Design and development of 1,3,5-triazine derivatives as protective agent against spinal cord injury in rat via inhibition of NF-?B

Article abstract of DOI:10.1016/j.bmcl.2021.127964

Spinal cord injury (SCI) is a chronic disease causing motor and sensory loss in the affected individuals. The SCI has a huge impact on the lives of patients that makes them susceptible to life-long disability. However, the current clinical modalities are ineffective to cope the aftermath of SCI. Thus, in the present study, we aimed to develop a series of 1,3,5-triazine derivatives as a protective agent against SCI. The molecules were developed by facile synthetic route and obtained in excellent yield. The compounds were tested for their efficacy to inhibit the transcription of NF-κB in RAW 264.7 cells, where they displayed mild to potent activity. Compound 8a was identified as most potent NF-κB inhibitor among the tested analogues. The effect of compound 8a was further scrutinized against the SCI injury in rats induced by contusion injury. It has been found that compound 8a improves motor function of rats together with reduction in inflammation and edema in spinal cord of rats. It also showed to inhibit oxidative stress and inflammation in the SCI rats. In a western blot analysis, after SCI induction, compound 8a inhibited NF-κB and its upstream regulator TLR4 in a dose-dependent manner. Collectively, our study provides a novel class of agent that provide protective action against SCI.

Full text of DOI:10.1016/j.bmcl.2021.127964

Bioorg. Med. Chem. Lett. 41 (2021) 127964
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and development of 1,3,5-triazine derivatives as protective agent
against spinal cord injury in rat via inhibition of NF-ĸB
,
*
Binggang Guana, Chang Jiangb
a Department of Spine Surgery, Tian Jin Hospital, Tianjin 300211, China
b Department of Bone Surgery, The First Affiliated Hospital of Dalian Medical University , Dalian, Liaoning 116011, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
1,3,5-Triazine
SCI
Spinal cord injury (SCI) is a chronic disease causing motor and sensory loss in the affected individuals. The SCI
has a huge impact on the lives of patients that makes them susceptible to life-long disability. However, the
current clinical modalities are ineffective to cope the aftermath of SCI. Thus, in the present study, we aimed to
develop a series of 1,3,5-triazine derivatives as a protective agent against SCI. The molecules were developed by
facile synthetic route and obtained in excellent yield. The compounds were tested for their efficacy to inhibit the
transcription of NF-κB in RAW 264.7 cells, where they displayed mild to potent activity. Compound 8a was
identified as most potent NF-κB inhibitor among the tested analogues. The effect of compound 8a was further
scrutinized against the SCI injury in rats induced by contusion injury. It has been found that compound 8a
improves motor function of rats together with reduction in inflammation and edema in spinal cord of rats. It also
showed to inhibit oxidative stress and inflammation in the SCI rats. In a western blot analysis, after SCI in-
duction, compound 8a inhibited NF-κB and its upstream regulator TLR4 in a dose-dependent manner. Collec-
tively, our study provides a novel class of agent that provide protective action against SCI.
Inflammation
NF-κB
TLR4
The injury of spine which is better known as spinal cord injury (SCI)
is a chronic disease causing motor and sensory loss in the affected in-
dividuals. The SCI has a huge impact on the lives of patients that makes
them susceptible to life-long disability. This has a serious financial
implication on the patients and their families. Accumulating shred of
evidences suggest that SCI arises in the course of mechanical insult
which initiate cascade of events classified as primary and secondary
injury.1 The primary injury mainly causes damage to the neurons that
cannot be regenerated; whereas, secondary injury which subsequently
occurs after primary injury considered as more serious but preventable,
if treated well in time. Thus, the clinical approach to treat SCI is mainly
reliant upon controlling the impact of secondary injury, such as
inflammation, oxidative stress and apoptosis of neurons.2,3
which is deemed as a distinctive feature of SCI. It plays a critical role in
the pathogenesis of acute and chronic SCI which leads to tissue damage
and neurodegeneration via the activation of innate immune response.
This activated immune system causes oligodendrocyte apoptosis, de-
myelination, axonal de-generation, and neuronal death. The nuclear
factor-kappaB (NF-kappaB), an important mediator of inflammatory
cascade belongs to a family of transcription factors which govern the
activation of a variety of genes. It controls inflammation, proliferation,
and cell death. Before the injury in non-inflammatory condition, the NF-
κB exists as inactive form in complex with IκB in cytoplasm (cyto).
Following the injury, the IκB kinase activates the NF-κB pathway by
degrading cyto- IκB. This degradation promotes the rapid translocation
of NF-κB from cytoplasm to nucleus which is responsible for the acti-
vation of microglia. This activation further recruits various inflamma-
tory cytokines under the influence of oxidative stress.6 Accumulating
shreds of evidences suggest that inhibition of activation of NF-κB and
production of free radical provide significant benefit against SCI.7–9
Imatinib, a protein tyrosine-kinase inhibitor used for the treatment of
chronic myelogenous leukemia (CML) and acute lymphocytic leukemia
(ALL) that are Philadelphia chromosome-positive (Ph+). It acts by
Studies have suggested that oxidative stress plays a significant role in
the patho-physiology of SCI which further aggravate the clinical status
of the patients.4 The over-production of free radicals coupled with low
level of antioxidants is considered as a main cause of oxidative stress. It
is considered as extremely aggressive to the surrounding tissues by
inducing lipid-peroxidation, increased infiltration, activation of the
nuclear enzyme PARP, depletion of nicotinamide adenin dinucleotide
and ATP, and ultimately cell death.5 It also promotes inflammation
inhibiting activation of Bcr-Abl tyrosine kinase caused by
a
* Corresponding author.
E-mail address: jiangxxl21@yahoo.com (C. Jiang).
https://doi.org/10.1016/j.bmcl.2021.127964
Received 26 January 2021; Received in revised form 26 February 2021; Accepted 10 March 2021
Available online 17 March 2021
0960-894X/© 2021 Published by Elsevier Ltd.

B. Guan and C. Jiang
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127964
Fig. 1. Structure of some 1,3,5-triazines, thiazole derivatives as inhibitor of NF-κB, imatinib and designed compounds.
chromosomal translocation.10 Recently, it showed beneficial effects
against SCI via improving blood-spinal cord-barrier integrity, hind-limb
locomotor function, sensori-motor integration, and bladder function. It
also showed to inhibit astrogliosis and deposition of chondroitin sulfate
proteoglycans, and increased tissue preservation.11 In another study,
imatinib improves hind limb locomotion and bladder recovery when
initiation of treatment was delayed until 4 h after injury and that bladder
function was improved with a delay of up to 24 h with no hypersensi-
tivity reaction.12 It is under Phase II clinical trial (NCT02363361) to
assess its uptake, safety and tolerability in acute SCI patients.13
1,3,5-Triazine, a highly active pharmacophore found in many of
clinically relevant pharmacological agent, such as, antibacterial,14–19
anti-fungal,20–22 antimalarial,23–28 anti-HIV29 and against diabetes14
and cystic fibrosis.30 Various studies have documented the significant
inhibitory activity of 1,3,5-triazine derivatives (compound 1, 2 and 3,
Fig. 1) against the activation of NF-κB. The PBI-1308, a 1,3,5-triazine
derivative, inhibits both inflammation and human prostate cancer cell
proliferation via inhibition of activation of NF-κB.31
Thiazole scaffold is also reported to exhibit strong NF-ĸB inhibitory
activity. Compound 4 (Imidazothiazole derivative) showed potent
2

B. Guan and C. Jiang
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127964
Scheme 1. Reagents and conditions: a) Liq⋅NH3 in acetone, 40–45 ◦C, heat, 2–3 h, b) NaOBu-t/THF 10 ◦C to rt, 2 h, c) THF-TEA, 0 ◦C, 3 h, d) K2CO3, Et3N, reflux 3–5
h, 120–135 ◦C.
inhibition of nitric oxide (NO) production in LPS-stimulated RAW 264.7
and prevented translocation of NF-κB from cytoplasm to nucleus by
using an immunofluorescent staining method.32 In an another study,
drugs designed to target SCI need to cross the BSCB and have lipophillic
in nature.35–38 In the present study, we have replaced phenyl instead of
methyl substituent of piperazine to provide more lipophilicity to the
target molecules.39–41 Therefore, prompted by the above, in the present
study, we have attempted to develop a novel class of hybrid molecule
containing imatinib and 1,3,5-triazine as a potential agent against SCI
(Fig. 1).
several
2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one
derivatives (5) showed excellent inhibition of NF-ĸB and AP-1 mediated
transcription activation in HEK293 cells and antinflammatory effect in
carrageenan induced rat paw edema assay in Sprague-Dawley rats.33
Singh et al. reported the development of novel 1,3,5-triazine-thiazole
derivatives via dual inhibition of NF-ĸB and EGFR-TKS for possible
benefit in rheumatoid arthritis. In molecular docking analysis, the most
potent molecule of the series showed strong interaction with Tyr57,
Val58, Cys59, His141, and Val142 in DNA binding domain of NF-ĸB.34
The blood-spinal cord barrier (BSCB) is the functional equivalent of
the blood–brain barrier (BBB) in the sense of providing a specialized
microenvironment for the cellular constituents of the spinal cord. The
The entire synthetic routes which give rise to final derivatives were
bifurcated in two steps as shown in Scheme 1. Initially, the synthesis was
achieved by reacting 2,4-dichloro-6-methyl-1,3,5-triazine (1) with liq.
ammonia to afford corresponding di-amine substituted 1,3,5-triazine
(2). The 2-(2-chloropyrimidin-4-yl)thiazole (3) was allowed to couple
with compound 2 in the presence NaO-tBu in THF from 10 ◦C to room
temperature to furnish 6-methyl-N2-(4-(thiazol-2-yl)pyrimidin-2-yl)-
1,3,5-triazine-2,4-diamine (4). The step
2 of the synthesis was
3

B. Guan and C. Jiang
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127964
to be act by multiple pathways against SCI which is a much sought
strategy to counteract the secondary damage in SCI. The NF-ĸB has been
shown to activate, via transcription, the genes encoding pro-
inflammatory cytokines, cell adhesion molecules, iNOS and COX-
2.43,44 In SCI, various studies have shown that activation of NF-ĸB has a
detrimental effect on CNS recovery, thus its inhibition offer significant
benefit following the traumatic CNS injury.45–48
Table 1
Inhibitory activity of compounds (8a-g) on NF-ĸB transcriptional activity in LPS-
stimulated RAW264.7 cells.a
Entry
R
IC50 (in µM)a
8a
4-Cl
1.04 ± 0.11
3.21 ± 0.42
9.90 ± 1.05
6.12 ± 0.87
54.23 ± 12.61
87.32 ± 18.26
136.41 ± 28.32
0.92 ± 0.27
1.34 ± 0.17
8b
4-Br
8c
4-CH3
4-NO2
4-OH
4-OCH3
H
8d
The designed compound showed significant to moderate range of NF-
ĸB transcriptional inhibitory activity in LPS-stimulated RAW264.7 cells.
Among the tested derivatives, compound 8a showed excellent inhibitory
activity (IC50 = 1.04 µM). It was found more potent than imatinib but
less potent than dexamethasome as a standard. The replacement of
chloro with bromo (8b) or with methyl (8c) results in reduction in
inhibitory activity with IC50 of 3.21 µM and 9.90 µM, respectively. The
compound 8d containing p-nitro group showed slight improvement in
inhibitory activity (IC50 = 6.12 µM) as compared to compound 8c.
However, the introduction of p-hydroxy (OH, 8e) or p-methoxy (OCH3,
8f) in the place of nitro (8d) significantly reduces the inhibitory activity.
The unsubstituted phenyl (8g) showed least activity among the tested
derivatives (Table 1).
8e
8f
8g
Dexamethasone (Reference)
Imatinib (Reference)
**P < 0.01 vs. Control.
##P < 0.01 vs. LPS.
a
IC50 values expressed as mean ± SD of at least three independent assays.
concentrated towards the development of other side chain which was
intended to be substituted on the 1,3,5-triazine core. In this step, 4-
(chloromethyl)benzoyl chloride (5) was act as starting material for the
development of 4-(chloromethyl)-N-(4-methyl-6-((4-(thiazol-2-yl)pyr-
imidin-2-yl)amino)-1,3,5-triazin-2-yl)benzamide (6) after reacting with
compound 4 in the presence of THF-TEA at 0 ◦C, 3 h. Finally, the
designed compounds 8 (a-f) were readily obtained after refluxing
compound 6 with substituted piparazine derivatives 7 (a-f) in the
presence of K2CO3 and Et3N at 120–135 ◦C for 3–5 h.
The exceptional NF-κB transcription inhibitory activity of compound
8a has compelled us to determine its effect in traumatic SCI injury in rats
to rationalize its potential clinical utility. The SCI injury in Sprague-
Dawley rats was induced by contusion injury via a weight drop
method where a rod was dropped on the spinal cord of the rats. This
method suggested producing human like SCI symptoms in rats. After
induction of injury, the rat received compound 8a in different dose (10,
20, and 30 mg/kg) by intra-peritoneal route (i.p.) after suspending in 2%
CMC (carboxy methylcellulose) for once a day for 14 days. Initially, the
effect of compound 8a was determined on the motor function of rats.
In the present study, we have developed a heterocyclic scaffold
consisting of imatinib and 1,3,5-triazine as NF-ĸB inhibitor against SCI.
In previous studies, these two scaffolds individually showed protective
effect against SCI, thus it is worthwhile to assess their effect when they
are used in combination.13,31,42 The designed hybrid skeleton envisaged
Fig. 2. Effect of compound 8a after SCI in rats. (A) BBB score for determination of motor function, (B) ratio of wet to dry weight of spinal cord, and (C) H & E staining
spinal cord. Values represent the mean ± SEM and are representative of three independent experiments. ##P < 0.05 vs sham; **P < 0.05 vs. SCI, one-way analysis of
variance followed by a Tukey’s post hoc test.
4

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Bioorganic & Medicinal Chemistry Letters 41 (2021) 127964
Fig. 3. Effect of compound 8a on the neuronal damage determined by (A) Nissl staining, and (B) quantitative analysis of (B) Nissl bodies. Values represent the mean
± SEM and are representative of three independent experiments. ##P < 0.05 vs sham; **P < 0.05 vs. SCI, one-way analysis of variance followed by a Tukey’s post
hoc test.
The loss of motor ability is the most frequently altered function of the
body after SCI. The Basso-Beattie-Bresnahan (BBB) score is a most
widely accepted method to determine function recovery and locomotors
testing in chronic SCI study. The scale ranges from 0 to 21 which stands
for chronological recovery phases and categorizes alone or together rat
functions, such as, rat joint movement, hindlimb movements, stepping,
forelimb and hindlimb coordination, trunk position and stability, paw
placement and tail position.49,50 As shown in Fig. 2A, the effect of
compound 8a was determined on the motor function of rats the BBB
score of rats on the day 1, 4, 7, 10 and 14 days. The results suggested that
SCI group showed altered motor function as compared to sham treated
group. The motor function of rats was found significantly restored in the
compound 8a treated group in dose-dependent manner with maximal
activity shown in 30 mg/kg treated group. The compound 8a treated rats
also showed improved ratio of wet to dry spinal cord weight 24 h post-
SCI (Fig. 2B). The effect of compound 8a was also investigated by his-
topathological architecture of spinal cord tissues via H and E staining. As
shown in Fig. 2C, compound 8a significantly alleviated the edema in
Fig. 4. Effect of compound 8a on the various indices of oxidative stress in spinal cord of rats after SCI induction. (A) MDA, (B) GSH, and (C) SOD. Values represent
the mean ± SEM and are representative of three independent experiments. ##P < 0.05 vs sham; **P < 0.05 vs. SCI, one-way analysis of variance followed by a
Tukey’s post hoc test.
5

B. Guan and C. Jiang
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127964
Fig. 5. Effect of compound 8a on the level of pro-inflammatory cytokines as determined by ELISA analysis (A) TNF-α, (B) IL-1β and (C) IL-6. Values represent the
mean ± SEM and are representative of three independent experiments. ##P < 0.05 vs sham; **P < 0.05 vs. SCI, one-way analysis of variance followed by a Tukey’s
post hoc test.
Fig. 6. Effect of compound 8a on the expression of (A) NF-κB, p-IĸBα, and TLR4 via western blot analysis, and qualitative analysis of (B) p-IĸBα, (C) NF-κB and (D)
TLR4 in the spinal cord of rats after SCI induction. Values represent the mean ± SEM and are representative of three independent experiments. ##P < 0.05 vs sham;
**P < 0.05 vs. SCI, one-way analysis of variance followed by a Tukey’s post hoc test.
spinal cord and inhibited the morphological changes and re-established
the histopathology of tissue nears to normal. On the basis of above
observation, it could be suggested that that compound 8a possessed the
ability of alleviating SCI-related symptoms. The effect of compound 8a
was investigated on neuronal damage via nissl staining (Fig 3). The SCI
treated rats showed reduced nissl granules suggesting significant dam-
age to neurons as compared to sham treated group. Compound 8a pre-
vented neuronal damage as shown by higher number of nissl bodies as
compared to SCI treated rats. The compound 8a showed dose-dependent
neuro-protective effective via averting the neuronal damage. In the next
part, we aimed to study the effect of compound 8a on various bio-
markers associated with SCI to elucidate its mechanism of action.
Oxidative stress and inflammation are closely linked and studies
have shown their significant role in progression of various neurode-
generative diseases, such as SCI.51,52 Thus, it is worthwhile to examine
the effect of compound 8a on the mediators of inflammation and
oxidative stress. As shown in Fig. 3, the activities of GSH and SOD were
found reduced together with increased level MDA in SCI rats in com-
parison to control. The compound 8a treated group showed increased
level of GSH and SOD with drop in MDA activity as compared to SCI
6

B. Guan and C. Jiang
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127964
14 Srivastava JK, Dubey P, Singh S, Bhat HR, Kumawat MK, Singh UP. Discovery of
novel 1,3,5-triazine-thiazolidine-2,4-diones as dipeptidyl peptidase-4 inhibitors with
antibacterial activity targeting the S1 pocket for the treatment of type 2 diabetes.
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group. Moreover, the level of tested inflammatory cytokines (IL-1β, IL-6,
and TNF-α) was found reduced significantly in 8a treated group as
compared to disease control, Fig 4.
´
´
´
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In the above sections, we have discussed the role of NF-κB in SCI, but
toll-like receptor 4 (TLR4) is another protein which is a upstream
regulator of NF-κB and regulates its activation.53,54 Various studies have
shown that TLR4 regulates inflammation, gliosis, and myelin sparing
after spinal cord injury, and its inhibition offers beneficial effects.55,56
Moreover, in steady state, the NF-κB dimers are sequestered by IκB in the
16 Singh UP, Singh RK, Bhat HR, et al. Synthesis and Antibacterial Evaluation of Series
of Novel Tri-Substituted-s-Triazine Derivatives. Vol. 20; 2011:1603-1610. doi:
10.1007/s00044-010-9446-7.
17 Kumar Ghosh S, Saha A, Hazarika B, Pratap Singh U, Raj Bhat H, Gahtori P. Design,
facile synthesis, antibacterial activity and structure-activity relationship of novel di-
and tri-substituted 1,3,5-triazines. Lett Drug Des Discov. 2012;9:329–335. https://doi.
org/10.2174/157018012799129846.
cytoplasm. Upon stimulation following the injury, IκB
(p-IκB ) to release the NF-κB, which then enters into the nucleus where
it activates the expression of proinflammatory cytokines, such as IL-1,
α phosphorylated
α
18 Bhat HR, Pandey PK, Ghosh SK, Singh UP. Development of 4-aminoquinoline-1,3,5-
triazine conjugates as potent antibacterial agent through facile synthetic route. Med
Chem Res. 2013;22:5056–5065. https://doi.org/10.1007/s00044-013-0521-8.
19 Singh B, Bhat HR, Kumawat MK, Singh UP. Structure-guided discovery of 1,3,5-
triazine-pyrazole conjugates as antibacterial and antibiofilm agent against pathogens
causing human diseases with favorable metabolic fate. Bioorg Med Chem Lett. 2014;
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IL-6, and TNF-α. Studies have shown that blockade of IκB degradation
prevented NF-κB activation. Therefore, the last part of the study was
aimed to determine the effect of compound 8a on the expression of NF-
κB, TLR4 and p-IκBα protein in the spinal cord tissues of rats. Towards
this, a western blot analysis was conducted and results have been shown
20 Singh UP, Bhat HR, Gahtori P. Antifungal activity, SAR and physicochemical
correlation of some thiazole-1,3,5-triazine derivatives. J Mycol Med. 2012;22:
134–141. https://doi.org/10.1016/j.mycmed.2011.12.073.
in Fig 5. It has been found that the expression of NF-κB, TLR4, and IκB
α
was found significantly elevated in SCI rats, whereas upon administra-
tion of compound 8a, the level of these proteins were found significantly
reduced (Fig. 6).
21 Singh U, Bhat H, Gahtori P, Singh RK. Hybrid phenylthiazole and 1,3,5-triazine
target cytosolic leucyl-tRNA synthetase for antifungal action as revealed by
molecular docking studies. Silico Pharmacol. 2013;1:3. https://doi.org/10.1186/
2193-9616-1-3.
Collectively, our study has demonstrated the pharmacological
benefit of imatanib and 1,3,5-triazine hybrid against SCI. These com-
pounds revealed as potent inhibitors of NF-κB transcription activity in
RAW264.7 cells. Moreover, the most potent NF-κB inhibitor, compound
8a showed neuro-protective activity.
22 Milata V, Reinprecht L, Kizlink J. Synthesis and antifungal efficacy of 1,3,5-triazines.
Acta Chim Slovaca. 2012;5:95–99. https://doi.org/10.2478/v10188-012-0015-1.
23 Bhat HRHR, Singh UPUP, Yadav PSPS, et al. Synthesis, characterization and
antimalarial activity of hybrid 4-aminoquinoline-1,3,5-triazine derivatives. Arab J
Chem. 9:S625-S631. doi:10.1016/j.arabjc.2011.07.001.
24 Bhat HR, Singh UP, Thakur A, et al. Synthesis, antimalarial activity and molecular
docking of hybrid 4-aminoquinoline-1,3,5-triazine derivatives. Exp Parasitol. 2015;
157:59–67. https://doi.org/10.1016/j.exppara.2015.06.016.
Declaration of Competing Interest
25 Bhat HR, Singh UP, Gahtori P, et al. Antimalarial activity and docking studies of
novel bi-functional hybrids derived from 4-aminoquinoline and 1,3,5-triazine against
wild and mutant malaria parasites as pf-DHFR inhibitor. RSC Adv. 2013;3:2942.
https://doi.org/10.1039/c2ra21915h.
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.
26 Sunduru N, Sharma M, Srivastava K, et al. Synthesis of oxalamide and triazine
derivatives as a novel class of hybrid 4-aminoquinoline with potent antiplasmodial
activity. Bioorg Med Chem. 2009;17:6451–6462. https://doi.org/10.1016/j.
bmc.2009.05.075.
Appendix A. Supplementary data
27 Gahtori P, Ghosh SK, Parida P, et al. Antimalarial evaluation and docking studies of
hybrid phenylthiazolyl-1,3,5-triazine derivatives: A novel and potential antifolate
lead for Pf-DHFR-TS inhibition. Exp Parasitol. 2012;130:292–299. https://doi.org/
10.1016/j.exppara.2011.12.014.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127964.
28 Bhat HR, Singh UP, Gahtori P, et al. Synthesis, docking, in vitro and in vivo
antimalarial activity of hybrid 4-aminoquinoline-1,3,5-triazine derivatives against
wild and mutant malaria parasites. Chem Biol Drug Des. 2015;86:265–271. https://
doi.org/10.1111/cbdd.2015.86.issue-310.1111/cbdd.12490.
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