R.S. Gani et al.
Bioorganic Chemistry 114 (2021) 105046
types of diabetes, namely, type I and type II. Among them, non-insulin-
dependent diabetes mellitus (type II) is the most prevalent diabetes
worldwide, with more than 80% of patients being affected by it [2].
Diabetes mellitus type 2 (T2DM) is characterized by severely critical
metabolic failure due to the production of less insulin and high blood
glucose level [3–5]. T2DM is recognized and identified as a major threat
to human health [6]. When glucose blood level increases, it affects and
leads to other clinical conditions such as kidney disease, blindness,
lower limb amputation due to gangrene, etc. [7,8]. The World health
organization (WHO) has assessed all over the world that more than 220
million people currently have diabetes, and this number is expected to
double by 2030 [9].
selected compounds were then fed to a genetically amenable model of
Drosophila melanogaster [38–42] and analyzed for glucose levels
[43–45]. Acarbose, a commercial glucosidase inhibitor, was used as a
comparative standard /positive control [46].
Summary of 5-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-1,3,4-
oxadiazole-2-thiol derivatives (2a-2i).
2. Materials and methods
2.1. Experimental details
All reagents and chemicals were purchased from common commer-
cial suppliers and were used in this experiment without further purifi-
α
-Glucosidase (EC 3.2.1.20) and -amylase enzymes originate in the
α
small intestine brush border, which breaks down the complex carbo-
hydrates into small sugars such as monosaccharides and disaccharides.
cation. Melting points were recorded by the open capillary method and
1
are uncorrected. HNMR spectra were recorded using CDCl
3
as solvent
α
-Glucosidase originates in the epithelium tissue of the small intestine
that catalyzes the hydrolysis of carbohydrates to produce an excess of
glucose [10]. When enzymatic action of -glucosidase and -amylase is
elevated during digestion, suddenly blood glucose level increases;
therefore, the inhibition of enzymes such as -glucosidase and -amylase
and TMS as an internal standard on a Bruker 400 MHz NMR spectrom-
eter. The mass spectra were recorded on a low-resolution mass spec-
trometer operating at 70 eV. The purity of the compounds was checked
on completion of the reaction by thin-layer chromatography (TLC) on
pre-coated silica gel plates (refer supplementary data).
α
α
α
α
have been potential remedial target to control hyperglycemia [11–15].
To cure or control T2DM, the key factor is to reduce postprandial hy-
2.2. 5-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-1,3,4-oxadiazole-2-thiol
(2a)
perglycemia [16]. In this context,
α
-glucosidase inhibitors have been
used to control T2DM. Many clinically used
α-glucosidase inhibitors are
based on sugar moieties such as miglitol, voglibose, and acarbose [17].
Heterocyclic compounds, particularly those containing sulfur, ni-
trogen, and oxygen, exhibit enormous applications in pharmacy, agri-
culture, and other industries [18]. Among them, oxadiazole derivatives
are playing a key role in pharmaceutical chemistry. The latest trend in
new drug discovery research indicated that combinatorial drugs are
playing an important role in pharmaceutical chemistry. It is desirable to
combine two or more pharmacophore moieties with different biologi-
cally active substances combining to form a hybrid drug with improved
affinity and efficiency compared to the standard [19]. In recent years
heterocyclic compounds and their derivatives have attracted strong
attention due to their pharmacological and biological properties. Among
them, the 1,3,4-oxadiazole derivatives belong to a family of heterocycles
with promising pharmaceutical applications [20]. The literature reports
reveal that 1,3,4-oxadiazole derivatives show anti-hyperglycemic ac-
tivities [9,21–25]. In addition, Hamadani et al. have synthesized a
molecule containing three fluorine and thiol groups with 1,3,4-oxadia-
zole ring (2-(2-(trifluoromethyl)benzylthio)-5-(4-methoxyphenyl)-
A 500 ml three-necked round bottom flask placed 3 g of potassium
hydroxide, 58 ml methanol, and 12 g starting material compound 1c.
◦
The whole reaction mass allowed to cool to 10–15 C. Then stirred the
◦
reaction mass at 10–15 C for 10 min, further carbon disulfide 4.1 g
added slowly, dropwise over 10–20 min. Continue stirring the reaction
mass for 10 min at room temperature. The obtained reaction mass was
refluxed for 6–7 h, and the completion of the reaction was monitored by
TLC using mobile phase (Hexane: Ethyl acetate; 3:2). After completion
of the reaction, cool the reaction mass and dilute with cold water. Upon
acidification with concentrated HCl, a white color solid compound
precipitated out. This was filtered and washed with cold water, dried at
◦
55–60 C for 10 h.
2.3. 5-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-1,3,4-oxadiazole-2-thiol
derivatives (2b-2i)
In a 500 ml round bottom flask, placed compound 2a, dime-
thylformamide (DMF) (10 vol), anhydrous potassium carbonate (1.5
eq.), along with different benzyl halides (1.2 eq.) and stir the reaction
mixture at room temperature for 2 h. Completion of the reaction was
monitored by TLC using mobile phase Hexane: Ethyl acetate (3:2). Upon
completion of the reaction, the mixture is slowly quenched with water
and vigorous stirring. A solid compound that precipitates out is filtered,
1
,3,4-oxadiazole) that showed good -amylase inhibitory activity [26].
α
It has been reported that thiol-containing molecules act as an antioxi-
dant due to proton donating potential [21,27,28]. Therefore oxadiazole
ring with thiol group containing electron-withdrawing / donating
groups are the two major functional groups that can make it an antidi-
abetic and antioxidant drug candidate [29–33]. A series of bis-
heterocyclic compounds containing benzothiazole and 1,3,4-oxadiazole
derivatives have been synthesized by Bhutani et al. [36]. These syn-
thesized compounds have exhibited moderate to an excellent reduction
in blood glucose levels. Hence, these novel hybrid compounds are
considered as potential molecules to become leads for the establishment
of new oral drugs eliciting the anti-hyperglycemic effect [34]. 5-Benzyl-
◦
washed with cold water, and dried at 55–60 C for 10 h.
2.3.1. Synthesis of 5-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-1,3,4-
oxadiazole-2-thiol (2a)
Molecular weight
=
8 6 2 3
374, Molecular formula C12H F N O S,
◦
ꢀ 1
Yield:92%, Melting point:140–144 C; IR; 3064 cm (Aromatic
C H
– –
1
Str), HNMR (400 MHz, CDCl ): δ 2.18 (s,1H, SH),4.50(m,2H,O-
3
1
,3,4-oxadiazole-2-thiol derivatives were synthesized, and antidiabetic
CH ),4.42(m,2H,O-CH near to oxadiazole ring),7.44(d,1H)(J
1-2
3.2
2
2
activity was performed by using in vitro models [35]. The results indicate
moderate antidiabetic activity when compared to standard acarbose. A
novel 2-methyl-2-{5-(4-chlorophenyl)-1,3,4-oxadiazole-2ylthiol-acet-
Hz),7.19(dd,1H),(J1-3 9.2 Hz)(J2-4 9.2 Hz), 7.09(d,1H),(J1-2 9.2 Hz). All
three aromatic protons. EI-MS m/z (% Relative abundance):374.95
(M+1), (100).
amide derivatives were synthesized and few acted as
hibitors [36]. Bis-heterocycles containing oxadiazole-based thiazolidine
,4 diones derivatives showed an excellent in vivo antidiabetic activity
37].
The present study is focused on synthesis, characterization, and in
α-glucosidase in-
2.3.2. 2-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-5-(4-nitrobenzylthio)-
1,3,4-oxadiazole (2b)
2
[
Molecular weight
=
6 3 5
509, Molecular formula C19H13F N O S,
◦
1
Yield:81%, Melting point:133–135 C; HNMR (400 MHz, CDCl ): δ 4.57
3
vitro antidiabetic activity. Also, the antioxidant assay (refer supple-
mentary data) and molecular docking study of novel 1,3,4-oxadiazole
derivatives were performed. To test the antihyperglycemic effects,
(s,2H,S-CH ),4.39(m,2H,O-CH ),4.47(m,2H,O-CH near to oxadiazole
2
2
2
ring),7.09(d,1H),7.15(dd,1H),(J1-39.2 Hz, J2-49.2 Hz),7.58(d,1H,),(J1-2
2.8 Hz) 8.30(d,2H)(J1-2 8.4 Hz) 7.67(d,2H), all seven aromatic protons.
2