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazol-8(2H)-ones 9(i-xiv) have
been reported via one-pot catalyst-free reaction of aldehydes, semicarbazide
hydrochloride/thiosemicarbazide with ninhydrin. All the synthesized compounds have
been screened for anti-microbial activity and some of them were observed to possess
broad spectrum anti-bacterial potential as well as significant antagonistic potential against
fungal pathogens.
Graphical Abstract:
1

KEYWORDS: Ninhydrin, tetrahydroindenoimidazoledione, 2-thioxotetrahydro
indenoimidazolone, anti-bacterial, anti-fungal.
INTRODUCTION
Hydrazones (semicarbazones and thiosemicarbazones) 1 play significant role in the
synthesis of biologically important heterocyclic compounds[1]. They are of immense
biological significance and are known to exhibit anti-cancer[2], anti-malarial[3], anti-
viral[4], anti-fungal[5], anti-bacterial[6], anti-tubercular[7] and anti-inflammatory [8]
properties. Ninhydrin has been employed in the synthesis of a variety of biologically
active imidazole derivatives[9]. For example, compound 2 obtained by the reaction of
ninhydrin with thiourea, exhibited promising anti-microbial activity against gram positive
and gram negative bacteria and a fungus Candida albicans[10]. Compound 3, a
hydrophobic analogue of 2 is devoid of two H-bond donors. Obtained[11] by the reaction
of ninhydrin with diphenylthiourea, compound 3 has shown improvement in activity
against some bacterial strains (Bacillus subtilis, Streptococcus pneumoniae,
Pseudomonas aeruginosa) and loss against some other strains (Shigella flexneri,
Escherichia coli). Loss in anti-fungal activity of compound 3 against C. albicans was
also noticed[10, 11]. In view of this irregular trend in activity, we wished to maintain a
balance between hydrophilicity and hydrophobicity by retaining one H-bond donor and
this led us to design a compound 4 possessing the attributes of hydrazones as well as
tetrahydroindeno[1,2-d]imidazolones (Figure 1).
2

RESULTS AND DISCUSSION
Chemistry
Benzaldehyde 5(i) (1 mmol) was reacted with semicarbazide hydrochloride 6(i) (1 mmol)
in ethanol to yield the corresponding semicarbazone 7(i) (96%), which upon reaction
with ninhydrin (1.2 mmol) in ethanol (TLC) at reflux led to the formation of 3-
(benzylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-
dione 8(i) (77%) (overall yield 74%) (Scheme 1).
In another set of experiment, one-pot reaction was carried out. Initially, benzaldehyde
5(i) (1 mmol) and semicarbazide hydrochloride 6(i) (1 mmol) were reacted in refluxing
ethanol (30 min) and noticing the completion of reaction (TLC), ninhydrin (1.2 mmol)
was added and refluxing was continued. After 90 minutes, the reaction got completed and
8% increase in the yield of the desired product 8(i) was noticed. Replacing ethanol with
various solvents (Table 1) led us to conclude that 1,4-dioxane was the best solvent for
this reaction.
Further, replacement of semicarbazide hydrochloride 6(i) with thiosemicarbazide 6(ii)
yielded the expected 3-(benzylideneamino)-3a,8a-dihydroxy-2-thioxo-1,3,3a,8a-
tetrahydroindeno[1,2-d]imidazol-8(2H)-one 9(i) in 87% yield. The structure of 9(i) was
supported by single-crystal X-ray crystallographic study (Figure 2). The ORTEP
diagram of 9(i) clearly indicates that the two hydroxyl groups are in cis-conformation.
3

A variety of aromatic aldehydes bearing electron donating and electron withdrawing
groups led to the successful formation of the desired products 8(i-xiv) and 9(i-xiv)
(Scheme2). The plausible mechanism for the formation of 3-(arylideneamino)-3a,8a-
dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-diones 8(i-xiv) and 3-
(arylideneamino)-3a,8a-dihydroxy-2-thioxo-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazol-
8(2H)-ones 9(i-xiv) is shown in Scheme 3. The terminal nitrogen of
semi/thiosemicarbazone 7(i-xxviii), formed in situ, underwent nucleophilic addition
reaction with ninhydrin to form hydrazine carboxamide/carbothioamide intermediate (A)
and this was followed by attack from the same side of the internal nitrogen to yield the
desired cis-products 8(i-xiv)/9(i-xiv) as illustrated in Scheme 3. It is pertinent to mention
that attack from the same side lead to the exclusive formation of cis-product since it is
well established [12] that cis-biquinane systems are far more stable than their trans-
counterparts.
BIOLOGICAL EVALUATION
Anti-Bacterial And Anti-Fungal Bioassays (In Vitro)
The anti-bacterial screening of the test compounds 8(i-xiv) and 9(i-xiv) was done against
eight bacterial strains at concentrations of 100 g/ml, 250 g/ml, 500 g/ml, 750 g/ml
and 1000 g/ml. No inhibitory activity was observed for the test compounds at 100
g/ml, 250 g/ml, 500 g/ml and 750 g/ml. At 1000 g/ml concentration, the test
compounds displayed perceptible potential against the screened bacterial strains (Table
2, Figure 3). The results clearly indicate that twenty-four out of the twenty-eight
compounds showed activity against one or more strains. Compounds 8(viii, xii) and 9(v)
4

possessed broad spectrum anti-bacterial activity against all the tested strains whereas
8(ix) and 9(vi) were found active against seven test cultures. 9(vii) and 9(xii) displayed
moderate inhibitory potential against five tested strains. Compounds 8(viii) and 9(vi)
were active against four, 8(xii) against three, 8(xiv) against two and 8(ix), 9(v), 9(x) and
9(xiii) against one bacterial strain. Four compounds 8(v, x) and 9(xi, xiv) did not exhibit
anti-bacterial activity against any of the organisms screened.
Anti-fungal potential of the test compounds 8(i-xiv) and 9(i-xiv) was represented as
percentage inhibition values (Table 3, Figure 4). The investigation of anti-fungal
screening of these compounds revealed their varying degrees of activity against all the
tested microorganisms. Compound 9(viii) exhibited very good anti-fungal activity with
70% and 78% growth inhibition against Fusarium oxysporum and Alternaria alternata
respectively. Compound 8(viii) displayed 71.43% growth inhibition against Alternaria
alternata. Rest of the test compounds showed varying degrees of % inhibition of tested
fungal pathogens ranging from 2.86 to 68%. Species of Alternaria and Fusarium are
reported to cause broad spectrum infections in humans and mostly affect immune
compromised patients. Therefore, the compounds showing significant activity against
these fungi can serve as potential candidates for anti-fungal therapy.
EXPERIMENTAL
General
All the experiments were performed in an oven dried glass apparatus. All the
commercially available reagents were purchased from Aldrich and were used
5

without further purification. Melting points (°C) were measured in open glass
capillaries using Perfit melting point apparatus and are uncorrected. The progress
of reaction was monitored by thin layer chromatography (TLC) using silica gel
pre-coated aluminum sheets (60 F254, Merck). Visualization of spots was effected
by exposure to ultraviolet light (UV) at 365 nm and 254 nm, iodine vapours and
2% 2,4-dinitrophenylhydrazine solution in methanol containing few drops of
H2SO4 and draggendroff reagent. IR spectra (ν, cm-1) were recorded on Perkin-
Elmer FTIR spectrophotometer using KBr discs. 1H and 13C NMR were recorded
on Bruker AC-400 spectrometer operating respectively at 400 MHz and 100 MHz
with tetramethylsilane (TMS) as an internal standard. The chemical shifts are
expressed in δ (ppm) downfield from TMS. J values are given in Hertz (Hz). The
abbreviations s, bs, d, t, q and m in 1H NMR spectra refer to singlet, broad singlet,
doublet, triplet, quartet and multiplet respectively. Electron impact mass spectra
(EIMS) were recorded on Micro Mass VG-7070 H mass spectrometer at 70eV.
Elemental analysis was performed on Leco CHNS 932 analyzer. Solvents were
removed using Heidolph rotary evaporator. Column chromatography was
performed using a gradient of ethylacetate and petroleum ether.
The synthesized 3-(arylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2-
d]imidazole-2,8-diones 8(i-xiv) and 3-(arylideneamino)-3a,8a-dihydroxy-2-thioxo-
1,3,3a,8a-tetrahydroindeno[1,2-d]imidazol-8(2H)-ones 9(i-xiv) were screened for their in
vitro anti-bacterial activity using agar well diffusion method[13]. The test pathogens used
in the study included four gram positive bacteria [Bacillus subtilis (MTCC 441),
6

Staphylococcus aureus (MTCC 3160), Klebsiellapneumoniae (MTCC 109), Bacillus
cereus (MTCC 430)] and four gram negative bacteria [Escherichia coli (MTCC 40),
Enterococcus faecalis (MTCC 439), Pseudomonas aeruginosa (MTCC 1934) and
Pseudomonas alcaligenes (MTCC 493)]. For anti-bacterial assay, test pathogens were
revived by growing overnight at 37C and 100 rpm. Test compounds were prepared by
dissolving in DMSO at concentrations of 100g/ml, 250g/ml, 500g/ml, 750g/ml and
1000g/ml whereas the standard drug chloramphenicol was used at a concentration of
100 g/ml. DMSO was used as negative control. Sterile petri-plates were poured with
35ml of Nutrient agar medium. 100 l of bacterial suspension was spread on the
solidified plates. Wells were bored in the plates with the help of borer of 6 mm diameter.
100 l of prepared compounds were added to labeled wells. Results were observed as
diameter of zone of inhibition after incubating the plates at 37C overnight.
Anti-fungal activity of these compounds was evaluated against Fusarium oxysporum
(MTCC 2485) and Alternaria alternata (MTCC 2724) by poison food technique [14]. 1000
g of each compound was added in sterile luke warm Potato dextrose agar medium
before pouring. Fungal agar plug of five days old test culture was placed at the centre of
the medium plate. Plates were incubated at 28ºC for seven days. Percentage inhibition of
fungal culture in presence of test compounds was assessed by comparing mycelia growth
diameter on poisoned (media + compound) and non-poisoned (media + DMSO) plates
and calculated using the formula
% age inhibition   R1 R2 / R1  100




7

R1 means radial growth of test fungi in non-poisoned plate; R2 means radial growth of
same in poisoned plate.
General Procedure For The Synthesis Of 8(I-Xiv) And 9(I-Xiv)
A mixture of aldehyde (5i-5xiv, 1mmol) and semicarbazide hydrochloride 6(i) (0.11g,
1mmol)/thiosemicarbazide 6(ii) (0.09g, 1mmol) in 1,4-dioxane (10 ml) was refluxed for
the time mentioned in Scheme 2 to achieve the complete formation of the desired
semicarbazones/thiosemicarbazones (TLC). At this stage, ninhydrin (0.21g, 1.2 mmol)
was added to the reaction mixture and refluxing was continued till the completion of
reaction (time given in Scheme2). The reaction mixture was poured into ice-cold water
(50 ml) and kept in refrigerator overnight. The solid separated was filtered, dried and
column chromatographed to obtain the pure product [8(i-xiv); 9(i-xiv); 78-93% yield].
Spectral Characterization Of (8i) And (9i)
3-(Benzylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-
dione (8i); white solid; m.p: 185 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.02 (bs, 2H),
7.98 – 7.77 (m, 3H), 7.72 -7.63 (m, 4H), 7.53 – 7.34 (m, 3H), 7.05 (bs, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 195.5, 152.6, 151.6, 145.7, 137.7, 135.5, 132.1, 131.1, 130.1,
129. 2, 127.1, 125.5, 124.2, 89.8, 84.5; IR (KBr)νmax/cm-1: 3365.78, 1724.36, 1695.48;
Anal. calcd. for C17H13N3O4 : C, 63.16; H, 4.05; N, 13.00; found C, 63.12; H, 4.07; N,
12.96; ESI-MS m/z : [M+H]+ = 324.
8

3-(Benzylideneamino)-3a,8a-dihydroxy-2-thioxo-1,3,3a,8a-tetrahydroindeno[1,2-
d]imidazol-8(2H)-one (9i); yellow crystalline solid; m.p: 203 °C; 1H NMR (400 MHz,
DMSO-d6) δ 10.28 (bs, 1H), 9.58 (s, 1H), 8.14-8.07 (d, J = 8 Hz, 1H), 7.97 – 7.86 (m,
4H), 7.79-7.69 (d, J = 8.0 Hz, 2H), 7.55 (s, 3H), 7.40 (bs, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 196.1, 174.9, 156.1, 148.4, 137.3, 134.4, 133.2, 131.5, 131.4, 129.4, 128.1,
127.4, 124.3, 92.7, 86.8; IR (KBr)νmax/cm-1: 3365.32, 1711.14, 1707.34,1285.10; Anal.
calcd. for C17H13N3O3S : C, 60.17; H, 3.86; N, 12.38; S, 9.45; found C, 60.01; H, 3.69; N,
12.84; S, 9.61; ESI-MS m/z : [M+H]+ = 340.
CONCLUSION
A series of novel 3-(arylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2-
d]imidazole-2,8-diones and 3-(arylideneamino)-3a,8a-dihydroxy-2-thioxo-1,3,3a,8a-
tetrahydroindeno[1,2-d]imidazol-8(2H)-ones have been synthesized via one-pot, catalyst-
free reaction of aldehydes, semicarbazide hydrochloride/thiosemicarbazide with
ninhydrin and screened for anti-microbial activity. Some of the synthesized compounds
showed promising results.
ACKNOWLEDGEMENTS
The authors are grateful to DST for NMR facility under PURSE and UGC, New
Delhi for funding (Project No. MRP-MAJOR-CHEM-2013-21745).
9

SUPPORTING INFORMATION
Experimental data, X-ray crystallographic data, 1H NMR and 13C NMR spectra of all the
synthesized compounds can be accessed at publisher’s website.
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Table 1. Optimization of solvent.
Entry
Solvent
Yield (%)
1
2
3
4
5
6
7
8
CH3CN
1,4-Dioxane
1,2-DCE
DMF
80
90
77
70
72
75
73
82
Toluene
THF
Benzene
EtOH
13

Table 2. Anti-bacterial activity of test compounds 8(i-xiv) and 9(i-xiv).
Test
Diameter of Inhibition Zone Against pathogens (mm)
Compound
8 (i)
B.s
-
B.c
10
11
13
-
S.a
11
12
11
-
K.p
-
E.c
9
E.f
12
-
P.a
-
P.al
-
8 (ii)
12
-
-
-
11
-
-
8 (iii)
8 (iv)
8 (v)
-
-
-
11
-
11
-
12
-
10
-
-
12
-
-
-
-
-
8 (vi)
8 (vii)
8 (viii)
8 (ix)
8 (x)
-
11
11
14
13
-
10
-
-
12
-
-
12
-
-
-
-
-
-
15
14
-
14
13
-
13
12
-
12
13
-
13
11
-
14
13
-
12
-
-
8 (xi)
8 (xii)
8 (xiii)
8 (xiv)
9 (i)
-
-
11
15
12
14
-
-
11
13
-
-
-
12
-
11
12
-
14
-
12
-
15
11
-
11
-
11
12
15
12
-
-
9
-
-
12
-
-
-
13
-
-
9 (ii)
13
-
-
-
11
-
12
12
-
9 (iii)
9 (iv)
9 (v)
-
-
-
12
-
11
10
13
13
13
-
-
11
12
-
14
12
11
13
13
14

9 (vi)
13
12
-
-
14
13
12
-
15
-
13
-
15
12
-
16
13
12
12
-
11
-
9 (vii)
11
-
9 (viii)
9 (ix)
-
10
11
9
13
-
13
-
12
-
-
-
9 (x)
14
-
-
6
12
-
9 (xi)
-
-
-
-
-
-
9 (xii)
-
11
-
12
13
-
-
12
-
-
13
-
13
-
9 (xiii)
9 (xiv)
+ve Control
(SD)
12
-
-
14
-
-
-
-
-
-
19
19
20
19
15
20
21
19
-ve Control
-
-
-
-
-
-
-
-
+ve Control = Chloramphenicol (at 100g/ml concentration); -ve Control = DMSO; Test
compounds (at 1000 g/ml concentration)
B.s, Bacillus subtilis; B.c, Bacillus cereus; S.a, Staphylococcus aureus; K.p, Klebsiella
pneumoniae; E.c, Escherichia coli; E.f, Enterococcus faecalis; P.a, Pseudomonas
aeruginosa; P.al, Pseudomonas alcaligenes.
‘-‘ sign indicates absence of clear zone; Weaker = 6–10 mm; Moderate = 10-13 mm,
above 13 mm = good.
15

Table 3. Anti-fungal activity of test compounds 8(i-xiv) and 9(i-xiv)
Test
% inhibition of test fungal pathogens
Compound
8 (i)
Fusariumoxysporum
24.21
Alternaria alternata
52.86
64.28
51.57
67.14
21.24
68.00
34.28
71.43
2.86
8 (ii)
43.22
8 (iii)
8 (iv)
8 (v)
41.00
51.67
58.00
8 (vi)
8 (vii)
8 (viii)
8 (ix)
8 (x)
17.21
29.70
47.22
21.90
21.12
-
8 (xi)
8 (xii)
8 (xiii)
8 (xiv)
9 (i)
29.00
62.14
39.00
64.28
34.28
19.32
33.12
60.00
43.00
18.21
33.00
42.00
29.33
12.80
31.21
9 (ii)
38.63
9 (iii)
9 (iv)
9 (v)
54.00
40.00
14.24
9 (vi)
22.12
16

9 (vii)
9 (viii)
9 (ix)
29.00
70.00
45.42
37.61
39.80
32.12
17.98
49.5
29.22
78.00
52.10
32.70
32.32
36.00
33.00
36.43
9 (x)
9 (xi)
9 (xii)
9 (xiii)
9 (xiv)
Test compounds (at 1000 g/ml concentration)
17

Scheme 1. Synthesis of 3-(benzylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-
tetrahydroindeno[1,2-d]imidazole-2,8-dione 8(i).
18

Scheme 2. One-pot synthesis of indeno-3-(arylideneamino)-3a,8a-dihydroxy-1,3,3a,8a-
tetrahydroindeno[1,2-d]imidazole-2,8-diones 8(i-xiv) and their 2-thioxo analogues 9(i-
xiv).
19

Scheme 3. Plausible mechanism for the formation of 8(i-xiv) and 9(i-xiv)
20

Figure 1.
21

Figure 2. ORTEP diagram of 3-(benzylideneamino)-3a,8a-dihydroxy-2-thioxo-1,3,3a,8a-
tetrahydroindeno[1,2-d]imidazol-8(2H)-one (9i).
22

Figure 3. Comparison of anti-bacterial activity of 8(i-xiv) and 9(i-xiv) with the standard
drug (chloramphenicol).
23

Figure 4. Anti-fungal potential of test compounds.
24