S.S. Abd El-Karim et al.
Bioorganic Chemistry 111 (2021) 104827
◦
ꢀ 1
Yield 62%, mp 194–195 C, brown solid, IR (
ν
max/cm ): 3418 (NH),
utilized and housed under standardized conditions with free access to
water and standard food pellets. Rats were acclimatized in our animal
facility for at least 1 week prior to the experiment.
–
–
–
–
–
3
055 (CH-aromatic), 2921, (), 1705 (C
O), 1637 (C
–
N), 1599 (C C).
1
H NMR (DMSO‑d
.88 (d, 1H, Ar-H, J = 2.00 Hz),7.30 (s, 1H, Ar-H), 7.56–7.58 (m, 6H, Ar-
H), 7.96–8.00 (m, 4H, Ar-H), 8.52 (s, 1H, CH = N proton), 9.04 (s, 1H,
6
): δ 2.46 (s, 3H, CH
3
), 6.40 (d, 1H, Ar-H, J = 2.00 Hz),
6
The anti-inflammatory activity of the target compounds 4–23 was
evaluated in correspondence to the carrageenan-induced paw edema
method [25,26]. More details were provided (Supplementary material).
1
3
pyrazole-H
5
); C NMR (DMSO‑d
19.28, 119.39, 127.56, 128.83, 129.00, 129.05, 129.14, 129.23,
29.31, 129.34, 129.38, 130.13, 130.20, 131.32, 132.63, 139.37,
6
3
): δ 14.39 (CH ), 110.41, 117.17,
1
1
1
4.2.2. Ulcerogenic activity
–
49.26, 151.88, 156.48 (aromatic-C), 170.01 (C
S (453.52): Calcd. C, 66.21; H, 4.22; N, 15.44; S, 7.07;
Found: C, 66.01; H, 4.36; N, 15.18; S, 7.22.
-(((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)hydrazono)-5-(thio-
–
O). Anal. For
Gastric hemorrhagic gross lesions of the examined compounds were
assessed after intragastric administration of 0.28 mmol/kg in tween 80
solution and 18 h starvation [35–38]. More details were provided
(Supplementary material).
25 19 5 2
C H N O
2
phen-2-ylmethylene)-thiazolidin-4-one (21)
◦
ꢀ 1
Yield 80%, mp 180–181 C, yellow solid, IR (
ν
max/cm ): 3397 (NH),
4.2.3. The analgesic activity
–
–
–
–
1
3
058 (CH-aromatic), 1707 (C
–
O), 1637 (C
–
N), 1597 (C
C). H NMR
The hot plate method was used to determine the analgesic activity of
the tested compounds [39,40]. More details were provided (Supple-
mentary material).
(
DMSO‑d
6
): δ 7.29–7.30 (m, 1H, Ar-H), 7.40–7.41 (m, 1H, Ar-H),
.52–7.58 (m, 6H, Ar-H), 7.81–7.86 (m, 1H, Ar-H), 7.88–7.89 (m, 2H,
7
Ar-H), 7.99–8.00 (m, 3H, Ar-H), 8.52 (s, 1H, CH = N proton), 9.04 (s,
1
3
1
1
1
1
H, pyrazole-H
5
); C NMR (DMSO‑d
6
): δ 117.10, 119.33, 119.41,
4.2.4. Acute toxicity study
27.57, 128.98, 129.09, 129.11, 129.15, 129.22, 129.31, 129.35,
The study was carried out on female swiss albino mice of weights
20–25 g and the calculated doses of the examined derivatves were given
orally [41]. More details were provided (Supplementary material).
29.39, 130.11, 130.18, 130.86, 131.92, 132.63, 133.14, 138.61,
–
–
O). Anal. For
39.37, 150.25, 152.18, 153.74 (aromatic-C), 168.95 (C
OS (455.55): Calcd. C, 63.28; H, 3.76; N, 15.37;S, 14.08;
Found: C, 63.03; H, 3.82; N, 15.19; S, 14.25.
-(((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)hydrazono)-5-(pyr-
C
24
H
17
N
5
2
4.2.5. In vitro TNF- inhibition assay
α
2
Rats were killed by cervical dislocation and their livers were
idin-4-ylmethylene)-thiazolidin-4-one (22)
immediately removed. Moreover, paw that injected with 0.1 mL carra-
◦
ꢀ 1
◦
Yield 80%, mp 265–267 C, brown solid, IR (
ν
max/cm ): 3420 (NH),
geenan 1% were kept at (-80 C) for determination of tumor necrosis
–
–
–
–
1
3
052 (CH-aromatic), 1716 (C
–
O), 1638 (C
–
N), 1597 (C
C). H NMR
factor-alpha (TNF- ) in tissue homogenate by sandwich ELISA kit
α
(
DMSO‑d
6
): δ 7.31–7.37 (m, 2H, Ar-H), 7.42–7.52 (m, 6H, Ar-H),
.64–7.89 (m, 4H, Ar-H), 7.95 (d, 2H, Ar-H, J = 7.65 Hz), 8.48 (s, 1H,
), 12.69 (br
): δ 116.95, 119.40,
23.82, 125.95, 127.68, 127.87, 128.95, 129.07, 129.40, 130.17,
31.18, 132.79, 139.41, 141.32, 150.96, 151.23, 152.41, 158.25(aro-
(Wuhan fine biotech Co.,Ltd.,China) according to the reported proced-
ure [28].
7
Ar-H), 8.72 (s, 1H, CH = N proton), 9.01 (s, 1H, pyrazole-H
5
s, 1H, NH, D
2
O exchangeable);13C NMR (DMSO‑d
6
4.2.5.1. Statistical analysis. In the present study, data analysis was
achieved by one-way analysis of variance (ANOVA) followed by LSD
comparison test using software program GraphPad Prism (version 7.00).
More details were provided (Supplementary material).
1
1
matic-C), 167.77 (C–
O). Anal. For C25
6.65; H, 4.03; N, 18.65; S, 7.12; Found: C, 66.46; H, 4.28; N, 18.49; S,
.30.
-((1H-indol-3-yl)methylene)-2-(((1,3-diphenyl-1H-pyrazol-4-yl)
–
18 6
H N OS (450.52): Calcd. C,
6
7
4
.2.5.2. Molecular modeling study on TNF-
performed using MOE 2008.10, from the Chemical Computing Group
Inc [31]. The X-ray crystal structure of TNF- was downloaded from
Protein Data Bank website (PDB ID: 2AZ5) [32] associated with its in-
hibitor, 6,7-dimethyl-3-[(methyl{2-[methyl({1-[3-(trifluoromethyl)
α
. The docking technique was
5
methylene)hydrazono)-thiazolidin-4-one (23)
α
Yield 81%, mp 249–250 ◦C, creamy solid, IR (
ν
max/cm ): 3441,
ꢀ 1
–
–
–
3
105 (2NH), 3049 (CH-aromatic), 1718 (C
O), 1638 (C
–
N), 1600
–
1
(
C
–
C). H NMR (DMSO‑d
6
): δ 7.24–7.47 (m, 2H, Ar-H), 7.50–7.57 (m,
phenyl]-1H-indol-3-yl}methyl)amino]ethyl}amino)methyl]-4H-chro-
men-4-one (307). More details were provided (Supplementary
material).
8
H, Ar-H), 7.86 (d, 2H, Ar-H, J = 5.50 Hz), 7.98 (d, 2H, Ar-H, J = 5.50
Hz), 8.10 (d, 1H, Ar-H, J = 5.50 Hz), 8.29 (s, 1H, Ar-H), 8.43 (s, 1H, CH
N proton), 8.96 (s, 1H, pyrazole-H ), 12.15, 11.90 (2br s, 2H, NH, D
): δ 112.89, 117.16, 118.63, 119.31,
21.29, 122.60, 123.93, 124.58, 127.56, 128.95, 129.03, 129.12,
30.11, 130.30, 132.53, 137.52, 138.94, 139.93, 152.06, 165.01 (aro-
=
5
2
O
Funding
1
3
exchangeable); C NMR (DMSO‑d
6
The authors are grateful to the Deanship of Scientific Research, king
Saud University for funding through Vice Deanship of Scientific
Research Chairs.
1
1
matic-C), 175.45 (C–
O). Anal. For C28
8.84; H, 4.13; N, 17.20; S, 6.56; Found: C, 68.92; H, 4.28; N, 17.01; S,
–
20 6
H N OS (488.57): Calcd. C,
6
6
Declaration of Competing Interest
.38.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
4
4
4
.2. Biological activity
.2.1. In vivo anti-inflammatory activity
Acknowledgments
.2.1.1. Drug and chemicals. Celecoxib was purchased from Pfizer,
United States. Diclofenac was purchased from Novartis Pharma, Cairo,
Egypt. Indomethacin was purchased from PHARCO, Cairo, Egypt.
Carrageenan lambda was purchased from Sigma Aldrich chemical Co.
The authors are grateful to the Deanship of Scientific Research, king
Saud University for funding through Vice Deanship of Scientific
Research Chairs.
(
USA). All other chemicals were of the highest available commercial
grade. All tested compounds were dissolved in tween 80 before being
orally intubated to the animals.
Appendix A. Supplementary data
4
.2.1.2. Animals. Adult male Wistar rats of weights 120–170 g were
1
6