Synthesis, crystal structure, molecular docking studies and bio-evaluation of some N4-benzyl-substituted isatin-3-thiosemicarbazones as urease and glycation inhibitors

Article abstract of DOI:10.1515/hc-2017-0148

Fifteen N⁴-benzyl-substituted isatin-3-thiosemicarbazones 5a-o were synthesized and evaluated for their urease and glycation inhibitory potential. Lemna aequinocitalis growth and Artemia salina assays were also done to determine their phytotoxi

Full text of DOI:10.1515/hc-2017-0148

Heterocycl. Commun. 2018; aop
Humayun Pervez*, Nazia Khan, Jamshed Iqbal, Sumera Zaib, Muhammad Yaqub,
Muhammad Nawaz Tahir and Muhammad Moazzam Naseer*
Synthesis, crystal structure, molecular docking studies
4
and bio-evaluation of some N -benzyl-substituted isatin-
3-thiosemicarbazones as urease and glycation inhibitors
https://doi.org/10.1515/hc-2017-0148
Received July 14, 2017; accepted September 4, 2017
Introduction
Abstract: Fifteen N4-benzyl-substituted isatin-3-thiosem- Isatin and its derivatives, including thiosemicarbazones
icarbazones 5a–o were synthesized and evaluated for exhibit a variety of biological properties [1–25] such as
their urease and glycation inhibitory potential. Lemna antiulcer [1], anticancer [1, 4, 7, 12, 21, 22], antimicrobial
aequinocitalis growth and Artemia salina assays were also [1–3, 5, 7, 22], antitubercular [23–25], antiviral [1, 2, 5, 7,
done to determine their phytotoxic and toxic effects. All 12, 25] and enzymatic inhibition [1, 4, 11, 17] activities.
compounds are potent inhibitors of the urease enzyme, We have recently reported the synthesis of a number of
displaying inhibition [half maximal inhibitory concentra- N4-aryl-substituted isatin-3-thiosemicarbazones (thio-
tion (IC50)ꢀ=ꢀ1.08ꢀ ꢀ0.12–11.23ꢀ ꢀ0.19 μm] superior to that of urea derivatives) as antimicrobial [26, 27], cytotoxic [27–
the reference inhibitor thiourea (IC50ꢀ=ꢀ22.3ꢀ ꢀ1.12 μm). Com- 29], phytotoxic [28, 29] and antiurease [27, 28] agents. The
pounds 5c, 5d, 5h, 5j,k are potent antiglycating agents, structure-activity relationship studies have revealed that
showing glycation inhibitory activity better than that of in some cases, the kind, number and position of substit-
the reference inhibitor rutin (IC50 values 209.87ꢀ ꢀ0.37– uents on the phenyl ring attached to the N4 atom of the
231.70ꢀ ꢀ6.71 vs. 294.5ꢀ ꢀ1.5 μm). In the phytotoxicity thiosemicarbazone moiety play a key role in the biologi-
assay, 11 thiosemicarbazones 5a–d, 5g, 5h, 5j–l, 5n,o cal properties, including urease inhibition. Several thio-
are active, demonstrating 5–100% growth inhibition of urea derivatives demonstrate promising antiglycation
L. aequinocitalis at the highest tested concentrations (1000 activity [30–34] and certain isatin-imines (Schiff bases)
or 500 μg/mL). In the brine shrimp (A. salina) lethality are potent inhibitors of glycation [35, 36]. Stimulated by
bioassay, three derivatives 5b, 5j and 5o are active with the above observations and in continuation of our efforts
median lethal dose (LD50) values of 3.63ꢀ×ꢀ10−5, 2.90ꢀ×ꢀ10−5 [37–44] in search of novel isatin-based bioactive organic
and 2.31ꢀ×ꢀ10−4 m, respectively.
molecules with diverse pharmacological properties, we
have synthesized 15 new title thiosemicarbazones and
evaluated them for the first time for urease and glyca-
tion inhibitory effects. Lemna aequinocitalis growth and
Artemia salina assays were also done to determine their
phytotoxic and toxic influences, respectively.
Keywords: antiglycation; antiurease; docking studies;
heterocycles; isatin derivatives.
*Corresponding authors: Humayun Pervez, Institute of Chemical
Sciences, Organic Chemistry Division, Bahauddin Zakariya
University, Multan 60800, Pakistan, e-mail: pdhpervez@hotmail.com;
and Muhammad Moazzam Naseer, Department of Chemistry,
Quaid-i-Azam University, Islamabad 45320, Pakistan,
e-mail: moazzam@qau.edu.pk
Nazia Khan and Muhammad Yaqub: Institute of Chemical Sciences,
Organic Chemistry Division, Bahauddin Zakariya University, Multan
60800, Pakistan
Jamshed Iqbal: Centre for Advanced Drug Research, COMSATS
Institute of Information Technology, Abbottabad 22060, Pakistan
Sumera Zaib: Centre for Advanced Drug Research, COMSATS
Institute of Information Technology, Abbottabad 22060, Pakistan;
and Department of Bioinformatics & Biotechnology, International
Islamic University, Islamabad 44000, Pakistan
Results and discussion
Chemistry of compounds 5a–o
Appropriate N-substituted thiosemicarbazides 3 were
allowed to react with isatin 4 in aqueous ethanol to give
the corresponding isatin-3-thiosemicarbazones 5a–o
(Scheme 1) in good to excellent yields (73–95%). Com-
pounds 5a and 5k have been reported previously [45, 46].
The structures of the synthesized thiosemicarbazones
were confirmed by analytical and spectral data. In addi-
tion, X-ray crystallographic analysis for compound 5h was
Muhammad Nawaz Tahir: Department of Physics, University of
Sargodha, Sargodha 45320, Pakistan
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ꢀꢀꢀꢁ
2ꢀ
ꢀH. Pervez et al.: N -Benzyl-substituted isatin-3-thiosemicarbazones as urease and glycation inhibitors
O
O
N
H
4
NNHCSNHCH2R
O
i, ii
iii
iv
RCH2NH2
RCH2NHCSSCH3
RCH2NHCSNHNH2
N
1a–o
3a–o
2a–o
H
5a–o
a: R = Ph
f: R = 3-CH3OC6H4
g: R = 4-CH3OC6H4
h: R = 2-FC6H4
i: R = 3-FC6H4
k: R = 2-ClC6H4
b: R = 2-CH3C6H4
c: R = 3-CH3C6H4
d: R = 4-CH3C6H4
e: R = 2-CH3OC6H4
l: R = 3-ClC6H4
m: R = 4-ClC6H4
n: R = 2,4-(Cl)2C6H3
o: R = 3,4-(Cl)2C6H3
j: R = 4-FC6H4
Scheme 1ꢀReagents and conditions: (i) Et3N, MeOH, CS2, 30oC, 75 min, then r.t., 1 h; (ii) CH3I, MeOH, −10°C, 20 min, then r.t., 2 h;
(iii) NH2NH2·H2O, EtOH, reflux, 2 h; (iv) 50% EtOH, reflux, 2 h.
conducted. The spectral data are in line with the relevant partial double bond character of the N-C bonds. The slightly
literature [22, 24, 47, 48].
longer N-C bond is directly connected to the imino (-C=N-)
function of the thiosemicarbazone moiety.
In crystal, compound 5h forms a centrosymmetric
amide dimer as the major supramolecular interaction,
dominating over a thioamide dimer. The three-dimensional
(3D) network structure of 5h is composed of various one-
dimensional (1D) tapes (Figure 2A), driven by supramolec-
ular centrosymmetric amide [N(1)-H(1)ꢀ·ꢀ·ꢀ·ꢀO(1) 2.05 Å] and
centrosymmetric CHꢀ·ꢀ·ꢀ·ꢀF [C(4)-H(4)ꢀ·ꢀ·ꢀ·ꢀF(1) 2.61 Å] interac-
tions. These tapes are stacked on each other by means of
CHꢀ·ꢀ·ꢀ·ꢀO [C(2)-H(2)ꢀ·ꢀ·ꢀ·ꢀO(1) 2.71 Å] and πꢀ·ꢀ·ꢀ·ꢀπ [C(6)ꢀ·ꢀ·ꢀ·ꢀC(8)
3.38 Å, C(1)ꢀ·ꢀ·ꢀ·ꢀC(5) 3.34 Å] interactions [51] to provide an
overall 3D-network (Figure 2B and C).
X-ray crystallographic analysis
of compound 5h
Quality crystals of 5h (Table S1) were cultivated by slow evap-
oration of the solution in CHCl3. The X-ray analysis shows
that compound 5h crystallizes in monoclinic lattice with
the P21/c space group. The molecular structure [Oak Ridge
Thermal-Ellipsoid Plot (ORTEP) diagram] of 5h along with
crystallographic numbering scheme is presented in Figure 1.
The central thiosemicarbazone (N-iminothiourea) moiety is
nearly planar adopting the S-cis/S-trans conformation, most
probably due to the formation of intramolecular hydrogen
bond [N(4)-H(4A)ꢀ·ꢀ·ꢀ·ꢀN(2) 2.269 Å] [46, 49, 50]. The dihedral
angles between S(1)-C(9)-N(3)-H(3A), S(1)-C(9)-N(4)-H(4A)
and C(9)-N(3)-N(2)-C(8) are −6.45°, −174.20° and 178.73°,
respectively. This planarity around the central thiosemicar-
bazone moiety may be attributed to substantial delocali-
zation of N lone electron pairs onto the thiocarbonyl (C=S)
group; this is clearly manifested by short N-C bond lengths
[N(3)-C(9) 1.366(3) Å and N(4)-C(9) 1.333(3) Å], signifying the
In vitro antiurease activity
The N4-benzyl-substituted isatin-3-thiosemicarbazones
5a–o were evaluated for their antiurease activity against
jack bean urease. Thiourea served as a reference inhibitor
in this assay. All compounds are potent inhibitors of the
enzyme, exhibiting inhibitory activity [half maximal inhibi-
tory concentration (IC50)ꢀ=ꢀ1.08ꢀ ꢀ0.12–11.23ꢀ ꢀ0.19 μm], which
is better than the activity of the reference inhibitor thiourea
(IC50ꢀ=ꢀ22.3ꢀ ꢀ1.12 μm) (Table 1). In comparison to compound
5a having no substituent in the phenyl ring of the benzyl
group attached to N4 of the thiosemicarbazone moiety, all
other compounds demonstrate enhanced enzymatic activ-
ity(IC50 values1.08ꢀ ꢀ0.12–7.97ꢀ ꢀ0.14vs. 11.23ꢀ ꢀ0.19μm). Com-
pound 5f bearing a methoxy substituent at position 3 of the
phenyl ring is the most potent urease inhibitor of the series,
displaying 10- and 20-fold more activity than compound
5a and the reference inhibitor thiourea (IC50ꢀ=ꢀ1.08ꢀ ꢀ0.12 vs.
11.23ꢀ ꢀ0.19 and 22.3ꢀ ꢀ1.12 μm, respectively). The other meth-
oxy-substituted compounds 5e and 5g having the substitu-
ent at positions 2 and 4 of the phenyl ring are less active
Figure 1ꢀThe ORTEP diagram of 5h.
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ꢁꢀꢀꢀ
ꢂ3
H. Pervez et al.: N -Benzyl-substituted isatin-3-thiosemicarbazones as urease and glycation inhibitorsꢂ
A
B
C
Figure 2ꢀThe crystal packing of compound 5h. (A) 1D-tapes viewed along the c-axis, (B) 3D-network viewed along the c-axis, (C) 3D-network
viewed along the b-axis.
respectively). Comparison of the antiurease activity of com-
pound 5b with that of closely related methyl-substituted
compounds 5c and 5d having the substituent at positions
3 and 4 of the phenyl ring, respectively, reveals that methyl
substitution at position 2 of the phenyl is more favora-
ble than at positions 3 and 4. Compound 5c is less active
than 5b but considerably more active than 5d (IC50 value
1.62ꢀ ꢀ0.13 vs. 1.22ꢀ ꢀ0.17 and 2.17ꢀ ꢀ0.11 μm, respectively). The
N4-benzyl-substituted isatin-thiosemicarbazones tested in
the present assay, 5a–i and 5k–m, are more active in com-
parison to the corresponding N4-phenyl-substituted isatin-
thiosemicarbazones tested in our earlier assays [27, 28].
Table 1ꢀInhibition of urease by compounds 5a–o.
Compoundꢁ
IC50ꢂ ꢂSEM (μm)
5a
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
11.23ꢁ ꢁ0.19
1.22ꢁ ꢁ0.17
1.62ꢁ ꢁ0.13
2.17ꢁ ꢁ0.11
1.51ꢁ ꢁ0.26
1.08ꢁ ꢁ0.12
3.11ꢁ ꢁ0.13
7.97ꢁ ꢁ0.14
2.62ꢁ ꢁ0.15
1.38ꢁ ꢁ0.15
2.53ꢁ ꢁ0.06
2.32ꢁ ꢁ0.21
3.46ꢁ ꢁ0.18
3.34ꢁ ꢁ0.14
2.69ꢁ ꢁ0.12
22.3ꢁ ꢁ1.06
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
In vitro antiglycation activity
5o
Thioureaa
The thiosemicarbazones 5a–o were further evaluated for
their glycation inhibitory potential using rutin as a ref-
erence inhibitor. Seven compounds 5b–d, 5f, 5h, 5j,k,
proved to be potent inhibitors of glycation. Compounds
SEM, Standard error of the mean. aReference inhibitor of urease
enzyme.
with IC50 values of 1.51ꢀ ꢀ0.26 and 3.11ꢀ ꢀ0.13 μm, respectively. 5c, 5d, 5h, 5j,k show antiglycation activity even better
The next most potent antiurease compound is 5b possess- than the reference inhibitor rutin (Table 2). Compound 5d
ing the methyl substituent at position 2 of the phenyl ring. bearing a methyl substituent at position 4 of the phenyl
This compound exhibits slightly lower inhibitory activity ring attached to N4 of the thiosemicarbazone moiety is the
than 5f but is more active than the reference inhibitor thio- most potent antiglycating agent of the series, displaying
urea (IC50 value 1.22ꢀ ꢀ0.17 vs. 1.08ꢀ ꢀ0.12 and 22.3ꢀ ꢀ1.12 μm, inhibition of glycation with IC50 value of 209.87ꢀ ꢀ0.37 μm.
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ꢀH. Pervez et al.: N -Benzyl-substituted isatin-3-thiosemicarbazones as urease and glycation inhibitors
Table 2ꢀAntiglycation activity of compounds 5a–o.
2.90ꢀ×ꢀ10−5 and 2.31ꢀ×ꢀ10−4 m, respectively]. The remaining
compounds gave LD50 values >2.64–3.22ꢀ×ꢀ10−4 m and, there-
fore, can be considered to be almost inactive.
Compoundꢁ Concentration (μm)ꢁ Inhibition (%)ꢁ IC50ꢂ ꢂSEM (μm)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
Rutina
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
500ꢃ
1000ꢃ
500ꢃ
40.98ꢃ
62.89ꢃ
57.97ꢃ
70.12ꢃ
18.26ꢃ
64.72ꢃ
28.45ꢃ
60.26ꢃ
25.54ꢃ
53.67ꢃ
59.78ꢃ
13.71ꢃ
10.32ꢃ
42.04ꢃ
39.57ꢃ
86.00ꢃ
605.26ꢁ ꢁ2.24
231.70ꢁ ꢁ6.71
209.87ꢁ ꢁ0.37
Molecular docking studies of compounds 5a–o
500ꢃ
1000ꢃ
1000ꢃ
125ꢃ
1000ꢃ
1000ꢃ
250ꢃ
1000ꢃ
125ꢃ
500ꢃ
500ꢃ
Molecular docking studies were performed as previously
reported [52–58]. Docking studies of compound 5f against
urease was carried out to gain further structural insights
of the binding mode and possible interactions with the
active site of the enzyme. Binding mode analysis of com-
pound 5f with urease, selected after Hyde assessment, is
given in Figure 3. Docking studies support the experimen-
tal results that inhibitors bind with the catalytic site of the
enzyme. The interactions within the active pocket of the
receptor for its ligand are very important in the design of
inhibitors. The π-stacked interactions are suggested for
3-methoxyphenyl ring of the inhibitor in the active site
with residues His519, His593 and Arg609. 2-Oxoindolin-
522.68ꢁ ꢁ9.10
224.34ꢁ ꢁ0.47
217.94ꢁ ꢁ1.98
228.55ꢁ ꢁ2.30
1000ꢃ
1000ꢃ
294.5ꢁ ꢁ1.50
aStandard inhibitor of glycation.
The isomer 5c having the substituent at position 3 of the 3-ylidene moiety is oriented in the hydrophobic pocket
phenyl ring has the IC50 value of 231.70ꢀ ꢀ6.7 μm. This com- of the active site, where amino acid residues Ala636 and
pound is significantly more active than the corresponding Met637 are present. Moreover, polar interactions are
methoxy-substituted derivative 5f. The next most potent observed by the central thiosemicarbazone moiety and
antiglycating agent is compound 5j possessing a fluoro the amino acid residues Arg439, Ala436 and Ala440.
substituent at position 4 of the phenyl ring. This compound
exhibits slightly less inhibition than the most active deriva-
tive 5d but a great deal more than the reference inhibitor
rutin. Overall, compounds with the CH3, F and Cl substitu-
tions cause effective inhibition of glycation.
In vitro phytotoxicity
Phytotoxic potential of compounds 5a–o was determined
by L. aequinocitalis growth bioassay. Eleven compounds,
5a–d, 5g, 5h, 5j–l, 5n,o, are active in this assay, display-
ing weak or non-significant (5–100%) growth inhibition
of L. aequinocitalis at the highest tested concentrations
(1000 or 500 μg/mL) in comparison to the standard drug,
paraquat, which shows 100% plant growth inhibition at
0.015 μg/mL concentration.
In vitro toxicity
Toxicity potential of compounds 5a–o was determined by a
Figure 3ꢀA possible binding mode of compound 5f to urease. Carbon
brine shrimp (A. salina) lethality bioassay, using etoposide
atoms of 5f are colored pink, while that of protein are light green;
(a standard anticancer drug) as a reference. Compounds
oxygen, sulfur and nitrogen atoms are colored red, yellow and blue,
respectively. The two nickel ions in the active site are represented as
small dark-green spheres.
3b, 3j and 3o are active in this assay, demonstrating moder-
ate to weak toxicity [median lethal dose (LD50)ꢀ=ꢀ3.63ꢀ×ꢀ10−5,
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H. Pervez et al.: N -Benzyl-substituted isatin-3-thiosemicarbazones as urease and glycation inhibitorsꢂ
C7-H), 7.15 (t, Jꢀ=ꢀ7.6 Hz, 1H, isatin C5-H), 7.19–7.57 (m, 5H, benzyl C2-H,
C4-H, C5-H, C6-H, isatin C6-H), 7.78 (d, Jꢀ=ꢀ7.6 Hz, 1H, isatin C4-H), 10.75
(s, 1H, CSNH), 11.36 (s, 1H, isatin NH), 12.68 (s, 1H, NNH); 13C NMR: δ
21.5 (CH3), 47.7 (CH2), 111.5, 120.4, 121.4, 122.8, 125.0, 128.1, 128.4, 128.7,
Conclusions
All compounds 5a–o are extremely potent inhibitors of the
urease enzyme. In addition, compounds 5c, 5d, 5h, 5j,k
inhibit glycation quite convincingly. The glycation inhibi-
tory activity of N4-benzyl-substituted isatin-3-thiosemicar-
bazones is described here for the first time.
+
131.7, 132.5, 137.8, 138.8, 142.8, 163.1, 178.1; MS: m/z 324 (M , 6), 178
(28), 147 (79), 132 (10), 120 (77), 118 (74), 105 (100), 91 (65), 77 (75), 65
(36%). Anal. Calcd for C17H16N4OS: C, 62.96; H, 4.94; N, 17.28. Found:
C, 62.86; H, 4.89; N, 17.22.
N-(4-Methylbenzyl)-2-(2- oxo -2, 3- dihydro -1H-indol-
3-ylidene)-1-hydrazinecarbothioamide (5d)ꢁYellow fluffy crystals;
yield 78%; mp 200°C; IR: 3300, 3196 (NH), 1683 (C=O), 1600 (C=N),
1153 cm−1 (C=S); 1H NMR: δ 2.26 (s, 3H, CH3), 4.80 (d, Jꢀ=ꢀ6.0 Hz, 2H, ben-
zyl CH2), 6.89 (d, Jꢀ=ꢀ8.8 Hz, 1H, isatin C7-H), 7.07 (t, Jꢀ=ꢀ7.6 Hz, 1H, isatin
C5-H), 7.13 (d, Jꢀ=ꢀ7.6 Hz, 2H, benzyl C2-H, C6-H), 7.24 (d, Jꢀ=ꢀ8.0 Hz, 2H,
benzyl C3-H, C5-H), 7.34 (t, Jꢀ=ꢀ7.6 Hz, 1H, isatin C6-H), 7.64 (d, Jꢀ=ꢀ7.6 Hz,
1H, isatin C4-H), 9.73 (t, Jꢀ=ꢀ6.0 Hz, 1H, CSNH), 11.18 (s, 1H, isatin NH),
12.62 (s, 1H, NNH); 13C NMR: 21.2 (CH3), 55.5, 111.5, 114.1, 120.4, 121.3,
Experimental
Melting points (uncorrected) were determined on a Fisher-Johns
melting point apparatus. Elemental analyses were performed on
a Leco CHNS-9320 (USA) elemental analyzer. Fourier transform-
infrared (FT-IR) spectra (KBr discs) were recorded on a Shimadzu
Prestige-21 FT-IR spectrophotometer. Proton nuclear magnetic
resonance (1H NMR) spectra were measured in dimethyl sulfox-
ide-d6 (DMSO-d6) on Bruker Spectrospin 300 and Bruker AVANCE
400 spectrometers operating at 300 MHz and 400 MHz, respec-
tively. Carbon-13 nuclear magnetic resonance (13C NMR) spectra
were recorded in DMSO-d6 on Bruker AVANCE 300 operating at
75 MHz. Electron impact mass spectra were obtained at 70 eV on
MAT312 and JEOL JMS-600 mass spectrometers. X-ray crystallo-
graphic data were taken on a Bruker Kappa APEXII charge coupled
device (CCD) instrument. Compounds 5a and 5k have been reported
previously [45, 46].
+
122.7, 127.8, 129.3, 131.7, 132.4, 136.6, 142.8, 163.1, 178.0; MS: m/z 324 (M ,
7), 194 (13), 178 (38), 161(20), 147 (100), 132 (13), 120 (67), 118 (62), 105
(91), 91 (38), 77 (39), 65 (14%). Anal. Calcd for C17H16N4OS: C, 62.96; H,
4.94; N, 17.28. Found: C, 62.87; H, 4.89; N, 17.20.
N-(2-Methoxybenzyl)-2-[2-oxo-2, 3-dihydro-1H-indol-
3-ylidene]-1-hydrazinecarbothioamide (5e)ꢁYellow crystals; yield
76%; mp 205°C; IR: 3360, 3140 (NH), 1685 (C=O), 1598 (C=N), 1184 cm−1
(C=S); 1H NMR: δ 3.83 (s, 3H, CH3), 4.37 (d, Jꢀ=ꢀ5.0 Hz, 2H, benzyl CH2),
6.87 (d, Jꢀ=ꢀ8.0 Hz, 1H, isatin C7-H), 6.91 (t, Jꢀ=ꢀ8.4 Hz, 1H, benzyl C5-H),
7.01 (t, Jꢀ=ꢀ8.0 Hz, 2H, benzyl C4-H, isatin C5-H), 7.21–7.27 (m, 2H, ben-
zyl C3-H, C6-H), 7.33 (t, Jꢀ=ꢀ8.0 Hz, 1H, isatin C6-H), 7.53 (t, Jꢀ=ꢀ6 Hz, 1H,
CSNH), 8.05 (d, Jꢀ=ꢀ7.6 Hz, 1H, isatin C4-H), 10.30 (s, 1H, isatin NH),
10.67 (s, 1H, NNH); 13C NMR: δ 55.8 (CH2), 70.2 (CH3), 110.8, 111.0, 116.1,
120.6, 122.0, 125.7, 127.3, 128.3, 128.7, 132.1, 134.0, 143.4, 155.4, 157.2,
Synthesis of isatin-thiosemicarbazones 5a–o
+
165.2; MS: m/z 340 (M , 2), 235 (100), 221 (30), 178 (56), 163 (16), 145
N-substituted thiosemicarbazides 3a–o were synthesized in accord-
ance with the literature route [59].
A solution of thiosemicarbazide 3 (5 mmol) in ethanol (10 mL)
was added to a hot solution of isatin 4 (5 mmol) in 50% aqueous
ethanol (15 mL), and the mixture was heated under reflux for 2 h. The
resultant crystalline precipitate was filtered and washed with hot
aqueous ethanol to afford the desired compounds 5a–o.
(27), 120 (100), 118 (32), 105 (100), 93 (41), 77 (43), 58 (89%). Anal.
Calcd for C17H16N4O2S: C, 60.00; H, 4.71; N, 16.47. Found: C, 59.89; H,
4.67; N, 16.39.
N-(3-Methoxybenzyl)-2-[2-oxo-2, 3-dihydro-1H-indol-
3-ylidene]-1-hydrazinecarbothioamide (5f)ꢁYellow fluffy crys-
tals; yield 74%; mp 170°C; IR: 3350, 3194 (NH), 1686 (C=O), 1600
(C=N), 1151 cm−1 (C=S); 1H NMR: δ 3.74 (s, 3H, CH3), 4.85 (d, Jꢀ=ꢀ4.5 Hz,
N-(2-Methylbenz yl)-2-[2- oxo -2 , 3- dihydro -1H-indol- 2H, benzyl CH2), 6.83 (d, Jꢀ=ꢀ9.0 Hz, 1H, isatin C7-H), 6.85–6.95 (m, 3H,
3-ylidene]-1-hydrazinecarbothioamide (5b)ꢁYellow crystals; benzyl C2-H, C4-H, C6-H), 7.09 (t, Jꢀ=ꢀ9.0 Hz, 1H, benzyl C5-H), 7.26 (t,
yield 73%; mp 240°C; IR: 3304, 3190 (NH), 1687 (C=O), 1616 (C=N), Jꢀ=ꢀ9.0 Hz, 1H, isatin C5-H), 7.36 (t, Jꢀ=ꢀ9.0 Hz, 1H, isatin C6-H), 7.65 (d,
1
1168 cm−1 (C=S); H NMR: δ 2.50 (s, 3H, CH3), 4.74 (d, Jꢀ=ꢀ6.0 Hz, 2H, Jꢀ=ꢀ8.0 Hz, 1H, isatin C4-H), 9.79 (t, Jꢀ=ꢀ6.0 Hz, 1H, CSNH), 11.22 (s, 1H,
benzyl CH2), 6.92 (d, Jꢀ=ꢀ8.0 Hz, 1H, isatin C7-H), 7.02–7.26 (m, 5H, ben- isatin NH), 12.66 (s, 1H, NNH); 13C NMR: δ 47.1 (CH2), 55.0 (CH3), 111.0,
zyl C3-H, C4-H,C5-H,C6-H, isatin C5-H), 7.28–7.40 (m, 1H, isatin C6-H), 112.2, 113.2, 119.5, 119.9, 120.9, 122.3, 129.3, 131.2, 132.0, 139.9, 142.3,
+
7.72 (d, Jꢀ=ꢀ7.6 Hz, 1H, isatin C4-H), 9.77 (t, Jꢀ=ꢀ6.0 Hz, 1H, CSNH), 11.30 159.2, 162.6, 177.7; MS: m/z 340 (M , 7), 194 (24), 161 (18), 147 (93), 136
(s, 1H, isatin NH), 12.76 (s, 1H, NNH); 13C NMR: δ 19.2 (CH3), 45.6 (CH2), (92), 121 (95), 91 (100), 77 (95), 65 (55%). Anal. Calcd for C17H16N4O2S:
111.5, 120.4, 121.4, 122.8, 126.1, 127.1, 127.1, 127.6, 130.3, 131.7, 132.5, 137.8, C, 60.00; H, 4.71; N, 16.47. Found: C, 59.82; H, 4.67; N, 16.38.
+
142.8, 163.1, 178.2; MS: m/z 324 (M , 4), 179 (37), 161 (100), 136 (20), 121
(46), 118 (10), 91 (69), 77 (22), 65 (13%). Anal. Calcd for C17H16N4OS: C,
62.96; H, 4.94; N, 17.28. Found: C, 62.78; H, 4.83; N, 16.87.
N-(4-Methoxybenzyl)-2-[2-oxo-2, 3-dihydro-1H-indol-
3-ylidene]-1-hydrazinecarbothioamide (5g)ꢁYellow fluffy crys-
tals; yield 82%; mp 230°C; IR: 3277, 3178 (NH), 1684 (C=O), 1605
N-(3-Methylbenzyl)-2-[2-oxo-2,3-dihydro-1H-indol-3-ylidene]-1- (C=N), 1157 cm−1 (C=S); 1H NMR: δ 3.72 (s, 3H, CH3), 4.79 (d, Jꢀ=ꢀ6.0 Hz,
hydrazinecarbothioamide (5c)ꢁYellow crystals; yield 79%; mp 2H, benzyl CH2), 6.89 (d, Jꢀ=ꢀ8.8 Hz, 2H, benzyl C3-H, C5-H), 6.91 (d,
209°C; IR: 3358, 3248 (NH), 1693 (C=O), 1599 (C=N), 1149 cm−1 (C=S); Jꢀ=ꢀ8.0 Hz, 1H, isatin C7-H), 7.07 (t, Jꢀ=ꢀ7.6 Hz, 1H, isatin C5-H), 7.30 (d,
1H NMR: δ 2.50 (CH3), 3.30 (benzyl CH2), 6.96 (d, Jꢀ=ꢀ8.0 Hz, 1H, isatin Jꢀ=ꢀ8.8 Hz, 2H, benzyl C2-H, C6-H), 7.34 (td, Jꢀ=ꢀ8.0, 0.8 Hz, 1H, isatin
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ꢀH. Pervez et al.: N -Benzyl-substituted isatin-3-thiosemicarbazones as urease and glycation inhibitors
(83), 104 (69), 89 (78), 77 (93%). Anal. Calcd for C16H13ClN4OS: C, 55.73;
C6-H), 7.64 (d, Jꢀ=ꢀ7.6 Hz, 1H, isatin C4-H), 9.70 (t, Jꢀ=ꢀ6.0 Hz, 1H, CSNH),
11.18 (s, 1H, isatin NH), 12.61 (s, 1H, NNH); 13C NMR: 47.2 (CH2), 55.5
(CH3), 111.5, 114.1, 120.4, 121.3, 122.7, 129.3, 130.8, 131.7, 132.4, 142.8,
H, 3.77; N, 16.26. Found: C, 55.69; H, 3.69; N, 16.20.
+
N-(4- Chlorobenzyl)-2-[2- oxo -2, 3- dihydro -1H-indol-
3-ylidene]-1-hydrazinecarbothioamide (5m)ꢁYellow fluffy crys-
tals; yield 85%; mp 250°C; IR: 3300, 3188 (NH), 1680 (C=O), 1604
(C=N), 1155 cm−1 (C=S); 1H NMR: δ 4.86 (d, Jꢀ=ꢀ6.0 Hz, 2H, benzyl CH2),
6.94 (d, Jꢀ=ꢀ8.0 Hz, 1H, isatin C7-H), 7.09 (t, Jꢀ=ꢀ7.6 Hz, 1H, isatin C5-H),
7.52–7.66 (m, 5H, benzyl C2-H. C3-H, C5-H, C6-H, isatin C6-H), 7.65 (d,
Jꢀ=ꢀ6.0 Hz, 1H, isatin C4-H), 9.83 (t, Jꢀ=ꢀ6.0 Hz, 1H, CSNH), 11.23 (s, 1H,
isatin NH), 12.68 (s, 1H, NNH); 13C NMR: δ 46.5 (CH2), 111.1, 119.9, 120.9,
122.3, 128.2, 129.2, 1313, 131.5, 132.2, 137.4, 142.4, 162.6, 177.8; MS: m/z
158.9, 163.1, 177.8; MS: m/z 340 (M , 15), 194 (55), 161 (47), 147 (52),
136 (52), 121 (100), 104 (13), 91 (17%). Anal. Calcd for C17H16N4O2S: C,
60.00; H, 4.71; N, 16.47. Found: C, 59.65; H, 4.66; N, 16.42.
N-(2-Fluorobenz yl)-2-[2- oxo -2 , 3- dihydro -1H-indol-
3-ylidene]-1-hydrazinecarbothioamide (5h)ꢁYellow fluffy crys-
tals; yield 79%; mp 210°C; IR: 3352, 3188 (NH), 1685 (C=O), 1610
1
(C=N), 1159 cm−1 (C=S); H NMR: δ 4.92 (d, Jꢀ=ꢀ6.0 Hz, 2H, benzyl
CH2), 6.93 (d, Jꢀ=ꢀ8.0 Hz, 1H, isatin C7-H), 7.10 (t, Jꢀ=ꢀ8.0 Hz, 1H, isatin
C5-H), 7.17–7.21 (m, 2H, benzyl C3-H, C6-H), 7.24–7.39 (m, 3H, benzyl
C4-H, C5-H, isatin C6-H), 7.66 (d, Jꢀ=ꢀ6.0 Hz, 1H, isatin C4-H), 9.77 (t,
Jꢀ=ꢀ6.0 Hz, 1H, CSNH), 11.24 (s, 1H, isatin NH), 12.71 (s, 1H, NNH); 13C
NMR: δ 41.0 (CH2), 111.1, 114.9, 115.2, 119.9, 120.9, 122.3, 124.2, 124.3,
124.9, 125.1, 128.9, 128.9, 131.3, 132.2, 142.4, 161.4, 162.6, 178.03; MS: m/z
+
346/344 (M , 3/1), 198(16), 147 (92), 140 (70), 125 (100), 118 (72), 104
(50), 90 (50), 77 (92%). Anal. Calcd for C16H13ClN4OS: C, 55.73; H, 3.77;
N, 16.26. Found: C, 55.69; H, 3.77; N, 16.26.
N-(2, 4-Dichlorobenzyl)-2-[2-oxo-2,3-dihydro-1H-indol-3-ylidene]-
1-hydrazinecarbothioamide (5n)ꢁYellow crystals; yield 82%; mp
265°C; IR: 3360, 3172 (NH), 1701 (C=O), 1599 (C=N), 1184 cm−1 (C=S); 1H
NMR: δ 4.45 (d, Jꢀ=ꢀ5.6 Hz, 2H, benzyl CH2), 6.88 (d, Jꢀ=ꢀ7.6 Hz, 1H, isatin
C7-H), 7.02 (t, Jꢀ=ꢀ8.0 Hz, 1H, isatin C5-H), 7.32–7.45 (m, 3H, benzyl C5-H,
C6-H, isatin C6-H), 7.61 (d, Jꢀ=ꢀ2.0 Hz, 1H, benzyl C3-H), 7.85 (t, Jꢀ=ꢀ6 Hz,
1H, CSNH), 8.06 (d, Jꢀ=ꢀ7.6.Hz, 1H, isatin C4-H), 10.38 (s, 1H, isatin NH),
10.69 (s, 1H, NNH)); 13C NMR: δ 41.0 (CH2), 110.9, 116.1, 122.0, 125.8, 127.8,
129.0, 130.3, 132.3, 132.6, 133.2, 134.6, 136.4, 143.5, 155.7, 165.2; MS: m/z
364/362 (3/5), 329/327 (4/11), 186 (10), 166 (15), 161 (100), 140 (26), 132
(18), 104 (17%). Anal. Calcd for C16H12Cl2N4OS: C, 50.66; H, 3.17; N, 14.78.
Found: C, 50.48; H, 3.14; N, 14.77.
+
328 (M , 10), 182 (13), 147 (51), 124 (52), 118 (31), 109 (100), 104 (24), 90
(16), 83 (47), 77 (32%). Anal. Calcd for C16H13FN4OS: C, 58.54; H, 3.96;
N, 17.07. Found: C, 58.38; H, 3.87; N, 16.98.
N-( 3-Fluorobenz yl)-2-[2- oxo -2 , 3- dihydro -1H-indol-
3-ylidene]-1-hydrazinecarbothioamide (5i)ꢁYellow fluffy crystals;
yield 80%; mp 215°C; IR: 3300, 3184 (NH), 1682 (C=O), 1600 (C=N),
1
1192 cm−1 (C=S); H-NMR: δ 4.87 (d, Jꢀ=ꢀ6.0 Hz, 2H, benzyl CH2), 6.92
(d, Jꢀ=ꢀ8.0 Hz, 1H, isatin C7-H), 7.08 (t, Jꢀ=ꢀ8.0 Hz, 2H, isatin C5-H,
benzyl C5-H), 7.15–7.20 (m, 2H, benzyl C2-H, C6-H), 7.33–7.41 (m, 2H,
benzyl C4-H, isatin C6-H), 7.64 (d, Jꢀ=ꢀ7.2 Hz, 1H, isatin C4-H), 9.81 (t,
Jꢀ=ꢀ6.0 Hz, 1H, CSNH), 11.20 (s, 1H, isatin NH), 12.67 (s, 1H, NNH); 13
C
N-(3, 4-Dichlorobenzyl)-2-[2-oxo-2,3-dihydro-1H-indol-3-ylidene]-
1-hydrazinecarbothioamide (5o)ꢁYellow crystals; yield 95%; mp
230°C; IR: 3348, 3217 (NH), 1707 (C=O), 1610 (C=N), 1190 cm−1 (C=S); 1H
NMR: δ 4.84 (d, Jꢀ=ꢀ6.0 Hz, 2H, benzyl CH2), 6.92 (d, Jꢀ=ꢀ8 Hz, 1H, isatin
C7-H), 7.08 (t, Jꢀ=ꢀ7.6 Hz, 1H, isatin C5-H), 7.34–7.36 (m, 2H, isatin C6-H,
benzyl C6-H), 7.59–7.64 (m, 3H, benzyl C2-H, C5-H, isatin C4-H), 9.81 (t,
NMR: δ 47.18 (CH2), 111.56, 114.09, 114.33, 114.62, 120.39, 121.37, 122.77,
123.79, 123.83, 130.65, 130.76, 131.75, 132.71, 141.82, 141.91, 142.87, 161.01,
+
163.12, 164.23, 178.36; MS: m/z 328 (M , 77), 300 (45), 252 (34), 203 (13),
182 (52), 161 (13), 147 (100), 132 (15), 124 (95), 118 (39), 109 (93), 104
(19), 83 (14), 77 (12%). Anal. Calcd for C16H13FN4OS: C, 58.54; H, 3.96;
N, 17.07. Found: C, 58.43; H, 3.87; N, 17.02.
Jꢀ=ꢀ6.0 Hz, 1H, CSNH), 11.20 (s, 1H, isatin NH), 12.68 (s, 1H, NNH)); 13
C
NMR: δ 46.6 (CH2), 111.6, 120.3, 121.3, 122.8, 128.2, 129.8, 130.0, 130.9,
+
N-(4-Fluorobenz yl)-2-[2- oxo -2 , 3- dihydro -1H-indol-
3-ylidene]-1-hydrazinecarbothioamide (5j)ꢁYellow fluffy crystals;
yield 74%; mp 230°C; IR: 3374, 3248 (NH), 1699 (C=O), 1608 (C=N),
1163 cm−1 (C=S); 1H NMR: δ 3.30 (DMSO, benzyl CH2), 6.95 (d, Jꢀ=ꢀ8.0 Hz,
1H, isatin C7-H), 7.17 (tt, Jꢀ=ꢀ8.0, 2.4 Hz, 2H, benzyl C3-H, C5-H), 7.42 (dd,
Jꢀ=ꢀ8.0, 2.4 Hz, 2H, benzyl C2-H, C6-H), 7.54–7.61 (m, 2H, isatin C5-H,C6-
H), 7.85 (d, Jꢀ=ꢀ7.2 Hz, 1H, isatin C4-H), 10.93 (s, 1H, CSNH), 11.38 (s, 1H,
isatin NH), 12.74 (s, 1H, NNH); 13C-NMR: δ 107.9, 108.3, 112.7, 121.1, 121.5,
131.3, 131.8, 132.8, 140.1, 142.9, 163.1, 178.4; MS: m/z 380/378 (M , 16/22),
352/350 (11/15), 234/232 (16/15), 203 (42), 176/174 (38/62), 161/159 (58/86),
147 (100), 144/142 (29/25), 140 (69), 118 (65), 104/102 (31/17), 91/89
(19/25), 77/75 (29/25), 63/61 (24/13%). Anal. Calcd for C16H12Cl2N4OS: C,
50.66; H, 3.17; N, 14.78. Found: C, 50.49; H 3.15; N, 14.76.
Crystallographic data collection and structural refinement
+
126.6, 130.9, 131.8, 141.3, 160.3, 162.4, 163.5, 175.9; MS: m/z 328 (M , 7),
182 (41), 161 (15), 147 (72), 132 (15), 124 (65), 118 (56), 109 (100), 104
(44), 90 (27), 83 (60), 77 (49%). Anal. Calcd for C16H13FN4OS: C, 58.54;
H, 3.96; N, 17.07. Found: C, 58.45; H, 3.87; N, 17.01.
A crystal of 5h was mounted on a thin glass fiber at room tempera-
ture and the reflection data were collected on a Bruker Kappa APE XII
CCD diffractometer equipped with graphite monochromated MoKα
radiation (λꢀ=ꢀ0.71073 Å). The data were corrected for Lorentz and
polarization effects. The structure was solved using SHELXS-97 [51].
A final refinement on F2 was carried out by full-matrix least-squares
techniques using SHELXL-97 [51].
N-( 3- Chlorobenz yl)-2-[2- oxo -2 , 3- dihydro -1H-indol-
3-ylidene]-1-hydrazinecarbothioamide (5l)ꢁYellow crystals; yield
86%; mp 220°C; IR: 3350, 3142 (NH), 1695 (C=O), 1605 (C=N), 1148 cm−1
(C=S); 1H NMR: δ 3.30 (DMSO, benzyl CH2), 6.91 (d, Jꢀ=ꢀ7.6 Hz, 1H, isatin
C7-H), 7.24 (t, Jꢀ=ꢀ7.6 Hz, 1H, isatin C5-H), 7.53 (d, Jꢀ=ꢀ7.8 Hz, 1H, benzyl
Biological assays
C2-H) 7.64–7.72 (m, 3H, benzyl C4-H, C5-H, C6-H), 7.99–8.01 (m, 2H,
isatin C4-H, C6-H), 9.76 (t, Jꢀ=ꢀ6.0 Hz, 1H, CSNH), 11.21 (s, 1H, isatin NH),
12.73 (s, 1H, NNH); 13C NMR: δ 93.6, 113.0, 114.2, 122.1, 123.7, 124.9, 130.3,
In vitro antiurease, antiglycation, phytotoxic and toxic activities of
thiosemicarbazones 5a–o were performed by using the reported
methods [52, 36, 38, 41].
+
131.2, 133.6, 134.7, 139.6, 141.6, 162.3, 176.2; MS: m/z 346/344 (M , 2/5),
200/198 (7/16), 147 (100), 142/140 (25/73), 132 (20), 127/125 (44/97), 118
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H. Pervez et al.: N -Benzyl-substituted isatin-3-thiosemicarbazones as urease and glycation inhibitorsꢂ
[15] Phogat, P.; Singh, P. A mini review on central nervous system
potential of isatin derivatives. Cent. Nerv. Syst. Agents Med.
Chem. 2015, 15, 28–31.
Molecular docking studies
Docking studies of compounds 5a–o were carried out in accordance
with the previously described protocols [52–58].
[16] Hussain, A. Z.; Meeran, M. N. Synthesis, characterization and
antimicrobial activity of some isatin based Schiff base com-
pounds. Res. J. Pharm. Biol. Chem. Sci. 2015, 6, 1598–1601.
[17] Rahim, F.; Malik, F.; Ullah, H.; Wadood, A.; Khan, F.; Javid, M. T.;
Taha, M.; Rehman, W.; Rehman, A. U.; Khan, K. M. Isatin based
Schiff bases as inhibitors of α-glucosidase: synthesis, charac-
terization, in vitro evaluation and molecular docking studies.
Bioorg. Chem. 2015, 60, 42–48.
Acknowledgments: The authors thank the Higher Educa-
tion Commission (HEC) of Pakistan for funding under the
National Research Support Program for Universities (Pro-
ject No. 20-873/R&D/07/452).
[18] Khan, M.; Khan, K. M.; Rahim, F.; Samreen; Perveen, S.; Karim,
A.; Imtiazuddin; Choudhary, M. I. Synthesis leishmanicidal
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[19] Corona, A.; Meleddu, R.; Esposito, F.; Distinto, S.; Bianco, G.;
Masaoka, T.; Maccioni, E.; Menéndez-Arias, L.; Alcaro, S.; Le
Grice, S. F. J.; et al. Ribonuclease H/DNA polymerase HIV-1
reverse transcriptase dual inhibitor: mechanistic studies on the
allosteric mode of action of isatin-based compound RMNC6.
PLoS One 2016, 11, 1–18.
[20] Ziarani, G. M.; Moradi, R.; Lashgari, N. Synthesis of spiro-fused
heterocyclic scaffolds through multicomponent reactions
involving isatin. ARKIVOC 2016, (i), 1–81.
[21] Karali, N.; Terzioğlu, N.; Gürsoy, A. Synthesis and primary
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ꢀH. Pervez et al.: N -Benzyl-substituted isatin-3-thiosemicarbazones as urease and glycation inhibitors
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