560 Egypt. J. Chem. Vol. 67, No. 12 pp.

97 - 109 (2024)

Egyptian Journal of Chemistry

http://ejchem.journals.ekb.eg/

Design, Synthesis, Biological and Docking Studies of Novel 6-

fluorobenzothiazole Substituted 1,2,4-Triazole Analogues as Prospective
Anti-inflammatory Agent

ShaikKhadarYazdana, Kurni Lakshmi Deepthib, Laxmi Devi BNc, Sajida Afreend,

Subramanyam Sibbalae, Banothu Bhadruf, Madhu Gudipatiig, Vijay Kishore Kanakarajuh,
NareshPodila*
a
Department of Pharmaceutical Sciences, Chebrolu Hanumaiah Institute of Pharmaceutical Sciences,
Chowdavaram, Guntur, Andhra Pradesh, India
b
Department of Pharmaceutical Chemistry, Sreedattha Institute of Pharmacy, Sheriguda, Ibrahimpatnam,
Hyderabad, Telangana, India
c
Department of Pharmaceutical Chemistry, Joginapally B.R. Pharmacy College, Yenkapally, Moinabad,
Hyderabad, Telangana, India
d
Department of Pharmaceutical Chemistry, RBVRR Women’s College of Pharmacy, Barkatpura,
Barkatpura, Hyderabad,
Telangana, India
f
Department of Pharmaceutical Analysis, CMR College of Pharmacy, Kandlakoya, Medchal
Medchal,, Hyderabad,
Telangana, India
g
Department of Pharmaceutics, KITS College of Pharmacy for Women, Divili, Tirupathi (V), Peddapuram (M),
Kakinada (Dt)-533 433, Andhra Pradesh
h
Department of Pharmaceutical Chemistry, College of Pharmaceutical Sciences, Acharya Nagarjuna University,
Guntur, Andhra Pradesh, India
e,I
DepartmentofPharmaceutical Sciences,Vignan’s Foundation for Science, Technology and Research, Guntur,
Andhra Pradesh, India

Abstract

The Part of the body's immunological reaction to an external stimulus is inflammation. It is helpful initially because it starts
with the mending process. It is concerning, though, because inflammation has the ability to self-replicate, causing new
inflammation to arise in reaction to pre-existing inflammation. In this study, a novel series of 6-Fluoro Benzothiazole
substituted 1,2,4-Triazole derivatives were synthesized as prospective anti-inflammatory agents. The newly created substances
were examined using mass spectrometry, 1H-NMR, 13C-NMR, and FTIR. First, the compounds underwent rigorous in vivo
testing for acute toxicity and anti-inflammatory activity.To further validate these findings, an in silico docking study was
carried out against COX-2 (PDB ID: 1pxx). The in vivo results revealed that three compounds-TZ9, TZ2, and TZ1, displayed
no acute toxicity and significant anti-inflammatory activity, surpassing the efficacy of the standard drug, diclofenac sodium.
Notably, TZ9, which featured diphenyl amino substitution, emerged as the most potent anti-inflammatory agent among the
screened compounds. The computational analysis demonstrated that TZ9, and TZ2, exhibited substantial binding affinity,
with the highest binding energies (-11.6 and -10.2, Kcal/mol) compared to diclofenac (-8.4 Kcal/mol). This alignment
between in vivo and in silico data supported the robust anti-inflammatory potential of these derivatives. According to this
work, the anti-inflammatory action of benzothiazole substituted with diphenyl amine, tyrosine, ortho phenylene diamine and
4-amino benzoic acid at the seventh position is enhanced. The synthesised compounds were also characterised by solubility,
TLC, analytical data, IR, 1HNMR, and mass spectrum examinations.

Keywords:Benzothiazole, COX-2, Anti-inflammatory activity, Binding affinity, Diclofen

1. Introduction chronic illnesses, such as lupus and rheumatoid

Inflammation is a common feature of both acute and

*Corresponding author e-mail:[email protected] (Naresh Podila)

EJCHEM use only: Received date 18 March 2024; revised date 18 June 2024;accepted date 19 July 2024
DOI: 10.21608/ejchem.2024.277247.9460
©2024 National Information and Documentation Center (NIDOC)
98 Shaik Khadar Yazdan et.al.
_____________________________________________________________________________________________________________

arthritis, cardiovascular diseases, neurological and the improvement of existing ones. Consequently,
illnesses including Alzheimer's disease, and several the 6-fluoro-bezothiazole ring has become a
cancers [1]. The creation of novel anti-inflammatory promising heteroaryl ring to be considered for the
medications may offer more potent therapies for creation and manufacturing of new compounds with
various illnesses, enhancing the prognosis and noteworthy biological properties. Due to their low
quality of life of affected individuals [2]. When bioavailability, the majority of new bioactive
taken over an extended period of time, existing anti- compounds are never commercialized. By
inflammatory medications such corticosteroids and lengthening the molecules' in vivo lifetime and
nonsteroidal anti-inflammatory medicines (NSAIDs) boosting tissue bioavailability, the addition of
can have serious side effects [3-5]. By creating new fluorine to the molecule enhances its lipophilicity [9]
drugs with better safety profiles, these side effects and inhibits metabolic detoxification [10].
can be lessened and patients' treatments can be more The incorporation of the chlorine group of the 6-
bearable. Researchers have been able to pinpoint fluoro benzothiazole moiety into drug molecules, for
particular inflammatory pathways and molecules example, has the benefit of acting as a Bioisosteres
implicated in a variety of diseases because to for the benzene ring. The substitution of this group
advancements in molecular biology and genetics.By with diphenyl amine, tyrosine, ortho phenylene
focusing on these particular pathways, new anti- diamine, 4-amino benzoic acid, anisidine,
inflammatory drugs can be created that provide more morpholine, and pyrrolidine will alter the
accurate and tailored treatments with fewer side physicochemical properties, affecting the
effects [6]. Treatment for chronic inflammatory interactions between the drug and the receptor[11].
diseases is frequently ongoing. Reducing the Additionally, benzothiazole derivatives are a subject
frequency of hospitalizations and interventions and of ongoing study in several areas of chemical
improving disease management are two benefits of research, such as polymer chemistry, dyes, and
developing new anti-inflammatory drugs with medications[12]. A wide range of biological
improved efficacy and tolerability. activities, such as antituberculosis, antiproliferative,
Advantageous heterocyclic rings with atoms of antibacterial, anthelmintic, antioxidant, and
sulfur and nitrogen are essential tools in the search antimicrobial properties, have led to the patenting of
for new medications, such as anti-inflammatory numerous benzothiazoles [13, 14]. Benzothiazole
ones. Several research published in scientific scaffolds are also found in several medications, such
journals have demonstrated that artificial chemicals as2-amino-6-trifluoromethoxybenzothiazole
with heterocyclic structures can reduce acute and (Riluzole), which is used to treat amyotrophic lateral
chronic inflammation and may even aid in healing. sclerosis, and 2-thiocyanomethylthio-benzothiazole
Because of their biological activity, target selectivity, (TCMTB-60), an antimicrobial agent; 1- (6-
structural variety, and therapeutic relevance, they are methoxy-2-benzothiazolyl) -3-phenyl urea
useful building blocks for developing safer and more (frentizole), a fungicide also used to prevent fungal
effective therapies for inflammatory disorders [7-8]. attacks on the skin; 2-(4-amino-3-methylphenyl)
The 6-fluoro-benzothiazole ring is one of the benzothiazole, an anticancer agent; and
scaffolds that medicinal chemists frequently utilize ethoxzolamide, a diuretic used to treat glaucoma and
to construct and alter compounds with desired duodenal ulcers [15]. Moreover, numerous
pharmacological properties, among other things.This benzothiazole compounds are presently undergoing
approach enables the development of novel drugs varying phases of clinical testing Figure 1 [16].

Figure 1: Structures of selected drug molecules decorated with benzothiazole substituted with 1,2,4-triazole scaffolds
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 DESIGN, SYNTHESIS, BIOLOGICAL AND DOCKING STUDIES OF.. 99
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Moreover, in the recent past, the tested anti- chlorine moiety and 1,3,4-thiadiazole nucleus into
inflammatory lead compounds were decorated with the same molecule will help in the development of
6-Fluoro benzothiazole and triazole rings [17-22]. In new class of anti-inflammatory agents. Hence, we
view of the above facts, we contemplated that designed, synthesized and tested a series of novel
incorporating diphenyl amine, ortho phenyl diamine, linked 6-Fluoro benzothiazole substituted 1,2,4-
pyrrolidine, diethyl amine, tyrosine, phenyl ethyl triazole Figure 2.
amine, and morpholine groups at 7th position of the

the slurry was heated at 850°C, and it was filtered

Figure 2: 6-fluoro-triazolo-benzothiazolescaffold hot. 10mlof glacial acetic acid, heated at 850°C,
2. Experimental were added to the orange residue in a reaction flask
before it was filtered while still hot. After cooling
2.1. MaterialsandMethods and neutralizing the combined filtrate with an
The produced compounds were characterised using ammonia solution to a pH of 6.0, a dark yellow
the following experimental techniques. The precipitate was recovered. Recrystalised from
synthesised compounds' uncorrected melting points benzene, ethanol of (1:1) after treatment with animal
were measured in open capillary tubes. Using charcoal gave yellow crystals of 2-amino-6-fluoro-7-
potassium bromide pellets, the ELICIO FTIR chloro-(1,3)-benzothiazole. After drying in an oven
spectrometer recorded the infrared spectrum. Using at 800C, the dry material (1gm 51.02%) melted at
a BRUKER Av 400 spectrometer, the 1H-NMR 210–212°C (Figure 3).
spectra of the chemicals in deutiriated
Synthesis of 7- chloro- 6- fluoro-2-hydrazinyl- 1,
dimethylsulfoxide were recorded. The mass 3- Benzothiazole[17]
spectrum was captured using the Shimadzu GCMS In 500ml of round bottom flask and added 10 ml of
QP 5000. Utilising precoated aluminium plates concentrated hydrochloric acid was added drop wise
coated with silica gel GF254 [E. Merck], thin layer with stirring of hydrazine hydrate 12 ml(0.02mol) at
chromatography was carried out. N-hexane: 5-10°C drop wise cool the mixture and add 20.2gm
theeluent employed was ethylacetate. In the chamber (0.1 mol) of 7- chloro- 6- fluoro 2-amino
with ultraviolet light, the spots were visible. benzothiazole i.e. slowly added then added 40ml to
2.2. Chemistry 60ml of ethylene glycol and the resulting mixture
refluxed for 3hrs and poured into crushed ice then
Synthesis of 2-amino-6-fluoro-7-chloro (1, 3) residue settle down to the beaker then filter the
Benzothiazole[17]
product and dry the product and recrystalised from
1.45gm (0.01 mol) of 3-chloro 4-
ethanol.
fluoroaniline and 8gm (0.08 mol) of potassium
thiocyanate were added to 20ml of glacial acetic acid Synthesis of 8-chloro-7-fluoro-1,9a-dihydro
that had been chilled below room temperature. A [1,2,4] triazolo [3,4-b] [1,3] Benzothiazole[17]
dropping funnel was used to add 1.6 ml of bromine The mixture of 0.01mol, or 2.19gm of 7-chloro-6-
to 6 ml of glacial acetic acid at a rate that ensured the fluoro-2-hydrazinyl-1, 3-benzothiazole and 1gm of
mixture never heated above room temperature. The anhydrous potassium carbonate, was added to a 250
liquid was then placed in a water bath and agitated ml round-bottom flask. The mixture was then
with a magnetic stirrer. After adding all of the refluxed with formic acid for two hours and poured
bromine, the mixture was shaken for ten hours at a into crushed ice, where the residue settled down to a
temperature below room temperature. After standing beaker. The product was then filtered and dried to
overnight, during which time an orange precipitate separate it from the ethanol to obtain the pure final
settled at the bottom, water (6 ml) was rapidly added, product.
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100 Shaik Khadar Yazdan et.al.
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Synthesis of 8-chloro-7-fluoro-1-[4-methylphenyl] 154.8; MS m/z: 229.87.

sulphonyl-1,9a-dihydro [1,2,4] triazolo [3,4-b]
8-chloro-7- fluoro- 1-tosyl-1,9a-dihydro Benzo
[1,3] Benzothiazole[17]
[4,5]thiazolo [2, 3-c] [1, 2, 4] triazole, mf:
8-chloro-7-fluoro-1,9a-dihydrol (0.013mol), or C15H11ClFN3O2S2; mw: 383.85 Da; Yield: 80%;
2.2gm, was added to a 500ml round-bottom flask [1, Green solid; mp: 304-306°C; Rf = 0.91 (EtOAc: n-
2, 4] triazole [3,4-b] [1,3]. The final product was hexane); FTIR (KBr, cm-1): 699.54, 1144.35,
obtained by treating benzothiazole with 0.01mol, or 1381.24, 1681.84; 2191.38; 1H- NMR (DMSO, 300
1.71gm, of p-toluene sulphonamide in the presence MHz) δ ppm: 7.81-7.6 (m, 6H, Ar), 7.03-7.38 (m,
of pyridine (1-2ml), refluxing the mixture for two 2H, Ar), 3.02 (m, 3H, CH3); 13C-NMR (CDCl3, 67.9
hours, and then pouring the mixture into crushed ice. MHz) δ ppm: 25.3, 58.9, 1135, 114.1, 118.2, 120.2,
The residue settled and the product was drained and 125.4, 127.8, 129.6, 129.9, 133.7, 142.8, 151.8,
recrystallized from ethanol. [4-methylphenyl]-8- 154.2; MS m/z: 383.14.
chloro-7-fluoro-1-1,2,4sulphonyl-1,9a-
dihydrotriazolo[3,4-b] Benzothiazole [1,3]. 6-fluoro-N, N-diphenyl-3,3a-dihydrobenzo [4,5]
thiazolo [3,2-b] [1,2,4] triiazol-5-amine (1), mf:
Synthesis of 8-chloro-7-fluoro-1-[4-methylphenyl] C21H21FN5O2S2; mw: 458.27 Da; Yield: 83%; white
sulphonyl-1,9a-dihydro [1,2,4] triazolo [3,4-b] powder; mp: 114-116°C;Rf = 0.68 (EtOAc: n-
[1,3] Benzothiazole derivatives (TZ 1-9)[17] Butanol: CHCl3 2:1:1); FTIR (KBr, cm-1): 1272.18,
Equimolar amounts of different primary and 1427.50, 1662.45, 1044.24, 1438.87, 1107.51, 1184.
secondary aromatic amines were added to a 100ml 31; 1H-NMR (DMSO, 300 MHz) δ ppm: 6.44-6.67
round-bottom flask containing 2.7gm(0.14988 (m, 10H, Ar),7.45-7.68 (m, 4H ArPh) 7.29-7.8 (s,
moles) of 8-chloro-7-fluoro-1-[4- 1H, CH), 4.14 (s, 2H, NH2) 3.01 (m, 3H, CH3), 8.17
methylphenylsulphonyl-1,9 dihydro [1,2,4] triazolo (s, 1H, NH); 13C-NMR (CDCl3, 67.9 MHz) δ ppm:
[3,4b] [1,3]benzothiazole. The mixture was refluxed 25.4, 58.3, 103.7, 112.7, 115.2, 119.4, 123.1, 124.2,
for two hours while N, N’-dimethyl formamide 124.9, 126.5, 126.8, 128.2, 129.1, 129.4, 129.9,
(DMF) was present. After cooling, the mixture was 131.2, 133.5, 137.8, 140.5, 148.1, 152.3; MS m/z:
added to crushed ice. Using a pinch of activated 457.50.
charcoal, the separated solid was filtered out, dried, 6-fluoro-3-tosyl-3,3a-dihydrobenzo [4,5] thiazolo
and recrystallized from alcohol and benzene. [3,2-b] [1,2,4] triaiazol-5-yl)amino)-3-(4-
2-amino-6-fluoro-7-chloro (1, 3) hydroxyphenyl) propanoic acid (2),mf:
Benzothiazole,mf:C7H14ClFN2S; mw: 202.63 C24H21FN4O5S2; mw: 527.12 Da; Yield: 68%, Brown
Da;yield: 94%; Brown crystalline; mp: 214°C;Rf = solid, mp: 120°C;Rf = 0.72 (EtOAc: n-Bu: CHCl3
0.95 (EtOAc: n-hexane), FTIR (KBr, cm-1): 667.22, 2:1:1); FTIR (KBr, cm-1): 1346.52, 1137.41,
827.01, 1021.14, 1635.21, 1227.12; 1H-NMR 1380.21, 1145.42, 1156.53, 1525.04, 1588.28; 1H-
(DMSO, 300 MHz) δ ppm: 5.99 (2H NH2), 7.27 (m, NMR (DMSO, 300 MHz) δ ppm: 6.13-6.57 (m,
2H, Ar); 13C-NMR (CDCl3, 67.9 MHz) δ ppm: 12H, Ar), 9.27 (s, 1H, NH), 1.89 (m, 3H, CH3)
114.0, 116.2, 122.3, 125.7, 145.8, 158.3, 166.1; MS 2.18(s, 1H, CH), 2.98 (s, 2H, CH2), 9.65, 12.90 (d,
m/z: 203.12 (M+1). 2H, OH); 13C-NMR (CDCl3, 67.9 MHz) δ ppm:
26.5, 34.6, 61.5, 66.4, 67.3, 83.5, 101.3, 103.6,
7-chloro-6-fluoro-2-hydrazinyl-1,3- 111.2, 115.1, 116.9, 126.1, 128.6, 129.1, 129.4,
Benzothiazole, m. f: C7H5ClFN3S,mw: 219.35 Da; 130.2, 132.5, 134.6, 135.7, 140.8, 141.5, 152.8,
yield: 78%; yellow crystalline; mp: 242°C, mw: 156.2, 173.4 MS m/z: 527.58.
219.63; Rf = 0.78 (n-hexane: EtOAc); FTIR (KBr,
cm-1): 682.02, 798.21, 1048.34, 1662.38, 1214.75; 6-fluoro-3-tosyl-3, 3a-dihydrobenzo [4,5] thiazolo
1
H-NMR (DMSO, 300 MHz) δ ppm: 3.80 (1H, NH), [3,2-b] [1,2,4] triazol-5-yl) benzene-1,2-diamine
3.24 (s, 2H, NH2), 7.37-7.98 (m, 2H, aromatic); 13C- (3),mf: C21H18FN5O2S2; mw: 457.80 Da; Yield:
NMR (CDCl3, 67.9 MHz) δ ppm: 114.5, 117.8, 75.5%; orange solid; mp: 167°C;Rf= 0.77 (CHCl3:
121.5, 123.6, 145.8, 173.2; m/z: 219.35. n-Bu: EtOAc 1:2:1); FTIR (KBr, cm-1): 1019.26,
1152.86, 1224.26, 1278.17, 1478.40, 1530.71,
8-chloro-7-fluoro-1,9a-dihydrol [1, 2, 4] triazole 1620.37; 1HNMR (300 MHz) DMSO) ) δ ppm: 7.04
[3, 4-b] [1, 3] Benzothiazole,mf: C8H5ClFN3S; mw: -7.19 (m, 8H, Ar), 9.08 (s, 1H, NH), 2.50 (m, 3H,
229.65 Da; Yield: 42%; brown solid; mp: 284- CH3) 2.99 (s, 2H, CH2), 9.70, 10.98 (d, 2H, OH),
286°C;Rf = 0.75, (n-hexane: EtOAc); FTIR (KBr,
3.21 (s, 1H, NH); 13C-NMR (CDCl3, 67.9 MHz) δ
cm-1): 714.82, 1064.62, 1321.01, 1589.97; 1H-NMR
ppm: 26.6, 61.4, 101.2, 111.4, 113.7, 115.4, 116.9,
(DMSO, 300 MHz) δ ppm: 7.0 (1H, CH), 7.33-8.04 121.2, 122.6, 125.2, 127.7, 128.3, 129.5, 129.9,
(m, 2H, Ar); 13C-NMR (CDCl3, 67.9 MHz) δ ppm: 131.3. 134.7, 142.5, 149.7, 149.6, 153.6, 161.6; MS
67.8, 112.8, 113.6, 118.2, 121.8, 133.7, 152.2, m/z: 457.15.
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N-(4-methoxy phenyl amino)-6-fluoro-3-[ (4- [5, 1-b] [1, 3] benzothiazole (8),mf:

methyl phenyl) sulfonyl]-3, 3a-dihydro [1, 2, 4] C23H21FN4O2S2; mw: 481.26 Da; Yield: 70.9%;
triazolo [5, 1-b] [1, 3] benzothiazol-5-amine (4), green; mp: 134°C; Rf = 0.68 (EtOAc: n-But: CHCl3:
mf: C22H19FN4O3S2; mw: 469.31 Da; Yield: 68.6%; 2:1:1); FTIR (KBr, cm-1): 1300.14, 1512.21,
pink solid; mp: 178°C;Rf = 0.62 (CHCl3: n-But: 1601.20, 1099.17, 1428.04, 1202.21, 1241.54; 1H-
EtOAc: 1:2:1); FTIR (KBr, cm-1): 1095.53, 1121.68, NMR (DMSO, 300 MHz) δ ppm: 7.21-7.40 (m,
1128.12, 1301.51, 1465.24, 1528.07, 1587.46. 1H- 11H, Ar), 3.15-3.59 (m, 4H, CH2) 7.08 (s, H, NH)
NMR (DMSO, 300 MHz) ) δ ppm: 7.02 -7.46 (m, 3.51 (m, 3H, CH3); 13C-NMR (CDCl3, 67.9 MHz) δ
10H, Ar), 9.21 (s, 1H, NH), 2.98 (m, 3H, CH3), 2.92 ppm: 20.4, 22.3, 41.0, 51.5, 60.4, 65.6, 69.1, 101.2,
( s, 2H, CH2), 3.27, 2.45 (s, 2H, CH2); 13C-NMR 104.8, 111.2, 115.3, 121.3, 126.5, 127.3, 128.5,
(CDCl3, 67.9 MHz) δ ppm: 25.7, 56.2, 62.5, 106.8, 129.9, 130.1, 131.0, 133.5, 134.2, 141.6, 143.2,
110.7, 114.1, 114.8, 115.2, 120.5, 120.9, 125.3, 147.6; MS m/z: 480.75.
126.9, 128.6, 129.3, 129.9, 130.5, 132.3, 140.5,
6-fluoro-3-[(4-methyl phenyl) sulfonyl]-5(naph
148.3, 149.8, 153.8, 155.1; MS m/z: 469.25.
thayl amino)-3, 3a-dihydro [1, 2, 4] triazolo [5, 1-
6-fluoro-3-[(4-methyl phenyl) sulfonyl]- b] [1, 3] Benzothiazole (9),mf: C25H19FN4O2S2; mw:
morphonyl-3, 3a-dihydro [1, 2, 4] triazolo [5,1-b] 475.70 Da; Yield: 60.02%; violet; mp: 172°C;Rf =
[1, 3] benzothiazol-5-amine (5),mf: 0.83 (EtOAc: n-Bul: CHCl3: 2:1:1); FTIR (KBr, cm-
1
C19H20FN5O3S2; mw: 448.81 Da; Yield: 71.14%, ): 1301.24, 1569.72, 1623.14, 1081.09, 1437.14,
milkfish; mp: 175°C;; Rf = 0.75 (EtOAc:n-Bu1: 1327.28, 1182.27; 1H-NMR (DMSO, 300 MHz) ) δ
CHCl3: 2:1:1); FTIR (KBr, cm-1): 1195.14, 1444.14, ppm: 7.03-7.63 (m, 6H, aromatic), 3.23-3.47 (m,
1659.07, 1135.35, 1500.28, 1181.44, 1221.04; 1H- 4H, CH2) 9.38 (s, 4H, NH) 2.52 (m, 3H, CH3); 13C-
NMR (DMSO, 300 MHz) δ ppm: 7.45-7.68 (m, 5H, NMR (CDCl3, 67.9 MHz) δ ppm: 23.2, 25.8, 26.2,
Ar), 1.89 (m, 3H, CH3) 3.18 (s, 2H, CH2), 3.01-3.47 27.5, 41.8 43.2, 55.6, 65.3, 82.8, 101.8, 111.4,
(m, 4H, CH2); 13C-NMR (CDCl3, 67.9 MHz) δ 115.3, 119.5, 121.3, 127.6, 127.2, 128.6, 129.1,
ppm: 23.4, 42.3, 54.3, 56.2, 62.4, 65.8, 67.2, 105.4, 129.3, 130.2, 131.2, 131.9, 132.7, 133.3, 140.27;
107.3, 113.5, 123.3, 125.3, 127.5, 127.1, 128.9, MS m/z: 475.30.
130.5, 132.4, 141.2, 143.3; MS m/z: 448.12.
6-fluoro- (4-pyrrolidinyl) 3-[(4-methyl phenyl)
sulphonyl]-3, 3a-dihydro [1, 2, 4 ] triazolo [5, 1-b]
[1, 3] benzthiazol-5-amine (6),mf: C19H19FN4O2S2;
mw: 421.20 Da; Yield: 63.8%; cream; mp: 184°C;Rf
= 0.74 (EtOAc: n-But:CHCl3 2:1:1); FTIR (KBr,
cm-1): 1304.00, 1548.21, 1621.08, 1078.51, 1490.09,
1142.71, 1212.10; 1H-NMR (DMSO, 300 MHz) δ
ppm: 6.42-6.59 (m, 6H, Ar), 3.00 (m, 3H, CH3) 1.99
(m, 2H, CH2), 2.96-3.47 (m, 4H, CH2); 13C-NMR
(CDCl3, 67.9 MHz) δ ppm:23.5, 24.8, 25.3, 50.5,
51.4, 60.4, 104.7, 104.8, 105.4, 112.3, 126.3, 126.9,
127.8, 129.3, 129.8, 132.5, 136.2, 140.5, 142.4; MS
m/z: 420.27.
6-fluoro-N-diethyl amino-3-[ (4-methyl phenyl)
sulfonyl]-3, 3a-dihydro [1, 2, 4] triazolo [5, 1- b]
[1, 3] benzothiazol-5-amine (7),mf:
C19H21FN4O2S2, mw: 428.28 Da; Yield: 68.5%, blue;
mp: 112°C; Rf = 0.46 (EtOAc : n-But: CHCl3 2:1:1);
); FTIR (KBr, cm-1): 1298.21, 1531.27, 1658.21,
1115.37, 1534.42, 1092.00, 1272.28; 1H-NMR
(DMSO, 300 MHz) δ ppm: 7.14 -7.52 (m, 5H, Ar),
2.00 - 2.94 (m, 6H, CH3) 2.97 (m, 4H, CH2); 13C-
NMR (CDCl3, 67.9 MHz) δ ppm: 22.50, 42.2, 50.2,
53.5, 62.4, 63.5, 65.8, 102.3, 105.3, 113.8, 121.9,
123.4, 125.3, 127.3, 128.8, 130.1, 132.6, 141.3,
143.8; MS m/z: 428.02.
1-[6-fluoro-7- (4-phenethyl amino)-3-[4-methyl
phenyl] sulphonyl]-3, 3a dihydro [1, 2, 4] triazole

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102 Shaik Khadar Yazdan et.al.
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2.3. Evaluation of Anti-inflammatory

inflammatory Activity: using a method [29].
2.3.1. Acute oral toxicity
Following the OECD 423 recommendations, we
employed the acute toxic class approach to assess the
Where,
toxicity of the target chemicals (TZ1(TZ1-TZ9) in the
current study. Swiss albino rats weighing between ‘Vc' represents edema volume in the control
200 and 250 grams were used in this investigation. ‘Vt’ stands for the volume of edoema in the group
To evaluate ate the toxicity of the synthesized receiving the test medication. The values are the
compounds, three rats of the same gender were mean +/- standard error of the mean (SEM) of six
included in each group. A starting dose of 200 mg/kg animals per group; p<0.001% inhibition indicates
body weight was given. Before receiving any statistically significant differences from the control.
medication, female rats were fasted for three to four Tuckey's test was run after an ANOVA was used for
hours without food or water. ater. The animals were statistical analysis.
weighed after the fasting period, and 200 mg of the
synthetic derivatives were administered orally for 2.3.3. Molecular Docking:
every kilogram of body weight [23]. Following the Using the Autodock Vina module of PyRx 0.8
delivery of the test chemical, the animals were software, Chemoffice 2016 tools, and Discovery
closely monitored for the first four hours at 30 30- Studio 2020 software, Molecular Docking and
minute intervals, and then every hour for up to simulation experiments were carried out [30–32].
[ It
twenty-four
four hours. For a total of 14 days, the animals was possible to obtain the co-crystal
crystal protein structure
were observed every day, and during that time, every via the Protein Data Bank (www.pdb.com or
animal was carefully examined for any strange www.rcsb.com) [33]. Downloaded loaded from the protein
alterations in its biological, behavioural
oural, or physical data bank (www.rcsb.com/www.pdb.com) is the
state [24]. target protein cyclooxygenase 2 (COX (COX-2) X-ray
crystal structure, co-crystallized
crystallized with diclofenac
Induced Rat Paw Edema
2.3.2. Carrageenan–Induced (PDB ID: 1pxx). The protein was created by
Model removing HET atoms, adding polar hydrogens,
We used male or female healthy rats weighing removing
ving water molecules, and confirming that no
between 100 and 190 grams as subjects in the amino acid residues were missing using the
carrageenan-induced
induced paw edema experiment [25]. Discovery Studio Visualizer 2021 program. After
Three sets of six test animals each were created out that, the file was saved in pdb format. The target
of these rats. The animals fasted for the whole night compounds' (2D) structures (TZ1––9) were drawn
before the trial started, with access to water given as using Chemdraw Professional onal and saved as.pdb files.
needed [26]. A normal saline solution was given to Using the macromolecule option in the PyRx Virtual
the control group (negative control), while NTD1 at screening program 0.8's Autodock tool, the protein
a dosage of 20 mg/kg was given to the second pdb file was converted to pdbqt format. The ligand
group, NTD2 to the third group, NTD3 to the fourth files were forced to field-off off (minimize energy)
group, and the standard medication Diclofenac using the Open Babel tool,, which created the
sodium at a dosage of 4.5 mg/kg to the fifth group. conformers (Autodock pdbqt files). The ligands and
Using an oral catheter, each test and standard macromolecule (protein pdbt file) for the docking
material was given orally after being dissolved
dissolve in process (auto dock pdbqt files) were chosen using
normal saline [27]. A 0.2 mL solution of 1% w/v Vina Wizard. by drawing a grid on a piece of paper.
carrageenan was injected into the rats' right paw's By placing a grid box around the area where the co co-
sub plantar area in order to cause edema. The paw crystal ligand exhibits amino acid iterations,
was inked up to the level of the lateral malleolus, the protein's active binding site for docking ligands
and then it was immersed in mercury until the was found. The ligands with the lowest binding
indicated
icated point was reached. A Plethysmometer was energies were the likely molecules having a high
then used to measure the amount of edema in the affinity for the target protein. The Discovery
Dis Studio
rat's paw [28]. Following carrageenan injection, the Visualizer 2021 program was used to visualize the
paw volumes of each group were measured binding interactions [34, 35].
immediately (at 0 hours) and then every hour for the
next two hours. The difference between the first and .Results and Discussion
final measurements was used to determine the actual 3.1. Spectral Studies:
increase in paw size. The average increase in paw The peak in the infrared spectrum provides
size between medication-treatedtreated and untreated information about the compound's likely structure.
control rats was measured, and the percentage that The infrared spectrum spans 4000––6666 cm–1. This
edema development was as suppressed was computed spectrum's radiation quanta are related to the energy
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Egypt. J. Chem. 67, No. 12 (2024)
 DESIGN, SYNTHESIS, BIOLOGICAL AND DOCKING STUDIES OF.. 103
__________________________________________________________________________________________________________________

differences between molecules' various vibrational motor activity, and other general toxicity indications.
states. Using the KBr pellet technique, the The compounds under title had an LD50 value of
compounds were recorded on the SHIMADZU class 5, meaning that at 200 mg/kg body weight of
FTIR-8400Sspectrophotometer, which displays animal weight, there was no evidence of toxicity.
various molecular vibration levels. Based on data from toxicity studies, five of the nine
synthesized compounds—TZ9, TZ2, TZ1, TZ3, and
The samples were examined using a 300MHz NTD8—were found to be well tolerated by the
BRUKER spectrometer. We may learn about the experimental animals and non-toxic at selected dose
various chemical and magnetic environments that levels. Of the nine compounds, four derivatives—
protons in molecules relate to thanks to proton NMR TZ5, TZ6, TZ7, and NTD8—were found to be toxic.
spectra.
3.3. InvitroAnti-inflammatory Activity
With extreme precision, the Relative molecular Rat paw edema (Carrageenan-induced) was used to
masses (also known as molecular weights) can be determine the synthetic compounds' anti-
calculated using this precise molecular formula. inflammatory efficacy. The activity was examined at
Finding the locations in the molecule where doses of 20 mg/kg body weight, and the effects were
fragmentation is preferred will allow us to infer the timed at 0 minutes, 30 minutes, one hour, and 2 h.
existence of identifiable groups. as a technique for The results are given in Table 1. The anti-
detecting analytes by comparing their digitalized inflammatory effects of the four produced substances
mass spectra with libraries of known substances. The ranged from slight to strong. For up to 2 h, all three
title compound's mass spectra are stored on an substances showed their peak action. The maximum
LCMS. The following is a representation of the activity was observed when R was substituted with
synthesized compounds' spectrum data. phenyl, -CH3, and phenyl carboxylate, according to
the data from the synthesized compounds at a dose
3.2. Acute Oral Toxicity Study of 20 mg/kg body weight [36].
The OECD guideline-423 approach was used to
carry out the oral acute toxicity study. This The anti-inflammatory activity of synthesized
methodology was developed to investigate derivatives (TZ1-TZ9) compared with the standard
compounds at fixed dosages and provides drug diclofenac sodium is represented in Figure 4
information for hazard evaluation as well as and the data suggests that these the three compounds
chemical ranking for hazard classification. A starting have remarkable (p 0.01) anti-inflammatory activity.
dose of 200 mg/kg body weight was administered by The high significant action was seen for the
floating the synthesized compounds in acacia and synthesized compounds at 60 and 120 minutes. This
water. The animals were observed for 14 days study demonstrates how the target compounds
following the sample administration. Careful blocked prostaglandins, particularly during the
monitoring was done at least twice a day to check for biphasic response.
any effects on the ANS, CNS, salivation, skin colour,

Table 1: Effect of selected derivatives on paw edema in rats

N=6, values are expressed in mean ± SEM, *p<0.05, Assessed using one-way ANOVA followed by Tukey’s multiple comparison test

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Egypt. J. Chem. 67, No. 12 (2024)
104 Shaik Khadar Yazdan et.al.
_____________________________________________________________________________________________________________

Figure 4: Bar diagram with mean and standard error of the mean at 0-2 hrs

Following carrageenan administration. In addition, clearly demonstrated the difference in test animals
these derivatives have the potential to selectively with paw edema before and after treatment with the
inhibit the cyclooxygenase enzyme. In Figure 5 it is tested synthetic compounds.

Figure 5: Anti-inflammatory activity in Wistar rats. A: Paw edema before treatment; B: Paw edema after treatment

3.4. Docking Assessment cyclooxygenase 2 (COX-2) protein was chosen as

Because it is essential for the synthesis of the target for in silico anti-inflammatory activity
inflammatory mediators such as prostaglandins, the screening [37]. Table 2 displays the findings of the
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Egypt. J. Chem. 67, No. 12 (2024)
 DESIGN, SYNTHESIS, BIOLOGICAL AND DOCKING STUDIES OF.. 105
__________________________________________________________________________________________________________________

title derivatives' docking investigation against the illustrated in Figure 6. These interactions occur
chosen protein (PDB ID: 1pxx). In comparison to because the derivatives have an aryl substitution
the co-crystal ligand diclofenac, which has a (TZ9 having diphenyl amino) or a substituted aryl
binding energy of -8.4 Kcal/mol, the derivatives substitution (TZ1 having benzene 1,2-diamine
TZ9 and TZ1 demonstrated substantial binding substitution) on the thiadiazole ring. The in-silico
affinities with the least binding energies of -8.5 and results seem merely correlated with the in vivo rat
-8.4 Kcal/mol, respectively, according to the data. paw edema test results which conforms to the
Table 2 lists all of the compounds' binding validation of in silico docking results. Moreover,
energies. The derivatives, on the other hand, the research findings reported by Redzicka et al.
exhibit significant binding affinities by interacting [38-40] Soni et al.,and Veerasamy et al., reported
with amino acid residues in the target protein's that compounds with aryl or heteroaryl
active site through different hydrogen and substitutions may have shown potent anti-
hydrophobic interactions given in Table 3 and inflammatory activity.

Table 2: Binding energies of the title derivatives against COX-2

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Egypt. J. Chem. 67, No. 12 (2024)
106 Shaik Khadar Yazdan et.al.
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Table 3: Interactions of the selected derivatives with Cox-2 protein active pocket residues

Figure 6: Interactions of selected derivatives (NTD2 and NTD3) with active pocket residues of COX-2
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Egypt. J. Chem. 67, No. 12 (2024)
 DEVELOPMENT OF PILOT SCALE SYSTEM FOR PRODUCTION .. 107
__________________________________________________________________________________________________________________

4. Conclusion Prescribe or Proscribe,Therapeutic Advances in

In conclusion, this study has successfully Musculoskeletal Disease13 (2021)
synthesized and characterized a series of 1759720X2110221.
Benzothiazole linked 1,3,4-thiadiazole derivatives [4] S. Drożdżal, K. Lechowicz, B. Szostak, J.
(TZ1-TZ9), through a well-defined synthetic Rosik, K. Kotfis, A. Machoy‐Mokrzyńska, M.
process. These derivatives were subjected to a Bielecki, K. Ciechanowski, B.
comprehensive evaluation, encompassing both Gawrońska‐Szklarz, Kidney Damage from
experimental and computational approaches, to Nonsteroidal Anti‐Inflammatory Drugs—Myth
assess their potential as anti-inflammatory agents. or Truth? Review of Selected Literature,
Notably, TZ9, featuring a benzoic acid substitution, Pharmacology Research & Perspectives9 (4)
emerged as a promising lead compound, (2021).
demonstrating remarkable anti-inflammatory [5] P. Naresh, R. Mithun, S. Subramanyam, R.
properties in both in vivo and in silico studies. Its Atul, R. Bendale, P. Yanadaiah, R.B.
binding affinity, stability, and interactions with the Molakpogu, M. Kiran, D.C. Renzon, Sreelatha
target protein COX-2 were found to be superior to Muddisetti. In vitro antimitotic activity and in
the standard drug diclofenac sodium. Additionally, silico study of some 6-fluoro-triazolo-
the safety profile of these derivatives was assessed, benzothiazole analogues, Pharmacia. 70(4)
revealing that TZ9, TZ2, and TZ1 exhibited no (2023) 887-894.
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and TZ7 displayed undesirable toxic effects. This Polypharmacology in Drug Discovery: A
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anovelstrategytoreducethe
Conflict of interest denguevectorcompetence, RSC
There are no conflicts to declare. Advances12(16) (2022) 9793–9814.
[9] L. Mouhid, M. Corzo-Martínez, C. Torres, L.
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members and management of the Vignan’s Potentially Antitumor Phytochemicals and
Foundation for Science, Technology and Research, Currently Available Lipid-Based Delivery
Vadlamudi, Guntur, for providing all necessary Systems, Oncol7 (2017) 7351976.
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