Synthesis of benzothiazole derivatives as a potent α-glucosidase inhibitor

Article abstract of DOI:10.1016/j.bioorg.2018.12.021

Diabetes is one of the pre-dominant metabolic disorders all over the world. It is the prime reason of mortality and morbidity due to hyperglycemia which is link with numerus obstacles. Delaying absorption and digestion of carbohydrate has great therapeutic impact for governing postprandial hyperglycemia. Consequently, alpha glucosidase is one of the potential therapeutic approaches that reduce absorption of glucose and delay carbohydrate digestion hence maintaining blood glucose level. In this regard we have synthesized benzothiazole based oxadiazole in search of potent anti-diabetic agent as α-glucosidase Inhibitors. Benzothiazole based oxadiazole derivatives 1–23 have been synthesized, characterized by ¹HNMR, ¹³CNMR, and MS and evaluated for α-glucosidase Inhibition. All analogs exhibited a varying degree of α-glucosidase inhibitory activity with IC₅₀ values ranging in between 0.5 ± 0.01–30.90 ± 0.70 μM when compared with the standard acarbose (IC₅₀ = 866.30 ± 3.20 μM). Structure activity relationship has been established for all compounds. Molecular docking studies were performed to predict the binding interaction of the compounds with the active site of enzyme.

Full text of DOI:10.1016/j.bioorg.2018.12.021

BioorganicChemistry85(2019)33–48
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis of benzothiazole derivatives as a potent α-glucosidase inhibitor
⁎
Mohammed Gollapallia, Muhammad Tahab, , Muhammad Tariq Javidc, Noor Barak Almandilb,
Fazal Rahimc, Abdul Wadoodd, Ashik Mosaddikb, Mohamed Ibrahimb, Mohammed A. Alqahtania,
Yasser A. Bamaroufa
a College of Computer Science & Information Technology (CCSIT), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia
b Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441,
Saudi Arabia
c Depatment of Chemistry, Hazara University, Mansehra-21300, Khyber Pakhtunkhwa, Pakistan
d Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
A R T I C L E I N F O
A B S T R A C T
Keywords:
Diabetes is one of the pre-dominant metabolic disorders all over the world. It is the prime reason of mortality and
morbidity due to hyperglycemia which is link with numerus obstacles. Delaying absorption and digestion of
carbohydrate has great therapeutic impact for governing postprandial hyperglycemia. Consequently, alpha
glucosidase is one of the potential therapeutic approaches that reduce absorption of glucose and delay carbo-
hydrate digestion hence maintaining blood glucose level. In this regard we have synthesized benzothiazole based
oxadiazole in search of potent anti-diabetic agent as α-glucosidase Inhibitors. Benzothiazole based oxadiazole
derivatives 1–23 have been synthesized, characterized by 1HNMR, 13CNMR, and MS and evaluated for α-glu-
cosidase Inhibition. All analogs exhibited a varying degree of α-glucosidase inhibitory activity with IC50 values
Benzothiazole
Oxadiazole
Synthesis
α-glucosidase inhibition
Molecular docking
ranging in between 0.5
(IC50 = 866.30
0.01–30.90
0.70 μM when compared with the standard acarbose
3.20 μM). Structure activity relationship has been established for all compounds. Molecular
docking studies were performed to predict the binding interaction of the compounds with the active site of
enzyme.
1. Introduction
discover new alpha glucosidase inhibitors. In this regard we have syn-
thesized benzothiazole based oxadiazole derivatives (see-Fig. 1.).
α-Glucosidase (EC 3.2.1.20) as a catabolic enzyme hydrolyzes car-
bohydrates to produce energy metabolic sugars essential for normal
physiological functions [1]. α-Glucosidase providing energy sources to
maintain healthy functioning. In contrast, glucose absorption in pa-
tients with type-2 diabetes can cause clinically serious problems be-
cause high activity of this enzyme increases plasma mellitus glucose
levels. Numerous reports address the relevance of α-glucosidase in-
hibition and the regulation of glucose levels in type-2diabetes mellitus
by α-glucosidase inhibitors [2–4]. Several types of α-glucosidase in-
hibitors have been clinically applied to inhibit α-glucosidase for med-
icinal purposes including acarbose, voglibose and miglitol [5–6]. In-
hibitors of this enzyme are designed to be orally taken, acting as an
anti-diabetic drug by preventing the digestion of carbohydrates and by
delaying the absorption of sugar. This allows plasma glucose to be
maintained at a steady level. However due to numerous side effects of
these drugs, medicinal chemists are continuously in struggles to
The benzothiazoles are heterocyclic compounds with diverse range
of biologically activity [7,8]. It shows numerous activities such as an-
timicrobial, antitumor, anti-inflammatory, antilieshmanial and anti-
fungal [9,10], anticancer [11], antidiabetic [12], anticonvulsant [13],
antiviral [14], antitubercular [15], antimalarial [16], antihelmintic
[17], analgesic [18] and fungicidal activities [19]. Recently, ben-
zothiazole derivatives have been evaluated as potential amyloid-
binding diagnostic agents in neurodegenerative disease [20]. The1,3,4-
oxadiazole constitute an important class of compounds in medicinal
and pharmaceutical chemistry. The compounds containing 1,3,4-ox-
adiazole nucleus possess a vast spectrum of biological activities [21].
Recently, differently substituted 1,3,4-oxadiazoles have been reported
for their biological activities, such as antibacterial [22], antifungal
[23], insecticidal [24] antiviral [25] inflammatory [26] antitubercular
[27] antitumoral [28], anticancer [29] and analgesic activity [30] (see-
Fig. 2.).
⁎ Corresponding author.
E-mail address: mtaha@iau.edu.sa (M. Taha).
https://doi.org/10.1016/j.bioorg.2018.12.021
Received 3 September 2018; Received in revised form 2 December 2018; Accepted 14 December 2018
Availableonline15December2018
0045-2068/©2018ElsevierInc.Allrightsreserved.

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
Table 1
Benzothiazole based oxadiazole analogs (1–23).
S. No.
1
R
S. No.
13
R
Fig. 1. Rational of the current study.
2
14
3
4
15
16
Fig. 2. Most potent analogs.
5
17
Our group has synthesized and screened benzothiazole esters and
hydrazide for α-glucosidase potential. These analogs were found to
have best activity [31]. Based on that, we have decided to synthesize
benzothiazole linked oxadiazole derivatives 1–23 for α-glucosidase
inhibition.
6
7
8
18
19
20
2. Experimental
2.1. Material and methods
Avance Bruker 500 MHz has been used for performing nuclear
magnetic resonance experiments. Carlo Erba Strumentazion-
Mod = 1106, Italy used for perofrming the lemental analysis. Finnigan
MAT-311A, Germany was used for recording Electron impact mass
spectra (EI-MS). Pre-coated silica gel aluminum plates (Kieselgel 60,
254, E. Merck, Germany) were used for performing Thin layer chro-
matography (TLC). UV at 254 and 365 nm were used for visualizing
Chromatograms (see-Table 1.).
9
21
2.2. General procedure
10
11
22
23
Methyl 4-formylbenzoate (41 mmol) and sodium metabisulfite
(41 mmol) was mixed in methanol and refluxed for 6 h at room tem-
perature to give us sodium hydroxy (4-(methoxycarbonyl)phenyl) me-
thane sulfonate intermediate (I). Then reaction mixture was poured into
ice water and the solid product was filtered. The progress of reaction
completion was checked by TLC. Compound (I) was then reacted with
2-amino-5-chlorobenzothiol in DMF (40 mL) and refluxed for 12 h to
give us methyl 4-(6-chlorobenzo[d]thiazol-2-yl) benzoate (II) which
was further mixed with hydrazine hydrate in methanol to form 4-(6-
chlorobenzo[d]thiazol-2-yl)benzo hydrazide (III). Compound (III) was
then reacted with different substituted aromatic carboxylic acids in
POCl3 to give us the desired benzothiazole based oxadiazole derivatives
1–23 in good yields. The synthetic compounds were fully characterized
by spectroscopy methods including 1H NMR, 13C NMR, HREI-MS.
12
136.7, 129.3, 129.1, 127.8, 127.8, 127.8, 127.8, 125.8, 125.4, 122.9,
120.6, 116.1, 116.1, 116.0, 116.0; HR-EI-MS: m/z calcd for
C21H12ClN3O2S, [M]+405.1438; Found 405.1436.
2.2.1. 4-(5-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-
yl)phenol
Yield: 81%;1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.92(d, J = 7.8 Hz, 2H, H-2′'/6″, Ar), 7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/
5′/6′, Ar), 7.68 (d, J = 7.5 Hz, 1H, H-4, Ar), 7.54 (d,J = 7.6 Hz, 1H, H-
5, Ar), 6.84 (d, J = 6.9 Hz, 2H, H-3″/5″, Ar), 5.34 (s, 1H, –OH); 13C
NMR (125 MHz, DMSO‑d6):δ 168.5, 164.1, 164.1, 158.0, 152.1, 142.7,
2.2.2. 4-(5-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-
yl)benzene-1,3-diol
Yield: 84%;1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.82(d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.68 (d, J = 7.5 1H, H-4,
Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5, Ar), 7.43 (d,J = 7.6 Hz, 1H, H-6′', Ar),
34

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
6.40 (d, J = 6.1 Hz, 1H, H-5′'Ar), 6.30 (s, 1H, H-3′', Ar), 5.34 (s, 2H,
–OH);13C NMR (125 MHz, DMSO‑d6):δ 168.6, 167.1, 164.2, 159.5,
156.4, 152.4, 143.1, 137.0, 130.1, 129.6, 127.8, 127.8, 127.8, 127.8,
126.0, 125.6, 122.9, 1210, 108.9, 105.4, 100.4; HR-EI-MS: m/z calcd
for C21H12ClN3O3S, [M]+421.1459; Found 421.1457.
Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5, Ar), 7.50 (d, J = 7.2 Hz, 1H, H-6″,
Ar), 7.11 (s, 1H, H-2″, Ar), 6.81 (d, J = 6.9 Hz, 1H, H-5″, Ar), 5.34 (s,
2H, –OH);13C NMR (125 MHz, DMSO‑d6): δ 168.5, 164.2, 164.3, 152.3,
147.1, 145.7, 143.1, 137.0, 129.6, 127.8, 127.8, 127.8, 127.8, 126.0,
125.6, 122.9, 121.0, 120.0, 116.0, 114.1, 108.7; HR-EI-MS: m/z calcd
for C21H12ClN3O3S, [M]+421.0135; Found 421.0132.
2.2.3. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-(3-nitrophenyl)-
1,3,4-oxadiazole
2.2.9. 2-(5-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-
yl)-5-methoxyphenol
Yield: 78%;1H NMR (500 MHz, DMSO‑d6):δ 8.63 (s, 1H, H-2″, Ar),
8.42(d, J = 8.8 Hz, 1H, H-6″, Ar), 8.18 (d, J = 7.8, 1H, H-4″, Ar), 8.10
(s, 1H, H-7, Ar), 7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.74 (t, 1H,
H-5″, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4, Ar), 7.54 (d, J = 7.6 Hz, 1H, H-
5, Ar); 13C NMR (125 MHz, DMSO‑d6): δ 168.7, 164.2, 164.2, 152.3,
148.5, 143.1, 137.0, 133.5, 130.0, 129.6, 127.8, 127.8, 127.8, 127.8,
126.9, 126.0, 125.6, 123.7, 122.9, 122.6, 121.0; HR-EI-MS: m/z calcd
for C21H11ClN4O3S, [M]+434.0448; Found 434.0445.
Yield: 78%; 1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.82(d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4,
Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5, Ar), 7.48 (d, J = 7.5 Hz, 1H, H-6″,
Ar), 6.57 (d, J = 6.8 Hz, 1H, H-5″, Ar), 6.56 (s, 1H, H-3″, Ar), 5.34 (s,
1H, –OH), 3.80 (s, 3H, –CH3);13C NMR (125 MHz, DMSO‑d6):δ 168.6,
167.1, 164.2, 161.8, 156.0, 152.3, 143.1, 137.0, 129.7, 129.6, 127.8,
127.8, 127.8, 127.8, 126.0, 125.6, 122.9, 121.0, 107.2, 104.0, 100.1,
55.6; HR-EI-MS: m/z calcd for C22H14ClN3O3S, [M]+435.1034; Found
435.1032.
2.2.4. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-(4-methoxyphenyl)-
1,3,4-oxadiazole
Yield: 75%;1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
8.00(d, J = 7.8, 2H, H-2″/6″, Ar), 7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/
6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4, Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5,
Ar), 7.02 (d, J = 7.3, 2H, H-3″/5″, Ar), 3.80 (s, 3H, –CH3);13C NMR
(125 MHz, DMSO‑d6):δ 168.6, 164.2, 164.2, 160.4, 152.3, 143.1, 137.0,
129.6, 128.8, 127.8, 127.8, 127.8, 127.8, 126.0, 125.6, 122.9, 121.0,
115.7, 115.7, 114.6, 114.6, 55.6; HR-EI-MS: m/z calcd for
C22H14ClN3O2S, [M]+419.0149; Found 419.0147.
2.2.10. 2-(5-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-
yl)-4-methoxyphenol
Yield: 76%; 1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4,
Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5, Ar), 7.15 (s, 1H, H-6″, Ar), 6.76 (d,
J = 6.8 Hz, 1H, H-3″, Ar), 6.75 (d, J = 6.8 Hz, 1H, H-4″, Ar), 5.34 (s,
1H, –OH), 3.80 (s, 3H, –OCH3);13C NMR (125 MHz, DMSO‑d6):δ 168.5,
167.2, 164.3, 153.5, 152.3, 149.5, 143.1, 137.0, 129.6, 127.8, 127.8,
127.8, 127.8, 126.0, 125.6, 122.9, 121.0, 117.2, 115.5, 113.0, 112.5,
55.6; HR-EI-MS: m/z calcd for C22H14ClN3O3S, [M]+435.1034; Found
435.1033.
2.2.5. 3-(5-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-
yl)phenol
Yield: 85%;1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H,H-4,
Ar), 7.59 (d, J = 7.6 Hz, 1H, H-6″, Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5,
Ar), 7.31 (t, 1H, H-5″, Ar), 7.30 (s, 1H, H-2″, Ar), 6.89 (d, J = 7.1 Hz,
1H, H-4″, Ar), 5.34 (s, 1H, –OH);13C NMR (125 MHz, DMSO‑d6):δ
168.8, 164.4, 164.4, 157.2, 152.3, 143.1, 137.0, 130.4, 129.6, 127.8,
127.8, 127.8, 127.8, 127.3, 126.0, 125.6, 122.9, 121.0, 120.0, 115.7,
112.8; HR-EI-MS: m/z calcd for C21H12ClN3O2S, [M]+405.1134; Found
405.1133.
2.2.11. 5-(5-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-
yl)-2-methoxyphenol
Yield: 74%; 1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4,
Ar), 7.56 (d, J = 7.5 Hz, 1H, H-6″, Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5,
Ar), 7.18 (s, 1H, H-2″, Ar), 6.85 (d, J = 7.0 Hz, 1H, H-5″, Ar), 5.34 (s,
1H, –OH), 3.80 (s, 3H, –OCH3);13C NMR (125 MHz, DMSO‑d6):δ 168.7,
164.2, 164.2, 152.3, 147.3, 147.2, 143.1, 137.0, 129.6, 127.8, 127.8,
127.8, 127.8, 126.0, 125.6, 122.9, 121.0, 120.0, 114.1, 111.2, 108.3,
55.8; HR-EI-MS: m/z calcd for C22H14ClN3O3S, [M]+ 435.0137; Found
435.0139.
2.2.6. 3-(5-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-
yl)benzene-1,2-diol
Yield: 86%; 1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.82(d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4,
Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5, Ar), 7.14 (d, J = 7.3 Hz, 1H, H-6″,
Ar), 6.89 (t, 1H, H-5″, Ar), 6.70 (d, J = 7.1 Hz, 1H, H-4″, Ar), 5.34 (s,
2H, –OH);13C NMR (125 MHz, DMSO‑d6): δ 168.7, 167.1, 164.3, 152.3,
145.4, 143.8, 143.1, 137.0, 130.5, 129.6, 127.8, 127.8, 127.8, 127.8,
126.0, 125.6, 123.0, 122.9, 121.0, 117.1, 113.2; HR-EI-MS: m/z calcd
for C21H12ClN3O3S, [M]+421.0241; Found 421.0240.
2.2.12. 2-(5-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-
yl)phenol
Yield: 78%; 1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4,
Ar), 7.60 (d, J = 7.7 Hz, 1H, H-6″, Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5,
Ar), 7.21 (t, 1H, H-4″, Ar), 7.04 (m, 1H, H-5″, Ar), 7.00 (d, J = 6.8 Hz,
1H, H-3″, Ar), 5.34 (s, 1H, –OH);13C NMR (125 MHz, DMSO‑d6):δ
168.6, 167.2, 164.2, 157.2, 152.3, 143.1, 137.0, 130.0, 129.6, 127.8,
127.8, 127.8, 127.8, 126.1, 126.0, 125.6, 122.9, 121.6, 121.0, 117.6,
107.8; HR-EI-MS: m/z calcd for C21H12ClN3O2S, [M]+405.0236; Found
405.0235.
2.2.7. 2-(5-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-
yl)benzene-1,4-diol
Yield: 85%; 1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.82(d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4,
Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5, Ar), 7.11 (s, 1H, H-6″, Ar), 6.87 (d,
J = 6.9 Hz, 1H, H-4″, Ar), 6.70 (d, J = 6.8 Hz, 1H, H-3″, Ar), 5.34 (s,
2H, –OH);13C NMR (125 MHz, DMSO‑d6):δ 168.6, 167.1, 164.2, 152.3,
150.0, 149.9, 143.1, 137.0, 129.6, 127.8, 127.8, 127.8, 127.8, 126.0,
125.6, 122.9, 121.0, 117.6, 117.1, 114.1, 113.3; HR-EI-MS: m/z calcd
for C21H12ClN3O3S, [M]+421.1309; Found 421.1310.
2.2.13. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-(2-nitrophenyl)-
1,3,4-oxadiazole
Yield: 76%; 1H NMR (500 MHz, DMSO‑d6): δ 8.10 (s, 1H, H-7, Ar),
8.02 (d, J = 8.2 Hz, 1H, H-6″, Ar), 8.00 (d, J = 8.1, 1H, H-3″, Ar), 7.88
(m, 1H, H-5″, Ar), 7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d,
J = 7.8 Hz, 1H, H-4, Ar), 7.65 (m, 1H, H-4″, Ar), 7.54 (d, J = 7.6 Hz,
1H, H-5, Ar);13C NMR (125 MHz, DMSO‑d6): δ 168.5, 164.3, 164.3,
152.3, 146.7, 143.1, 137.0, 135.1, 131.4, 129.6, 129.3, 128.2, 127.8,
127.8, 127.8, 127.8, 126.0, 125.6, 124.1, 122.9, 121.0; HR-EI-MS: m/z
calcd for C21H11ClN4O3S, [M]+434.0447; Found 434.0446.
2.2.8. 4-(5-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-
yl)benzene-1,2-diol
Yield: 82%; 1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.82(d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4,
35

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
2.2.14. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-(4-nitrophenyl)-
1,3,4-oxadiazole
2.2.20. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-(4-chlorophenyl)-
1,3,4-oxadiazole
Yield: 81%; 1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
8.30 (d, J = 8.4 Hz, 2H, H-3″/5″, Ar), 8.20 (d, J = 8.1, 2H, H-2″/6″,
Ar), 7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar),7.65 (m, 1H, H-4, Ar),
7.54 (d, J = 7.6 Hz, 1H, H-5, Ar);13C NMR (125 MHz, DMSO‑d6): δ
168.6, 164.1, 164.1, 152.3, 147.6, 143.1, 137.0, 132.0, 130.6, 130.6,
129.6, 128.6, 128.6, 127.8, 127.8, 127.8, 127.8, 126.9, 125.6, 122.9,
121.0; HR-EI-MS: m/z calcd for C21H11ClN4O3S, [M]+434.0448; Found
434.0446.
Yield: 75%; 1H NMR (500 MHz, DMSO‑d6): δ 8.10 (s, 1H, H-7, Ar),
7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.70 (d, J = 7.8 Hz, 2H, H-
2″/6″, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4, Ar), 7.54 (d, J = 7.6 Hz, 1H, H-
5, Ar), 7.52 (d, J = 7.6 Hz, 2H, H-3″/5″, Ar); 13C NMR (125 MHz,
DMSO‑d6):
δ 168.6, 164.2, 164.2, 152.3, 143.1, 137.0, 134.1,
129.6,129.0, 129.0, 128.7, 128.7, 127.8, 127.8, 127.8, 127.8, 126.0,
125.6, 124.0, 122.9, 121.0; HR-EI-MS: m/z calcd for C21H11Cl2N3OS,
[M]+423.0241; Found 423.0240.
2.2.15. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-o-tolyl-1,3,4-
oxadiazole
2.2.21. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-(pyridin-3-yl)-
1,3,4-oxadiazole
Yield: 78%; 1H NMR (500 MHz, DMSO‑d6):δ 8.10 (s, 1H, H-7, Ar),
7.82(d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-
6″, Ar), 7.65 (d, J = 7.4 Hz, 1H, H-4, Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5,
Ar), 7.30 (t, 1H, H-5″, Ar), 7.27 (t, 2H, H-3″/4″, Ar), 2.56 (s, 3H,
–CH3);13C NMR (125 MHz, DMSO‑d6): δ 168.5, 164.2, 164.2, 152.3,
143.1, 137.0, 137.0, 136.7, 129.6, 129.3, 128.3, 127.8, 127.8, 127.8,
127.8, 127.2, 126.1, 126.0, 125.6, 122.9, 121.0, 18.5; HR-EI-MS: m/z
calcd for C22H14ClN3OS, [M]+403.0136; Found 403.0135.
Yield: 77%; 1H NMR (500 MHz, DMSO‑d6): δ 9.21 (s, 1H, H-2″, Ar),
8.40 (d, J = 8.5 Hz, 1H, H-6″, Ar), 8.68 (d, J = 8.8 Hz, 1H, H-4″, Ar),
8.10 (s, 1H, H-7, Ar), 7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67
(d, J = 7.8 Hz, 1H, H-4, Ar), 7.55 (t, 1H, H-5″, Ar), 7.54 (d, J = 7.6 Hz,
1H, H-5, Ar); 13C NMR (125 MHz, DMSO‑d6): δ 168.6, 164.1, 164.1,
152.5, 152.3, 147.6, 143.1, 137.0, 133.8, 129.6, 127.8, 127.8, 127.8,
127.8, 126.0, 125.6, 124.1, 123.8, 122.9, 121.0; HR-EI-MS: m/z calcd
for C20H11ClN4OS, [M]+390.0140; Found 390.0138.
2.2.16. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-m-tolyl-1,3,4-
oxadiazole
2.2.22. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-(pyridin-4-yl)-
1,3,4-oxadiazole
Yield: 75%; 1H NMR (500 MHz, DMSO‑d6): δ 8.10 (s, 1H, H-7, Ar),
7.78 (s, 1H, H-2″, Ar), 7.84 (d, J = 7.9 Hz, 1H, H-6″, Ar), 7.82 (d,
J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4, Ar),
7.54 (d, J = 7.6 Hz, 1H, H-5, Ar), 7.37 (t, 1H, H-5″, Ar), 7.16 (d,
J = 7.2 Hz, 1H, H-3″, Ar), 2.32 (s, 3H, –CH3);13C NMR (125 MHz,
DMSO‑d6): δ 168.5, 164.1, 164.1, 152.3, 143.1, 138.6, 137.0, 130.2,
129.6, 128.9, 128.8, 127.8, 127.8, 127.8, 127.8, 126.0, 125.8, 125.6,
124.2, 122.9, 121.0, 21.4; HR-EI-MS: m/z calcd for C22H14ClN3OS,
[M]+403.01435; Found 403.01439.
Yield: 78%; 1H NMR (500 MHz, DMSO‑d6): δ 8.71 (d, J = 8.8 Hz,
2H, H-3″/5″, Ar), 8.10 (s, 1H, H-7, Ar), 7.97 (d, J = 8.1 Hz, 2H, H-2″/
6″, Ar), 7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz,
1H, H-4, Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5, Ar); 13C NMR (125 MHz,
DMSO‑d6): δ 168.5, 164.2, 164.2,152.3, 149.5, 149.5, 143.4, 143.1,
137.0, 129.6, 127.8, 127.8, 127.8, 127.8, 126.0, 125.6, 122.9, 121.1,
121.1, 121.0; HR-EI-MS: m/z calcd for C20H11ClN4OS, [M]+390.0142;
Found 390.0141.
2.2.17. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-p-tolyl-1,3,4-
oxadiazole
2.2.23. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-(pyridin-2-yl)-
1,3,4-oxadiazole
Yield: 76%; 1H NMR (500 MHz, DMSO‑d6): δ 8.10 (s, 1H, H-7,
Ar),7.92 (d, J = 7.9 Hz, 2H, H-2″/6″, Ar), 7.82 (d, J = 7.7 Hz, 4H, H-2′/
3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4, Ar), 7.54 (d, J = 7.6 Hz, 1H,
Yield: 76%; 1H NMR (500 MHz, DMSO‑d6): δ 8.57 (d, J = 8.6 Hz,
1H, H-3″, Ar), 8.10 (s, 1H, H-7, Ar), 8.00 (d, J = 8.2 Hz, 1H, H-6″, Ar),
7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.81 (d, J = 7.6 Hz, 1H, H-
5″, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4, Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5,
Ar), 7.34 (t, 1H, H-4″, Ar); 13C NMR (125 MHz, DMSO‑d6): δ 168.6,
164.1, 164.1, 157.2, 152.3, 149.0, 143.1, 137.0, 137.0, 129.6, 127.8,
127.8, 127.8, 127.8, 126.0, 125.6, 124.0, 123.2, 122.9, 121.0; HR-EI-
MS: m/z calcd for C20H11ClN4OS, [M]+390.0122; Found 390.0121.
H-5, Ar), 7.26 (d, J = 7.3 Hz, 2H, H-3″/5″, Ar), 2.32 (s, 3H, –CH3);13
C
NMR (125 MHz, DMSO‑d6): δ 168.4, 164.2, 164.2, 152.3, 143.1, 142.0,
137.0, 131.5, 129.6, 127.8, 127.8, 127.8, 127.8, 127.2, 127.2, 126.1,
126.1, 126.0, 125.6, 122.9, 121.0, 21.1; HR-EI-MS: m/z calcd for
C
22H14ClN3OS, [M]+403.0137; Found 403.0136.
2.2.18. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-(2-chlorophenyl)-
1,3,4-oxadiazole
2.3. α-Glucosidase inhibition assay
Yield: 72%; 1H NMR (500 MHz, DMSO‑d6): δ 8.10 (s, 1H, H-7, Ar),
7.82 (d, J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.70 (d, J = 7.8 Hz, 1H, H-
6″, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4, Ar), 7.54 (d, J = 7.6 Hz, 1H, H-5,
Ar), 7.52 (d, J = 7.5 Hz, 1H, H-3″, Ar), 7.37 (t, 1H, H-5″, Ar), 7.33 (t,
1H, H-4″, Ar);13C NMR (125 MHz, DMSO‑d6): δ 168.5, 164.2, 164.2,
152.3, 143.1, 137.0, 136.8, 132.0. 130.0, 129.6,129.1, 128.8, 127.8,
127.8, 127.8, 127.8, 127.1, 126.0, 125.6, 122.9, 121.0; HR-EI-MS: m/z
calcd for C21H11Cl2N3OS, [M]+423.0143; Found 423.0142.
Total volume of 100 μL reaction mixture contained 70 μL 50 mM
phosphate buffer pH 6.8, 10 μL test compound (0.5 mM in methanol)
followed by the addition of 10 μL enzyme solution (0.057 units, Sigma
Inc; “α-Glucosidase from Saccharomyces cerevisiae”) in the buffer. The
contents were mixed, pre-incubated for 10 min at 37 °C and pre-read at
400 nm. The reaction was initiated by the addition of 10 μL of 0.5 mM
substrate (p-nitrophenyl glucopyranoside, Sigma Inc.). After 30 min of
incubation at 37 °C, absorbance of p-nitrophenol released was measured
using Synergy HT 96-well plate reader, BioTek, USA. Acarbose was used
as positive control [32,33]. All experiments were carried out in tripli-
cates. The percent inhibition was calculated by the following equation:
2.2.19. 2-(4-(6-chlorobenzo[d]thiazol-2-yl)phenyl)-5-(3-chlorophenyl)-
1,3,4-oxadiazole
Yield: 74%; 1H NMR (500 MHz, DMSO‑d6): δ 8.10 (s, 1H, H-7, Ar),
8.00 (s, 1H, H-2″, Ar), 7.90 (d, J = 8.0 Hz, 1H, H-6″, Ar), 7.82 (d,
J = 7.7 Hz, 4H, H-2′/3′/5′/6′, Ar), 7.67 (d, J = 7.8 Hz, 1H, H-4, Ar),
7.54 (d, J = 7.6 Hz, 1H, H-5, Ar), 7.42 (t, 2H, H-4″/5″, Ar); 13C NMR
(125 MHz, DMSO‑d6): δ 168.5, 164.1, 164.1, 152.3, 143.1, 137.0,
134.6, 129.6,129.4, 128.6, 127.8, 127.8, 127.8, 127.8, 127.3, 127.2,
126.0, 125.6, 125.4, 122.9, 121.0; HR-EI-MS: m/z calcd for
Inhibition(%) = (Abs of Control - Abs of Test/Abs of Control) × 100
Active compound solutions were suitably diluted, and their inhibi-
tion studies were determined. Data obtained was used for the de-
termination of IC50 values (concentration at which there is 50% en-
zyme inhibition) using EZ-Fit Enzyme Kinetics Software (Perrella
Scientific Inc. Amherst, USA).
C
21H11Cl2N3OS, [M]+423.0122; Found 423.0120.
36

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
2.4. Molecular docking
Table 2
α-Glucosidase inhibitory potential of Benzothiazole Based oxadiazole.
To understand the binding interactions of the newly synthesized
Benzothiazole derivatives in the active site ofα-glucosidase, molecular
docking was performed using MOE-Dock program. The crystal structure
of α-glucosidase is not available yet, so, we used homology model as
described by Taha M et al [32]. The energy of the modelled protein
molecule was minimized after the 3D protonation using the default
parameters of MOE energy minimization algorithm (gradient: 0.05,
Force Field: Amber99). The three-dimensional coordinates of the Ben-
zothiazole derivatives were constructed using MOE. Then, the molecule
was energy minimized using the default parameters of MOE energy
minimization algorithm (gradient: 0.05, Force Field: Amber99). The
minimized molecule was saved in the mdb file format as input file. The
binding pocket of the enzyme was selected by the site finder, im-
plemented in MOE software. The compound was docked into the
binding pocket of α-glucosidase enzyme using default parameters of
MOE-Dock. The top ranked pose of each compound was selected on the
basis of docking score (S) for further analysis.
S.No.
IC50
SEMa
S. No.
IC50
SEMa
1
5.3
0.01
0.01
0.5
13
8.50
0.3
2
3.30
27.5
12.80
3.8
14
15.50
12.20
36.50
18.40
8.80
0.6
3
15
0.30
0.50
0.40
0.2
4
0.1
16
5
0.05
0.01
0.01
0.01
0.10
0.10
0.10
0.3
17
6
0.8 0
1.14
0.5
18
7
19
16.90
9.80
0.3
8
20
0.20
0.70
0.5
9
3.6
21
30.90
26.2
10
11
12
2.4
22
2.6
23
12.10
866.30
0.2
6.50
Acarbose
3.20
SEMa = standard mean error.
outstanding inhibitory potential with IC50 values 1(5.3
0.01),
2(3.30
0.01), 3(27.5
7(1.14
0.5), 4(12.80
0.01), 8(0.5
0.10), 12(6.50
0.1), 5(3.8
0.05), 6(0.8
0
0.01),
0.01),
9(3.6
0.10),
0.3),
10(2.4
14(15.50
0.40),
21(30.90
0.10), 11(2.6
0.6), 15(12.20
0.3), 13(8.50
3. Results and discussion
0.30), 16(36.50
0.50), 17(18.40
18(8.80
0.2),
19(16.90
0.3),
20(9.80
0.20),
3.1. Chemistry
0.70), 22(26.2
0.5) and 23(12.10
0.2) μM, respec-
tively when compared with the standard acarbose.
The synthesis of intermediate compounds II was carried out as re-
ported [12] from compound I. Compound II was then reacted with
diverse aromatic carboxylic acids in POCl3 to synthesize benzothiazole
derivatives 1–23 in good yields [32]. The synthetic compounds were
fully characterized by spectroscopy methods including 1H NMR, 13C
NMR, HR MS, of the synthesized compounds Scheme 1.
The structure activity relationship has been also established. The
SAR was mainly based upon by bringing about difference of sub-
stituents on phenyl ring. The compound 8, a 3,4-dihydroxy analog was
found to be the most potent among the series with (IC50 value
0.5
0.01 μM). If we compare it with other dihydroxy analogs like
compound 6 a 2,3-dihydroxy analog (IC50 value 0.80
7, a 2,5-dihydroxy analog (IC50 value 1.14 0.01 μM), and 2, a 2,4-
0.01 μM) and
dihydroxy analog (IC50 value 3.30
0.01 μM), the analog 8 is su-
perior. The little bit difference in their potential is seems to be due to
the difference in the position of hydroxyl groups on phenyl ring.
Similarly, if we compare mono-hydroxy analogs like
1
(IC50 = 5.3
0.01 μM)
5
(IC50 = 3.8
0.05 μM)
and
12
(IC50 = 6.50
0.3 μM), analog 5 was found to be more superior. This
3.2. α-Glucosidase inhibitory potential
higher potential indicates that hydroxyl group at meta position is more
favorable for inhibition. Comparing the hydroxyl methoxy analogs 9
To continue our research works on enzyme inhibition [34–41]. We
have synthesized benzothiazole based oxadiazole analogs (1–23) and
screened for α-Glucosidase inhibitory activity. All analogs have varied
degree of α-glucosidase inhibition with IC50 values ranging in between
(IC50 = 3.6
(IC50 = 2.6
0.10 μM), 10 (IC50 = 2.4
0.10 μM), and 11
0.10 μM), analog 10 was found more potent. This higher
inhibition is attributed to the position of hydroxyl and methoxy group
at ortho and meta position.
0.5
0.01–36.50
0.50 μM when compared with the standard acar-
By comparing analog o-methyl 15 (IC50 = 12.20
0.30 μM) with
0.50 μM) and 17, a p-methyl
0.40 μM), the analog 15 is superior. The reason for
greater potential is might be due position of methyl group on phenyl
ring. Comparing the chloro analogs 18 (IC50 = 8.80 0.2 μM), 19
(IC50 = 16.90 0.3 μM) and 20 (IC50 = 9.80 0.20 μM), analog 18
bose (IC50 = 866.30
3.20 μM) (Table 2.). All Compounds 1–20 showed
16, a m-methyl analog (IC50 = 36.50
(IC50 = 18.40
was found more superior. This greater potential indicate that chloro at
ortho position is more ideal for inhibition. Similar pattern was observed
by comparing analog 21, 22 and 23 having nitrogen is present at meta,
para and ortho position. It was concluded from this study that either
EWG or EDG on phenyl part showed potential but the slight difference
in potential was mainly affected by the position of the substituent as
well as in some cases the number of substituent also play a role. To
understand the binding interaction of the most active analogs molecular
docking study was performed.
3.3. Molecular docking
MOE-Dock module implemented in MOE program was utilized to
explore the binding conformations of the compounds within the active
site of α-glucosidase enzyme. The default parameters of MOE-Dock
program were used in the docking protocol. At the end of docking
Scheme 1. Synthesis of novel benzothiazole derivatives 1–23.
37

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
experiment, the best conformations based on docking score were ana-
lyzed for hydrogen bonding/arene-arene/arene-cation interactions.
From the docking calculation study, it was observed that the top ranked
conformations of almost all compounds were well accommodated in-
side the active site of α-glucosidase enzyme and were involved in
various type of interactions with the active site residues of α-
glucosidase enzyme. i.e., Lys 155, Leu 237, Glu 276, Phe 300, Phe 310,
Asp 347, Asp 349, Arg 439, etc. The detail of docking scores and in-
teractions for all compounds are listed in Table 3. The structural fea-
tures observed in this group for the active nature of compounds are the
presence of electron donating groups like –OH. Fig. 3 displays the in-
teraction modes of some most active compounds among these docked
Table 3
Docking scores and report of predicted interactions of docked conformations.
Compounds Docking
Interaction Report
score
1
-7.0065
Ligand Receptor
(kcal/mol)
Interaction Distance E
S9 12
S9 12
C15 21
6-ring
6-ring
6-ring
O
O
TRP 154
LYS 155
LYS 155
H-donor
H-donor
H-donor
pi-H
3.82
2.66 10.3
3.31 -0.6
3.77 -0.2
-1.7
O
CG LYS 155
CD ARG 312
6-ring PHE 300
pi-H
3.94
3.75
-0.2
-0.0
pi-pi
2
-7.8112
S9 12 OE1 GLU 304
C15 21 OE1 GLU 304
CL21 28 OH TYR 344
H-donor
H-donor
H-donor
H-donor
3.21
3.32
0.3
-0.4
3.40 -0.6
2.62 -2.6
-4.1
-0.7
-0.3
O28 38
N18 25 ND2 ASN 153
N18 25 PHE 157
O
PRO 309
H-acceptor 3.04
N
H-acceptor 3.53
H-acceptor 3.46
CL21 28 ND2 ASN 347
6-ring CG LYS 155
6-ring CG LYS 155
6-ring CE LYS 155
6-ring CD2 LEU 237
pi-H
pi-H
pi-H
pi-H
pi-H
pi-H
4.10
5.01
3.54
4.16
4.23
3.47
-0.4
-0.2
-0.3
-0.2
-1.1
-0.6
6-ring
N
ARG 312
5-ring CD ARG 312
S9 12 OE2 GLU 276
CL21 28 OD1 ASN 347
CL21 28 ND2 ASN 347
3
-5.5623
H-donor
H-donor
H-acceptor 4.33
3.96
-0.1
4.28
-0.0
-0.2
(continued on next page)
38

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
Table 3 (continued)
O29 40 CB GLN 238
O30 41 CB ASN 153
H-acceptor 3.30
H-acceptor 2.57
H-acceptor 3.09
-0.2
0.5
O30 41
6-ring
6-ring
5-ring
6-ring
5-ring
C6 8
S9 12
N
GLN 238
-1.1
CA LYS 155
CG LYS 155
CE LYS 155
CD ARG 312
CD ARG 312
OD1 ASN 153
pi-H
pi-H
4.05
4.24
4.62
4.24
4.53
-0.2
-0.3
-1.7
-0.9
-0.5
pi-H
pi-H
pi-H
4
-6.1002
H-donor
H-donor
H-donor
H-donor
pi-H
3.25
3.59
3.30 -0.5
3.02 0.2
-0.3
-0.7
-0.4
O
TRP 154
-0.5
C12 16 OE1 GLU 304
CL21 28
5-ring
6-ring
6-ring
5-ring
6-ring
5-ring
6-ring
O
SER 235
ND2 ASN 153
CG LYS 155
CE LYS 233
CA PHE 311
CD2 PHE 311
CD2 PHE 311
4.88
4.00
3.94
4.06
4.73
3.60
4.35
pi-H
pi-H
-0.2
-0.2
-0.3
-0.4
-0.4
pi-H
pi-H
pi-H
N
ARG 312
pi-H
5
-7.6914
C14 19 OE1 GLU 304
O28 39 OD2 ASP 349
N18 25 NH1 ARG 312
C6 8 5-ring HIS 239
H-donor
H-donor
3.27
2.62
-0.3
-1.9
H-acceptor 2.96
-3.8
H-pi
4.29
4.35
3.93
4.38
-0.2
5-ring
6-ring
5-ring
CG LYS 155
CE LYS 155
CD2 LEU 237
pi-H
pi-H
pi-H
-1.0
-0.2
-0.6
(continued on next page)
39

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
Table 3 (continued)
6-ring
5-ring
6-ring
6-ring
CD2 LEU 237
CG GLU 304
CA PRO 309
CD ARG 312
pi-H
pi-H
pi-H
pi-H
4.14 -0.6
3.54
4.09
4.44
-0.5
-0.2
-0.2
6
-8.4590
O28 38 OD2 ASP 349
O28 38 OD2 ASP 349
N18 25 NH1 ARG 312
H-acceptor 1.62 -4.0
H-donor 3.22 -3.0
H-acceptor 2.05 -6.3
O
NH LYS 155
CA LYS 155
CG LYS 155
CD1 LEU 237
CD2 LEU 237
CD2 LEU 237
CD ARG 312
H-donor
3.13
4.43
4.04
4.38
4.17
4.30
4.57
-0.3
5-ring
5-ring
5-ring
5-ring
6-ring
6-ring
pi-H
pi-H
pi-H
pi-H
pi-H
pi-H
-0.3
-0.3
-0.4
-0.4
-0.2
-0.3
7
-8.3401
O29 40 OE2 GLU 276
N18 25 NH1 ARG 312
O28 38 OD2 ASP 439
O29 40 NH LYS 155
H-donor
1.56
-3.6
-6.7
3.51 -6.0
H-acceptor 2.10
H-donor
H-acceptor 2.61
-0.3
5-ring
5-ring
6-ring
5-ring
CA LYS 155
CG LYS 155
CA LEU 237
CD2 LEU 237
pi-H
4.29
3.87
4.40
4.21
-0.3
pi-H
pi-H
pi-H
-0.7
-0.2
-0.4
-6.0
-1.2
H-acceptor 2.00 -2.3
H-acceptor 2.03 -1.3
8
-8.7654
O28 38 OD2 ASP 349
O29 40 OD2 ASP 349
N18 25 NH1 ARG 312
O28 38 ND2 ASN 347
H-donor
H-donor
1.21
1.61
(continued on next page)
40

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
Table 3 (continued)
O29 40 NH LYS 155
H-acceptor 3.41
-0.3
5-ring
5-ring
6-ring
6-ring
5-ring
6-ring
6-ring
CA LYS 155
CG LYS 155
CG LYS 155
CA LEU 237
CD2 LEU 237
CD2 LEU 237
CB PHE 300
pi-H
4.16
-0.2
pi-H
pi-H
3.86 -0.7
4.92
4.30
3.90
4.11
4.33
3.71
4.48
3.64
-0.2
-0.4
-0.3
-0.3
-0.3
0.1
pi-H
pi-H
pi-H
pi-H
6-ring 6-ring PHE 310
pi-pi
pi-H
6-ring
N
O
ARG 312
PHE 310
-0.8
0.1
9
-7.7645
S9 12
H-donor
C25 34 OE2 GLU 276
O28 38 OE2 GLU 276
N7 10 CA LYS 155
H-donor
H-donor
3.20
2.53
-0.3
-2.9
-0.4
H-acceptor 3.76
6-ring
6-ring
CG LYS 155
CB ASP 349
pi-H
pi-H
4.20
3.69
-0.3
-0.4
10
-8.0001
O29 40 NH LYS 155
H-acceptor 3.51
-0.3
6-ring
5-ring
CG LYS 155
CB PHE 300
pi-H
pi-H
4.20 -0.6
4.51 -0.4
N18 25 NH1 ARG 312 H-acceptor 3.60
-6.7
5-ring
6-ring
5-ring
6-ring
S9 12
CD ARG 312
CD ARG 312
pi-H
pi-H
3.96 -0.7
4.40 -0.2
4.12 -2.1
3.39 -0.0
NH1 ARG 312 pi-cation
6-ring PHE 300
TRP 154
pi-pi
11
-7.8832
O
H-donor
3.28
-0.1
C22 29 OE1 GLU 304
H-donor
3.31 -0.8
(continued on next page)
41

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
Table 3 (continued)
C22 29 OE2 GLU 304
O29 39 OE2 GLU 276
H-donor
H-donor
3.11
2.81
-0.4
-3.4
5-ring
6-ring
6-ring
5-ring
C3 4
CD2 LEU 237
CA PHE 311
pi-H
3.78
-0.8
pi-H
4.13 -0.9
N
ARG 312
pi-H
4.68
3.53
-0.4
-0.4
1.5
CB ARG 312
OE2 GLU 304
pi-H
12
-6.6783
H-donor
3.18
N17 24 CD2 PHE 311
N18 25 ND2 ASN 153
H-acceptor 2.80 67.3
H-acceptor 2.38 23.1
6-ring
6-ring
6-ring
6-ring
6-ring
6-ring
5-ring
C3 4
CG LYS 155
CE LYS 155
CA LEU 237
CA PHE 311
pi-H
pi-H
3.93
4.64
-1.0
-0.6
pi-H
4.87 -0.2
pi-H
4.48
3.94
4.27
-0.6
-2.1
-0.2
N
ARG 312
pi-H
CB ARG 312
CB ARG 312
OE2 GLU 304
pi-H
pi-H
4.22 -0.2
3.19 1.3
13
-6.5534
H-donor
N17 24 CD2 PHE 311
N18 25 ND2 ASN 153
O29 40 CG LYS 155
H-acceptor 2.77 77.9
H-acceptor 2.37 25.2
H-acceptor 2.68 354.1
6-ring
6-ring
6-ring
6-ring
6-ring
6-ring
CG LYS 155
CE LYS 155
CA LEU 237
CA PHE 311
pi-H
pi-H
pi-H
pi-H
pi-H
pi-H
3.93
4.66
4.88
-1.0
-0.6
-0.2
4.49 -0.6
N
ARG 312
3.94
4.27
-2.1
-0.2
CB ARG 312
(continued on next page)
42

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
Table 3 (continued)
5-ring
CB ARG 312
pi-H
4.21 -0.2
14
-6.2599
S9 12
C15 21
O
TRP 154
LYS 155
H-donor
H-donor
H-donor
2.97
2.91
1.6
O
-1.0
C22 29 OE1 GLU 304
O29 40 CG GLN 350
2.90
-1.5
-0.4
H-acceptor 2.81
pi-H 3.65 -0.3
5-ring
6-ring
6-ring
6-ring
5-ring
5-ring
CA LYS 155
CA LYS 155
CA PHE 311
pi-H
pi-H
pi-H
pi-H
pi-H
4.13
3.88
3.82
-0.2
-0.5
-0.5
N
ARG 312
CB ARG 312
CD ARG 312
3.99 -0.3
3.74 -0.2
15
-6.3409
S9 12 OE1 GLU 304
S9 12 OE2 GLU 304
H-donor
2.04 141.7
1.71 485.0
2.03 634.5
H-donor
H-donor
C22 29
O
PHE 310
N7 10 CE LYS 155
C24 33 6-ring PHE 157
H-acceptor 3.38
-0.3
-0.2
-0.0
6.7
H-pi
pi-pi
4.64
3.65
2.75
6-ring
S9 12
S9 12
6-ring PHE 311
16
-4.8923
O
O
TRP 154
LYS 155
H-donor
H-donor
H-donor
H-pi
2.41 31.1
1.90 17226.
C28 39 OE2 GLU 304
C12 16 6-ring TYR 313
4.50
4.12
-0.2
-0.3
6-ring
6-ring
5-ring
6-ring
5-ring
CA SER 156
CB PHE 157
CB PHE 157
CD2 PHE 300
CD ARG 312
pi-H
pi-H
4.69
4.30
4.56
3.58
-0.3
-0.9
-0.3
-1.3
pi-H
pi-H
pi-H
(continued on next page)
43

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
Table 3 (continued)
5-ring
S9 12
S9 12
6-ring PHE 311
pi-pi
H-donor
H-donor
H-pi
3.20
-0.0
17
-6.0010
O
O
TRP 154
LYS 155
2.60 13.1
2.61 12.6
C12 16 6-ring TYR 313
4.56
4.12
-0.2
-0.2
6-ring
6-ring
5-ring
5-ring
5-ring
6-ring
C3 4
C3 4
CA SER 156
CB PHE 157
CB PHE 157
CD ARG 312
6-ring PHE 311
6-ring PHE 311
OE1 GLU 304
OE2 GLU 304
pi-H
pi-H
4.77
4.20
3.63
3.27
3.99
-0.2
-0.7
-1.6
-0.0
-0.0
pi-H
pi-H
pi-pi
pi-pi
18
-8.6784
H-donor
H-donor
2.80 131.5
2.99 9.6
N17 24 CD2 PHE 311
N18 25 ND2 ASN 153
H-acceptor 2.87 69.0
H-acceptor 2.60 0.8
6-ring
6-ring
6-ring
6-ring
5-ring
6-ring
5-ring
CG LYS 155
CE LYS 155
CA PHE 311
pi-H
3.67
4.16
4.79
4.21
4.58
4.43
3.49
-0.2
pi-H
pi-H
pi-H
pi-H
pi-H
pi-H
-0.3
-0.4
-0.2
-0.3
-0.5
-0.2
N
ARG 312
CB ARG 312
CB ARG 312
CD ARG 312
19
-6.0112
S9 12 OE2 GLU 304
C14 19 PRO 309
H-donor
H-donor
H-donor
1.67 556.0
3.65 -0.2
4.14 -0.1
O
CL21 28 OE1 GLN 350
N7 10 CE LYS 155
H-acceptor 2.78
H-acceptor 3.97
-0.1
-0.2
CL28 39
N
PHE 157
(continued on next page)
44

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
Table 3 (continued)
6-ring
CD2 LEU 237
pi-H
4.40 -0.2
20
-7.9965
S9 12
C15 21
O
TRP 154
LYS 155
H-donor
H-donor
H-donor
H-donor
3.14
3.06
0.2
O
-1.0
C22 29 OE1 GLU 304
CL28 39 OD1 ASN 347
3.04
4.17
-0.3
-0.8
-0.1
5-ring
6-ring
6-ring
6-ring
6-ring
5-ring
5-ring
CA LYS 155
CA LYS 155
CA PHE 311
CD2 PHE 311
pi-H
pi-H
pi-H
pi-H
pi-H
pi-H
3.69
4.12
3.98
4.41
3.85
4.00
-0.2
-0.8
-0.3
-0.7
-0.2
-0.3
N
ARG 312
CB ARG 312
NH1 ARG 312
pi-cation 4.68
21
-5.3478
S9 12 OE1 GLU 304
S9 12 OE2 GLU 304
N7 10 CE LYS 155
N25 35 CB ASN 153
H-donor
H-donor
2.63 10.5
2.23 65.5
H-acceptor 3.06
H-acceptor 3.23
-0.8
-0.4
6-ring
CE LYS 155
pi-H
4.18
3.24
2.21 70.5
2.87 1.0
-0.4
-0.7
22
-5.8993
S9 12
S9 12
CL21 28
O
O
TRP 154
LYS 155
SER 235
H-donor
H-donor
H-donor
0.6
O
N24 33 CG GLN 350
H-acceptor 3.32
6-ring
5-ring
6-ring
6-ring
5-ring
CG LYS 155
NZ LYS 155
pi-H
4.16
-0.9
-2.2
-0.7
pi-cation 3.83
N
ARG 312
pi-H
pi-H
pi-pi
4.43
3.97
3.30
CB ARG 312
6-ring PHE 311
-0.2
-0.0
(continued on next page)
45

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
Table 3 (continued)
23
-6.4578
S9 12
S9 12
C15 21
6-ring
6-ring
6-ring
6-ring
5-ring
5-ring
O
O
TRP 154
LYS 155
LYS 155
H-donor
H-donor
H-donor
pi-H
3.22
2.73
3.15
-1.7
7.3
O
-0.9
-0.6
CE LYS 155
CA PHE 311
4.44
pi-H
4.57
4.05
4.46
4.34
3.42
-0.4
-0.8
-0.3
-0.3
-0.3
N
ARG 312
pi-H
CB ARG 312
CB ARG 312
CD ARG 312
pi-H
pi-H
pi-H
Standard
Acarbose
-5.2311
O
O
N
O
O
29 ND2 ASN 412
67 NZ LYS 155
58 OE1 GLU 276
H-acceptor 2.94
-2.6
H-acceptor 2.94 -1.7
ionic
2.71
2.76
-6.7
-2.9
67
O
ASP 349
H-donor
84 NH1 ARG 439
H-acceptor 2.75
0.4
conformations. The docking conformation of the most active compound
(compound 8) showed five hydrogen bonds and several hydrophobic
interactions with active site residues of the enzyme (Fig. 3A and
Table 3). The oxygen atoms of the hydroxyl moieties attached to the
phenyl ring of the compounds formed three hydrogen bonds with active
site residues Lys155, Arg312, Asn347 and Asp349 at distance of 3.4 Å,
2.0 Å, 2.0 Å, 1.2 Å and 1.6 Å respectively. Whereas the Glu276 and
Arg312 formed hydrogen bonds with the oxygen and nitrogen atoms of
the oxadiazole moiety of the compound at distance 3.4 Å and 2.0 Å
respectively. In case of second most active compound (compound 6),
four hydrogen bonds with active residues Lys155, Arg312 and Asp349
were observed (Fig. 3B and Table 3). Lys155 established hydrogen
bond with the oxygen atom and Arg312 formed hydrogen bond with
nitrogen atom of oxadiazole moiety and oxygen atom of hydroxyl
moiety of the compound at distances 3.1 Å, 2.0 Å and 3.2 Å respec-
tively. Whereas Asp349 formed hydrogen bond with oxygen atom of
hydroxyl moiety of compound with distance of 1.6 Å. In case of com-
pound 7, the third most active compound in the series, four hydrogen
bonds at distances 2.4, 1.6, 2.0 and 1.5 with active site residues Lys155,
Glu276, Arg312 and Asp349 respectively were observed (Fig. 3C and
Table 3). The docking conformation of compound 10, which is the
fourth most active compound in the series, showed only two hydrogen
bonds with active site residues (Fig. 3D and Table 3). In case of least
active compounds of the series (compound 16, 21 and 22), the docking
results showed that these compounds showed poor interaction with the
active site residues as compare to the most active compounds (com-
pound 6, 7, 8 and 10). As in shown in Table 3, the distances polar
interactions as well as bonding energies of least active compounds are
more as compare to the most active compounds (Table 3). This poor
interaction might be one of the reasons for least active compounds to
show less activities. In case of reference compound (Acarbose), the
docking results showed that the bonding distances of this compound are
more as compare to the most active compounds (Table 3). The reference
compound also showed less number of interactions as compare to the
interactions of the most active compounds. The larger bonding dis-
tances and less number of interactions with the active site residues
showed by the refence compound might be the reasons for less activity
showed by this compound. Overall the docking results showed that
compounds having more hydroxyl moieties showed good biological
activities and good interaction with active site residues as compare to
the compounds having less hydroxyl moieties. Furthermore, not only
the number but also the position of hydroxyl moieties might play a role
in the biological activities as well as binding mode of these compounds.
The correlation coefficient graph (Fig. 4) showed that a good correla-
tion between the docking scores and biological activities of compounds
exist.
4. Conclusion
Benzothiazole based oxadiazole derivatives (1–23) have been syn-
thesized and evaluated for α-glucosidase inhibitory potential.All deri-
vatives displayed potent α-glucosidase inhibitory potential ranging
between0.5
0.01–30.90
0.70 µM as a compare to acarbose. The
dihydroxy analogs were found to be the most potent among the series.
Molecular docking revealed that the top ranked conformations of al-
most all compounds were well accommodated inside the active site of
α-glucosidase enzyme and were involved in various types of interac-
tions with the active site residues of α-glucosidase enzyme.
46

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
Fig. 3. Docking conformations of compounds onα-glucosidase enzyme. A. 3D binding mode of compound 8 as inhibitor of α-glucosidase enzyme. B. 3D binding mode
of compound 6. C. 3Dbinding mode of compound 7. D. 3D binding mode of compound 10 in binding cavity of α-glucosidase enzyme. Ligands are shown green color.
Fig. 4. A correlation graph for predicted docking score and IC50 values.
Acknowledgment
development: magic molecules for the treatment of carbohydrate mediated dis-
eases, Mini Rev. Med. Chem. 12 (2012) 713–720.
[3] W. Benalla, S. Bellahcen, M. Bnouham, Antidiabetic medicinal plants as a source of
alpha glucosidase inhibitors, Curr. Diabetes Rev. 6 (2010) 247–254.
[4] R. Tundis, M.R. Loizzo, F. Menichini, Natural products as alpha-amylase andalpha-
glucosidase inhibitors and their hypoglycaemic potential in thetreatment of dia-
betes: an update, Mini Rev. Med. Chem. 10 (2010) 315–331.
Higher Education commission of Pakistan for financial support
under the National Research Program for Universities, project number
5721.
[5] K. Kaku, Efficacy of voglibose in type 2 diabetes, Expert Opin. Pharmacother. 15
(2014) 1181–1190.
References
[6] L.J. Scott, C.M. Spencer, Miglitol: a review of its therapeutic potential in type
2diabetes mellitus, Drugs 59 (2000) 521–549.
[1] S. Chiba, Molecular mechanism in alpha-glucosidase and glucoamylase, Biosci.
Biotechnol. Biochem. 61 (1997) 1233–1239.
[7] S.K. Yadav, S.M. Malipatil, S.K. Yadav, Synthesis and biological evaluation of
benzothiazole derivatives, Int. J. Drug Disc. Herbal Res. 1 (2011) 42–43.
[8] P.P. Prabhu, S. Pande, C.S. Shastry, Synthesis and biological evaluation of Schiff’s
[2] N.S. Moorthy, M.J. Ramos, P.A. Fernandes, Studies on alpha-glucosidase inhibitors
47

M. Gollapalli et al.
BioorganicChemistry85(2019)33–48
bases of some new benzothiazole derivatives as antimicrobial agents, Int. J. Chem.
[25] A.A. El-Emam, O.A. Al-Deeb, M. Al-Omar, Synthesis, antimicrobial, and anti-HIV-1
activity of certain 5-(1-adamantyl)-2-substituted thio-1,3,4-oxadiazoles and 5-(1-
adamantyl)-3-substituted aminomethyl-1,3,4-oxadiazoline-2-thiones, J. Bioorg.
Med. Chem. 12 (2004) 5107–5113.
Tech. Res. 3 (2011) 185–191.
[9] A. Latrofa, M.L.A. Franco, A. Rosato, D. Carone, C. Vitali, Structural modifications
and antimicrobial activity of N-cycloalkenyl- 2-acylalkylidene-2,3-dihydro-1,3-
benzothiazoles, II Framaco 60 (2005) 291–297.
[26] S. Bansal, M. Bala, S.S. Suthar, S. Choudhary, S. Bhattacharya, V. Bhardwaj,
S. Singla, A. Joseph, Design and synthesis of novel 2-phenyl-5-(1,3-diphenyl-1H-
pyrazol-4-yl)-1,3,4-oxadiazoles as selective COX-2 inhibitors with potent anti-in-
flammatory activity, Eur. J. Med. Chem. 80 (2014) 167–174.
[10] S.K. Sonwane, S.D. Srivastava, S.K. Srivastava, Synthesis and biological significance
of 4-oxothiazolidenes and 5-arylidenes of 2- mercaptobenzothiazole, J. Ind.
Council. Chem. 25 (2008) 15–19.
[11] S.T. Huang, I.J. Hsei, C. Chen, Synthesis and anticancer evaluation of bis(benzi-
midazoles), bis(benzoxazoles), and benzothiazoles, Bioorg. Med. Chem. 14 (2006)
6106–6119.
[27] S.G. Kucukguzel, E.E. Oruc, S. Rollas, F. Sahin, A. Ozbek, Synthesis, characteriza-
tion and biological activity of novel 4-thiazolidinones, 1,3,4-oxadiazoles and some
related compounds, Eur. J. Med. Chem. 37 (2002) 197–206.
[12] (a) S.R. Pattan, V.D. Ch Suresh, V.V.K. Pujar, V.P. Reddy, B.C Koti Rasal, Synthesis
and antidiabetic activity of 2-amino [50(4-sulphonylbenzylidene-2,4- thiazolide-
nedinone]-7-chloro-6-flourobenzothiazole, Ind. J. Chem. 44B (2005) 2404–2408;
(b) Z. Gong, Y. Peng, J. Qiu, A. Cao, G. Wang, Z. Peng, Synthesis, vitro α-gluco-
sidase inhibitory activity and molecular docking studies of novel benzothiazole-
triazole derivatives, Molecules 22 (2017) 1555;
[28] S. Bondock, S. Adel, H.A. Etman, F.A. Badria, Synthesis and antitumor evaluation of
some new 1,3,4-oxadiazole-based heterocycles, Eur. J. Med. Chem. 48 (2012)
192–199.
[29] N. Demirbas, A. Demirbas, S.A. Karaoglu, Synthesis and biological activities of new
1,2,4-triazol-3-one derivatives, Russ. J. Bioorg. Chem. 31 (2005) 387–397.
[30] A. Husain, M. Ajmal, Synthesis of novel 1,3,4-oxadiazole derivatives and their
biological properties, Acta Pharm. 59 (2009) 223–233.
(c) S. Shah, Arshia, K. Javaid, H. Zafar, K.M. Khan, R. Khalil, Z. Haq, S. Perveen,
M.I. Choudhary, Synthesis, and In vitro and in silico α-glucosidase inhibitory stu-
dies of 5-chloro-2-aryl benzo[d]thiazoles, Bioorg. Chem. 78 (2018) 269–279;
(d) N.V. Puranik, H.M. Puntambekar, P. Srivastava, Antidiabetic potential and
enzyme kinetics of benzothiazole derivatives and their non-bonded interactions
with a-glucosidase and a-amylase, Med. Chem. Res. 25 (2016) 805–816;
(e) E. Meltzer-Mats, G. Babai-Shani, L. Pasternak, N. Uritsky, T. Getter, O. Viskind,
J. Eckel, E. Cerasi, H. Senderowitz, S. Sasson, A. Gruzman, J. Med. Chem. 56 (2013)
5335–5350.
[31] M. Taha, N.H. Ismail, S. Lalani, M.Q. Fatmi, A. Wahab, S. Siddiqui, K.M. Khan,
S. Imran, M.I. Choudhary, Synthesis of novel inhibitors of a-glucosidase based on
the benzothiazole skeleton containing benzohydrazide moiety and their molecular
docking studies, Eur. J. Medi. Chem. 92 (2015) 387–400.
[32] E.P. Carreiro, P. Louro, G. Adriano, R.A. Guedes, N. Vannuchi, A.R. Costa,
C.M.M. Antunes, R.C. Guedes, A.J. Burke, 3-hydroxypyrrolidine and (3, 4)-dihy-
droxypyrrolidine derivatives: inhibition of rat intestinal α-glucosidase, Bioorg.
Chem. 54 (2014) 81–88.
[13] N. Siddiqui, S.N. Pandeya, S.A. Khau, J. Stables, A. Rana, M. Alam, F.Md. Arshad,
M.A. Bhat, Synthesis and anticonvulsant activity of sulfonamide derivatives hy-
drophobic domain, Bioorg. Med. Chem. 17 (2007) 255–259.
[33] K.M. Khan, F. Rahim, A. Wadood, N. Kosar, M. Taha, S. Lalani, A. Khan, M.I. Fakhri,
M. Junaid, W. Rehman, M. Khan, S. Perveen, M. Sajid, M.I. Choudhary, Synthesis
and molecular docking studies of potent α-glucosidase inhibitors based on biscou-
marin skeleton, Eur. J. Med. Chem. 81 (2014) 245–252.
[14] T. Akhtar, S. Hameed, N. Al-Masoudi, R. Loddo, P. Colla, In vitro antitumor and
antiviral activities of new benzothiazole and 1,3,4-oxadiazole-2-thione derivatives,
Acta Pharm. 58 (2008) 135–149.
[34] M. Taha, N.H. Ismail, S. Imran, A. Wadood, F. Rahim, M. Ali, A.U. Rehman, Novel
quinoline derivatives as potent in vitro α-glucosidase inhibitors: in silico studies
and SAR predictions, Med. Chem. Commun. 2015 (1826) 6.
[15] F.J. Palmer, R.B. Trigg, J.V. Warrington, Benzothiazolines as antituberculous agent,
J. Med. Chem. 14 (1971) 248–251.
[35] N.K.N.A. Zawawi, M. Taha, N. Ahmat, A. Wadood, N.H. Ismail, F. Rahim, S.S. Azam,
N. Abdullah, Benzimidazole derivatives as new α-glucosidase inhibitors and in si-
lico studies, Bioorg. Chem. 64 (2016) 29–36.
[16] A. Burger, S.N. Sawhey, I.I.I. Antimalarials, Benzothiazole amino alcohols, J. Med.
Chem. 11 (1968) 270–273.
[17] C.H. Suresh, J.V. Rao, K.N. Jayaveera, S.K. Subudhi, Synthesis and anthelmintic
activity of 3-(2-hydrozino benzothiazole)-substituted indole-2-one, Int J. Pharma. 2
(2013) 257–261.
[36] S. Imran, M. Taha, N.H. Ismail, S.M. Kashif, F. Rahim, W. Jamil, H. Wahab,
K.M. Khan, Synthesis, in-vitro, and docking studies of new flavone ethers as α-
glucosidase inhibitors, Chem. Biol. Drug. Des. 87 (2016) 361–373.
[37] M. Taha, N.H. Ismail, S. Imran, M.H. Mohamad, A. Wadood, F. Rahim, S.M. Saad,
A.U. Rehman, K.M. Khan, Synthesis, α-glucosidase inhibitory, cytotoxicity and
docking studies of 2-aryl-7-methylbenzimidazoles, Bioorg. Chem. 65 (2016)
100–109.
[18] N. Siddiqui, M. Alam, A.A. Siddiqui, Synthesis and analgesic activity of some 2-[{4-
(alkyl thioureido) phenyl} sulphonamido]-6-substituted benzothiazoles, Asian J.
Chem. 16 (2004) 1005–1008.
[19] S.P. Singh, S. Segal, Study of fungicidal activities of some benzothiazoles, Ind. J.
Chem. 27B (1988) 941–943.
[38] M. Taha, N.H. Ismail, S. Imran, A. Wadood, F. Rahim, S.M. Saad, K.M. Khan, A.
Nasir. Synthesis, Molecular Docking and α-Glucosidase Inhibition of 5-Aryl-2-(6’-
nitrobenzofuran-2’-yl)-1,3,4-oxadiazoles. 66 (2016) 117-123.
[20] G. Henriksen, A.I. Hauser, A.D. Westwell, B.H. Yousefi, M. Schwaiger, A. Drzega,
H.J. Wester, Metabolically stabilized benzothiazoles for imaging of amyloid pla-
ques, J. Med. Chem. 50 (2007) 1087–1089.
[39] F. Rahim, H. Ullah, M.T. Javid, A. Wadood, M. Taha, M. Ashraf, A. Shaukat,
M. Junaid, S. Hussain, W. Rehman, R. Mehmood, M. Sajid, M.N. Khan, K.M. Khan,
Synthesis, in vitro evaluation and molecular docking studies of thiazole derivatives
as new inhibitors of α-glucosidase, Bioorg. Chem. 62 (2015) 15–21.
[40] F. Rahim, F. Malik, H. Ullah, A. Wadood, F. Khan, M.T. Javid, M. Taha, W. Rehman,
A.U. Rehman, K.M. Khan, Isatin based Schiff bases as inhibitors of α-glucosidase:
Synthesis, characterization, in vitro evaluation and molecular docking studies,
Bioorg. Chem. 60 (2015) 42–48.
[21] A.S. Shawali, 1,3,4-Thiadiazoles of pharmacological interest: Recent trends in their
synthesis via tandem 1,3-dipolar cycloaddition: review, J. Adv. Res. 5 (2014) 1–17.
[22] N.N. Farshori, M.R. Banday, A. Ahmad, A.U. Khan, A. Rauf, Synthesis, character-
ization, and in vitro antimicrobial activities of 5-alkenyl/hydroxyalkenyl-2-pheny-
lamine-1,3,4-oxadiazoles and thiadiazoles, Bioorg. Med. Chem. Lett. 20 (2010)
1933–1938.
[23] Z.N. Cui, Y.X. Shi, L. Zhang, Y. Ling, B.J. Li, Y. Nishida, X.L.J. Yang, Synthesis and
fungicidal activity of novel 2, 5-disubstituted-1, 3, 4-oxadiazole derivatives, Agric.
Food Chem. 60 (2012) 11649–11656.
[41] K.M. Khan, F. Rahim, A. Wadood, N. Kosar, M. Taha, A. Khan, M.I. Fakhri,
M. Junaid, W. Rehman, M. Khan, S. Perveen, O. Abid, B. Mohammad, M. Sajid,
M.I. Choudhary, Synthesis and molecular docking studies of potentn α-glucosidase
inhibitors based on biscoumarin skeleton, Eur. J. Med. Chem. 81 (2014) 245–252.
[24] Y.H. Li, H.J. Zhu, K. Chen, R. Liu, A. Khalaf, X.N. Zhang, J.P. Ni, Synthesis, in-
secticidal activity, and structure–activity relationship (SAR) of anthranilic diamides
analogs containing oxadiazole rings, Org. Biomol. Chem. 11 (2013) 3979–3988.
48