Synthesis and bioevaluation of Schiff and Mannich bases of isatin derivatives with 4-amino-5-benzyl-2,4-dihydro-3H-1,2,4-triazole-3-thione

Article abstract of DOI:10.1007/s00044-011-9838-3

Isatin (2,3-dioxindole) and its derivatives show a wide range of biological activities. In the present study, a series of Schiff and Mannich bases of isatin derivatives were prepared using 4-amino-5-benzyl-2,4-dihydro-3H- 1,2,4-triazole-3-thione. The stru

Full text of DOI:10.1007/s00044-011-9838-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-011-9838-3
ORIGINAL RESEARCH
Synthesis and bioevaluation of Schiff and Mannich bases of isatin
derivatives with 4-amino-5-benzyl-2,4-dihydro-3H-1,2,4-triazole-
3-thione
•
Yellajyosula Lakshmi Narasimha Murthy
•
Boddeti Govindh Bhagavathula S. Diwakar
•
•
Karthikeyan Nagalakshmi Kothagorla Venkata Raghava Rao
Received: 26 March 2011 / Accepted: 25 October 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Isatin (2,3-dioxindole) and its derivatives show
a wide range of biological activities. In the present study, a
series of Schiff and Mannich bases of isatin derivatives
were prepared using 4-amino-5-benzyl-2,4-dihydro-3H-
1,2,4-triazole-3-thione. The structures of these derivatives
were characterized by IR, 1H NMR and elemental analysis.
In vitro antimicrobial activities were evaluated by agar
dilution method and the zone of inhibition values of these
derivatives were compared with ciprofloxacin and fluco-
nazole. Chloro and Bromo groups at fifth position of isatin
broaden the spectrum of antibacterial activity against
S. aures, P. aeruginoa, and E. coli, respectively. For the
antifungal activity, the compound 6h showed equipotent
activity against A. niger. The remaining majority of the
compounds were found active in the biological screening.
The efforts were also made to establish structure activity
relationships among synthesized compounds.
potential biological properties. They are reported to show
a variety of pharmaceutical properties such as antibacte-
rial (Pandeya and Sriram, 1998), antifungal (Jarrahpour
et al., 2007; Varma and Nobels, 1975), antiviral (Jarrah-
pour et al., 2007 and Varma and Nobels, 1975), anti HIV
(Bal et al., 2005; Pandeya et al., 1999), antitubercular
(Hussein et al., 2005), anticancer (Vine et al., 2007), and
anticonvulsant (Varma et al., 2004; Sridhar et al., 2002).
Literature survey reveals that 1,2,4-trizole ring containing
compounds exhibit potential chemotherapeutic properties
such as antimicrobial (Hacer et al., 2009), anti-inflam-
matory (Asif and Arif 2009; Knysh et al., 1983), analeptic
(Knysh et al., 1983), neuroleptic (Parmar et al., 1972),
analgesic (George et al., 1971), and antiviral (Khim,
1976). Currently the substituted 1,2,4-triazole ring consist
chemotherapeutics viz., vorozole, letrozole, and anas-
trozole (Fig. 1), are being used for the treatment of breast
cancer (Clemons et al., 2004). Schiff and Mannich bases
containing 1,2,4-trizole derivatives were reported to pos-
sess some biological activities like anti tumor (Demirbas
et al., 2004) and antimicrobial (Ashok et al., 2007). He-
trocycles containing mercapto and amino groups are an
attractive synthones for the construction of condensed
hetrocyclic rings. The amino and mercapto groups are the
convenient nucleophiles to react with electrophiles (Hacer
et al., 2009). For example, some alkylation and Mannich
reactions can take place at S- or N- atoms were reported
(Bijev and Prodanova, 2007; Krasovskii et al., 2000;
Mekuskiene et al., 2003). Prompted by these observa-
tions, it was contemplated to synthesize some isatin
containing congeners of 1,2,4-triazole Schiff and Mannich
bases with a view to explore their potency as better
chemotherapeutic agents. All newly synthesized com-
pounds were screened for the antibacterial antifungal
activity.
Keywords Isatin Á 1,2,4-Triazole Á Schiff bases Á
N-Mannich bases Á Antimicrobial activity
Introduction
Schiff and Mannich bases of isatin derivatives play an
important role in the medicinal chemistry because of their
Y. L. N. Murthy (&) Á B. Govindh Á B. S. Diwakar Á
K. Nagalakshmi
Organic Research Labs, Department of Organic Chemistry,
Andhra University, Visakhapatnam 530 003, India
e-mail: murthyyln@gmail.com
K. V. R. Rao
Department of Biochemistry, Andhra University,
Visakhapatnam, India
123

Med Chem Res
Fig. 1 Substituted 1,2,4-
triazole ring drug moieties
CH
NC
3
N
N
N
N
H C
3
N
N
N
N
CH
N
3
N
N
H C
CH
3
3
N
CN
NC
CN
Cl
Anastrozole
Letrozole
Vorozole
Results and discussion
However, the compound 5b, 5c, 6b, 6c showed good
activity (nearly equal to the inhibition zone value of cip-
rofloxacin) against to the E. coli bacteria. In general the
antimicrobial activity of the Schiff bases of isatin has
shown less activity than Mannich bases of isatin. It is
because of the presence of[N-CH2–N\bond. Among the
Schiff and Mannich bases of isatin, the 5th position
substituted isatin containing compounds showed more
activity than unsubstituted isatin containing compounds. It
concludes that, the 5-Cl and 5-Br substituent’s of isatin
increases the activity against S. aureus, B. subtilis, E. coli,
and P. aeruginosa. For the antifungal activity, the com-
pound 6h showed equipotent activity against A. niger.
Compounds with piperidine and morpholine showed better
activity than the diethyl amine, against almost all the
organisms used. Thus, from the above discussion it may be
conjectured that Mannich bases are playing their role in
enhancing the antibacterial activity.
Compound 3 was synthesized first time by direct heating an
equimolar mixture of phenyl acetic acid 1 and thiocarbo-
hydrazide 2 and all the synthesized compounds from
Scheme 1 viz., 3, 5a–c, and 6a–i were characterized by the
IR, 1H-NMR, and elemental analysis. IR-spectra (cm-1) of
compound 3 showed absorption bands at 3309 (NH2),
3153, 3097 (NH), 1625 (C=N), 1296 (C–N), 1045 (C=S).
Compounds 5 and 6 showed additional peak belonging to
isatin C=O functional group in the region 1,688–1,698
(cm-1). The other peaks observed were same as compound
1
3. In the H NMR spectra for 5a–c, the characteristic NH2
protons of compound 3 were observed at d 5.6 ppm. The
compounds 5a–c were not shown characteristic signal of
NH2 protons, it concludes that, the formation of –N=C\
bond between triazole moiety and isatin ring. The Schiff
bases 5a–c displayed the NH protons of indole ring around
d 11.45–11.30 ppm. The 1H NMR spectra of Mannich
bases 6a–i were not shown signal corresponding to NH
protons of indole ring and showed additionally the char-
Experimental
acteristic signal of [N–CH2–N\ bond around
d
4.81–4.51 ppm, it confirms that, the NH protons of indole
ring participate to the formation of[N-CH2-N\bond with
secondary amines in the presence of formaldehyde. The
physical constants of synthesized compounds 5a–c and 6a–
i were shown in the Table 1.
Methods and materials
All the chemicals used in the present study are of analytical
grade and were obtained from local suppliers. Melting points
(m.p) were recorded on Kumar capillary melting point
apparatus and are uncorrected. The infrared (IR) spectra
were recorded from KBr disks on Thermo Nicolet (Model:
6700) spectrophotometer. The nuclear magnetic resonance
(NMR) spectra were recorded on 400 MHz Fourier trans-
form-nuclear magnetic resonance (Bruker Model: Avance-
II) spectrophotometer using trimethoxysilane as an internal
The synthesized compounds 5a–c and 6a–i were tested
for in vitro antimicrobial activity. The activity was reported
by measuring the diameter of inhibition zone in mm,
against gram-positive and gram-negative bacteria and fungi
and is presented in Table 2. The tested compounds have
shown moderate activity against tested bacteria and fungi.
H
N
H
N
O
N
N
S
S
S
OH
N
N
0
(190 C)
HN
NH
Schiff Reaction
Δ
NH
N
2
R
+
NH NH
O
2
2
O
R
N
H
O
N
H
5a - c
R = H,Cl,Br
Scheme 1 Synthesis of Schiff bases 5a–c
123

Med Chem Res
Table 1 Physical constant of
the synthesized compounds
H
N
N
S
1
N
N
R
O
N
R
Compound
R
R1
Yield (%)
m.p (°C)a
Molecular
formula
Molecular
weight
5a
5b
5c
6a
6b
6c
H
H
72
67
69
74
66
71
247–249
274–278
278–280
258–260
265–268
262–265
C17H13N5OS
335.38
369.82
414.27
420.53
454.97
499.42
Cl
Br
H
H
C
C
17H12 ClN5OS
17H12BrN5OS
H
CH2N(C2H5)2
CH2N(C2H5)2
CH2N(C2H5)2
C22H24N6OS
Cl
Br
C22H23ClN6OS
C22H23BrN6OS
74
72
70
225–228
238–241
266–268
C23H24N6OS
432.54
466.98
511.43
6d
6e
6f
H
C23H23ClN6OS
C23H23BrN6OS
Cl
Br
73
68
252–256
263–266
C22H22N6O2S
434.51
468.95
6g
6h
H
C22H21ClN6O2S
Cl
C22H21BrN6O2S
513.41
6i
Br
63
255–257
a
Melting points are based on
decomposition temperatures
standard. Elemental analyses were performed on an Ele-
mentar Vario EL elemental analyzer. The determination of
the products purity and reaction monitoring were accom-
plished by TLC on silica gel plates.
Yield 79%; m.p 142–143°C; IR KBr (cm-1): 3309
(NH2), 3153, 3097 (NH), 1625 (C=N), 1296 (C–N), 1045
1
(C=S); H NMR 90 MHz (DMSO-d6) ppm: 13.02 (s, 1H,
NH), 7.20–7.59 (br, s, 5H Ar–H), 5.65 (s, 2H, NH2), 4.15
(s, 2H benzyl CH2); Anal. Calcd. for C9H10N4S: C, 52.41;
H, 4.89; N, 27.16. Found: C, 52.39; H, 4.87; N, 27.18.
General procedure for the synthesis of compounds
Synthesis of 4-amino-5-benzyl-2,4-dihydro-3H-1,2,4-
triazole-3-thione (3)
Synthesis of Schiff bases 5a–c
An equimolar mixture of compound 3 was condensed with
isatin or substituted isatin (5-Cl and 5-Br) in the presence
of few drops of 50% H2SO4 in methanol. The reaction
mixture was refluxed for 4 h and then kept at room tem-
perature overnight. The solid product was washed with
dilute ethyl alcohol and dried. The synthesized compounds
5a–c were recrystalized from ethanol–water (1:2) mixture
(Scheme 2).
An equimolar mixture of phenyl acetic acid 1 and thio-
carbohydrazide 2 were heated at 190°C for 5 min. The
mixture was cooled to room temperature and then treated
with dilute sodium bicarbonate to remove unreacted phenyl
acetic acid. The crude was washed with water and dried.
The synthesized compound 3 was recrystalized from
methanol.
123

Med Chem Res
Table 2 Antibacterial and
antifungal in vitro activity
expressed as diameter of growth
inhibitory zone (GIZ, mm) for
tested compounds (applied
400 lg per disk)
Bacteria
Fungi
Compound
Conc. of
compound
E .coli P. aeruginosa S .aureus B. subtilis C. albicans A. niger
Ciprofloxacin
Fluconazole
A
A
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
30
–
28
–
26
–
25
–
–
20
15
9
–
18
14
9
Compound 5a
23
19
12
27
18
11
27
17
11
22
15
9
24
16
13
25
13
9
22
16
10
23
11
–
20
15
9
–
–
Compound 5b
Compound 5c
Compound 6a
Compound 6b
Compound 6c
Compound 6d
Compound 6e
Compound 6f
Compound 6g
Compound 6h
Compound 6i
20
14
9
16
9
12
9
–
–
25
15
10
20
13
9
20
12
9
22
15
9
17
11
–
14
10
–
23
16
11
21
12
9
20
13
9
17
10
–
13
9
–
27
17
11
26
16
10
23
18
11
25
16
10
25
16
10
23
15
9
22
16
9
20
14
9
15
9
12
9
–
–
23
14
9
20
14
9
20
13
9
16
10
–
13
9
–
20
16
10
21
15
10
22
15
10
22
12
9
20
14
9
20
12
9
16
10
–
13
9
–
20
12
9
22
13
9
16
11
9
15
9
–
21
14
9
20
15
10
20
13
9
16
10
–
15
9
–
19
15
10
20
14
9
15
10
–
12
9
–
25
16
11
24
16
9
25
15
9
22
13
9
17
10
–
17
9
–
24
15
10
20
13
9
21
12
9
15
10
–
12
9
A 200 lg/ml, B 100 lg/ml,
C 50 lg/ml
–
Synthesis of Mannich bases 6a–i
washed with petroleum ether. The synthesized compounds
6a–i were recrystalized from methanol–chlorofrom (1:2)
mixture.
A mixture of various secondary amines (diethyl amine,
piperidine, and morpholine) (1 mmol) was added drop wise
to 0.5 ml of 37% formaldehyde solution under vigorous
stirring. The resulting solution was mixed with corre-
sponding Schiff bases 5a–c (1 mmol) dissolved in 100 ml
methanol. The reaction mixture was refluxed for 10 h.
After the completion of reaction, the solid product was
Characterization of synthesized compounds
Compound 5a 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)
triazol-4-ylimino]-1,3-dihydro-indol-2-one IR KBr (cm-1):
3196, 3059 (NH), 1699 (C=O), 1621 (C=N), 1266 (C–N),
123

Med Chem Res
Scheme 2 Synthesis of
Mannich bases 6a–i
H
N
H
N
N
N
S
S
N
N
CH O
2
N
N
R
1
R
R
O
O
HN
N
2
N
H
R
1
Mannich Reaction
N
R
R
2
6a - i
1
R
R
CH
3
O
N
N
N
N
=
2
,
,
CH
3
1
1123 (C=S); H NMR (DMSO-d6) ppm: 13.00 (s, 1H, tri-
zole NH), 11.33 (s, 1H, isatin NH), 8.31–7.59 (m, 5H),
7.44–6.97 (m, 4H), 4.52 (s, 2H, benzyl CH2); Anal. Calcd.
for C17H13N5OS: C, 60.88; H, 3.91; N, 20.88. Found: C,
60.90; H, 3.90; N, 20.86.
benzyl CH2), 2.64 (br, s, 4H, 2CH2), 1.32 (br, s, 6H, 2CH3);
Anal. Calcd. for C22H23ClN6OS: C, 58.08; H, 5.10; N, 18.47.
Found: C, 58.05; H, 5.12; N, 18.47.
Compound 6c: 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)
triazol-4-ylimino]-5-bromo-1-diethylaminomethyl-1,3-
dihydro-indol-2-one IR KBr (cm-1): 3231, 3086(NH),
Compound 5b 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)
triazol-4-ylimino]-5-chloro-1,3-dihydro-indol-2-one IR KBr
(cm-1): 3215, 3071 (NH), 1705 (C=O), 1620 (C=N), 1286
1
1700 (C=O), 1657 (C=N), 1256 (C–N), 1112 (C=S); H
NMR (DMSO-d6) ppm: 13.04 (s, 1H, triazole NH),
7.63–7.39 (m, 3H), 7.06–6.82 (m, 5H), 4.79 (s, 1H, N–CH2–
N), 4.41 (s, 2H benzyl CH2), 2.34 (br, s, 4H, 2CH2), 1.22 (br,
s, 6H, 2CH3); Anal. Calcd. for C22H23BrN6OS: C, 52.91; H,
4.64; N, 16.83. Found: C, 52.90; H, 4.64; N, 16.82.
1
(C–N), 1130 (C=S); H NMR (DMSO-d6) ppm: 12.90 (s,
1H, trizole NH), 11.45 (s, 1H, isatin NH), 7.65–7.57 (m,
5H), 6.94–6.92 (m, 3H), 4.16 (s, 2H benzyl CH2); Anal.
Calcd. for C17H12ClN5OS: C, 55.21; H, 3.27; N, 18.94.
Found: C, 55.20; H, 3.27; N, 18.95.
Compound 6d: 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)
triazol-4-ylimino]-1-piperidin-1-ylmethyl-1,3-dihydro-in-
dol-2-one IR KBr (cm-1): 3210, 3054 (NH), 1691 (C=O),
Compound 5c 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)
triazol-4-ylimino]-5-bromo-1,3-dihydro-indol-2-one IR KBr
(cm-1): 3245, 3096 (NH), 1700 (C=O), 1619 (C=N), 1290
1
1608 (C=N), 1270 (C–N), 1177 (C=S); H NMR (DMSO-
1
(C–N), 1122 (C=S); H NMR (DMSO-d6) ppm: 12.90 (s,
d6) ppm: 13.08 (s, 1H, triazole NH), 7.63–7.44 (m, 4H),
7.33–7.16 (m, 5H), 4.74 (s, 1H, N–CH2–N), 4.44 (s, 2H
benzyl CH2), 2.08 (br, s, 4H, piperidine N–(CH2)2), 1.48
(br, s, 4H, piperidine 2CH2), 1.35(br, s, 1H, piperidine
CH); Anal. Calcd. for C23H24N6OS: C, 63.87; H, 5.59; N,
19.43. Found: C, 63.86; H, 5.59; N, 19.45.
1H, triazole NH), 11.45 (s, 1H, isatin NH), 7.65–7.42 (m,
3H), 7.25–6.9 (m, 5H), 4.34 (s, 2H benzyl CH2); Anal.
Calcd. for C17H12BrN5OS: C, 49.29; H, 2.92; N, 16.90.
Found: C, 49.30; H, 2.93; N, 16.89.
Compound 6a: 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)
triazol-4-ylimino]-1-diethylamino methyl-1,3-dihydro-in-
dol-2-one IR KBr (cm-1): 3240, 3061(NH), 1693 (C=O),
Compound 6e: 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1, 2,4)
triazol-4-ylimino]-5-chloro-1-piperidin-1-ylmethyl-1,3-
dihydro-indol-2-one IR KBr (cm-1): 3223, 3098 (NH),
1
1609 (C=N), 1265 (C–N), 1183 (C=S); H NMR (DMSO-
1
d6) ppm: 13.58 (s, 1H, triazole NH), 7.64–7.28 (m, 4H),
7.25–6.51 (m, 5H), 4.74 (s, 2H, N–CH2–N), 4.58 (s, 2H,
benzyl CH2), 2.08 (br, s, 2CH2), 1.21 (br, s, 6H, 2CH3);
Anal. Calcd. for C22H23N6OS: C, 62.83; H, 5.75; N, 19.98.
Found: C, 62.82; H, 5.74; N, 19.99.
1699 (C=O), 1618 (C=N), 1253 (C–N), 1137 (C=S); H
NMR (DMSO-d6) ppm: 13.10 (s, 1H, triazole NH),
7.79–7.34 (m, 3H), 7.18–6.82 (m, 5H), 4.71 (s, 1H, N–
CH2–N), 4.46 (s, 2H benzyl CH2), 2.39 (br, s, 4H, piperi-
dine –N–(CH2)2), 1.34 (br, s, 4H, piperidine 2CH2), 1.26
(br, s, 1H, piperidine CH); Anal. Calcd. for
C22H23ClN6OS: C, 59.16; H, 4.96; N, 18.00. Found: C,
59.15; H, 4.97; N, 17.99.
Compound 6b: 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)
triazol-4-ylimino]-5-chloro-1-diethylaminomethyl-1,3-dihy-
dro-indol-2-one IR KBr (cm-1): 3241, 3105 (NH), 1700
1
(C=O), 1621 (C=N), 1285 (C–N), 1134 (C=S); H NMR
Compound 6f: 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)
triazol-4-ylimino]-5-bromo-1-piperidin-1-ylmethyl-1,3-
dihydro-indol-2-one IR KBr (cm-1): 3253, 3100 (NH),
(DMSO-d6) ppm: 13.09 (s, 1H, triazole NH), 7.69–7.39 (m,
3H), 7.23–6.93 (m, 5H), 4.81 (s, 2H, N–CH2–N), 4.45 (s, 2H
123

Med Chem Res
1
1696 (C=O), 1607 (C=N), 1240 (C–N), 1168 (C=S); H
possible to use as lead compounds for other biological
activities. The mechanism of antimicrobial activity is
unknown and requires further investigation.
NMR (DMSO-d6) ppm: 13.11 (s, 1H, triazole NH),
7.74–7.42 (m, 3H), 7.21–6.95 (m, 5H),4.74 (s, 1H,
N–CH2–N), 4.46 (s, 2H benzyl CH2), 2.39 (br, s, 4H,
piperidine –N–(CH2)2), 1.34 (br, s, 4H, piperidine 2CH2),
1.26 (br, s, 1H, piperidine CH); Anal. Calcd. for
C23H23BrN6OS: C, 54.01; H, 4.53; N, 16.43. Found: C,
54.00; H, 4.54; N, 16.45.
Acknowledgment We gratefully acknowledge the DRDO (Defense
Research & Development Organization), New Delhi, India for its
financial support. We would also like to thank Central Instrumenta-
tion Facility-Pondicherry, puducherry, India for providing instru-
mentation facilities.
Compound 6g: 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)
triazol-4-ylimino]-1-morpholin-4-ylmethyl-1,3-dihydro-in-
dol-2-one IR KBr (cm-1): 3220, 3159 (NH), 1692 (C=O),
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Compound 6h: 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)
triazol-4-ylimino]-5-chloro-1-morpholin-4-ylmethyl-
1,3-dihydro-indol-2-one IR KBr (cm-1): 3226, 3159(NH),
1700 (C=O), 1653 (C=N), 1261 (C–N), 1153(C=S); 1H
NMR (DMSO-d6) ppm: 13.04 (s, 1H, triazole NH),
7.83–7.56 (m,3H), 7.33–6.98 (m, 5H), 4.61 (s, 1H,
N–CH2–N), 4.48 (s, 2H benzyl CH2), 3.75 (br, s, 4H,
morpholine O–(CH2)2), 2.61 (br, s, 4H, morpholine
N–(CH2)2); Anal. Calcd. for C22H21ClN6O2S : C, 56.35; H,
4.51; N, 17.92. Found: C, 56.34; H, 4.50; N, 17.93.
Compound 6i: 3-[(3-benzyl-5-thioxo-1,5-dihydro-(1,2,4)triazol-
4-ylimino]-5-bromo-1-morpholin-4-ylmethyl-1,3-dihydro-indol-
2-one IR KBr (cm-1): 3247, 3111(NH), 1688 (C=O),
1
1613 (C=N), 1256 (C–N), 1143 (C=S); H NMR (DMSO-
d6) ppm: 13.04 (s, 1H, triazole NH),7.79–7.47 (m, 3H),
7.34–7.08 (m, 5H), 4.69 (s, 1H, N–CH2–N), 4.56 (s, 2H
benzyl CH2), 3.70 (br, s,4H, morpholine O–(CH2)2), 2.52
(br, s, 4H, morpholine N–(CH2)2); Anal. Calcd. for
C22H21BrN6O2S : C, 51.47; H, 4.12; N, 16.37. Found: C,
51.48; H, 4.10; N, 16.37.
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In conclusion, 12 new derivatives of isatin were synthe-
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good (nearly equal to the zone of ciprofloxacin) antibac-
terial activity against E. coli. For the antifungal activity, the
compound 6h showed equipotent activity against A. niger.
The remaining derivatives displayed moderate activity to
the tested cell cultures. Therefore, these derivatives may
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