New indole based hybrid oxadiazole scaffolds with N-substituted acetamides: As potent anti-diabetic agents

Article abstract of DOI:10.1016/j.bioorg.2018.08.010

Current study is based on the sequential conversion of indolyl butanoic acid (1) into ethyl indolyl butanoate (2), indolyl butanohydrazide (3), and 1,3,4-oxadiazole-2-thiol analogs (4) by adopting chemical transformations. In a parallel series of reaction

Full text of DOI:10.1016/j.bioorg.2018.08.010

Accepted Manuscript
New Indole Based Hybrid Oxadiazole Scaffolds with N-Substituted Acet-
amides: As Potent Anti-diabetic Agents
Majid Nazir, Muhammad Athar Abbasi, Aziz-ur-Rehman, Sabahat Zahra
Siddiqui, Khalid Mohammed Khan, Kanwal, Uzma Salar, Muhammad Shahid,
Muhammad Ashraf, Muhammad Arif Lodhi, Farman Ali Khan
PII:
S0045-2068(18)30633-3
DOI:
https://doi.org/10.1016/j.bioorg.2018.08.010
YBIOO 2467
Reference:
Bioorganic Chemistry
To appear in:
Please cite this article as: M. Nazir, M.A. Abbasi, Aziz-ur-Rehman, S.Z. Siddiqui, K.M. Khan, Kanwal, U. Salar,
M. Shahid, M. Ashraf, M. Arif Lodhi, F. Ali Khan, New Indole Based Hybrid Oxadiazole Scaffolds with N-
Substituted Acetamides: As Potent Anti-diabetic Agents, Bioorganic Chemistry (2018), doi: https://doi.org/10.1016/
j.bioorg.2018.08.010
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New Indole Based Hybrid Oxadiazole Scaffolds with N-Substituted Acetamides: As Potent
Anti-diabetic Agents
Majid Nazir,a Muhammad Athar Abbasi,a Aziz-ur-Rehman,a Sabahat Zahra Siddiqui,a Khalid
Mohammed Khan,b,f* Kanwal,b Uzma Salar,b Muhammad Shahid,c Muhammad Ashraf,d
Muhammad Arif Lodhi,e Farman Ali Khane
aDepartment of Chemistry, Government College University, Lahore-54000, Pakistan.
bH E J Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi-75270, Pakistan.
cDepartment of Biochemistry, University of Agriculture, Faisalabad-38040, Pakistan.
dDepartment of Chemistry, The Islamia University of Bahawalpur, Bahawalpur-63100, Pakistan,
eDepartment of Biochemistry, Abdul Wali Khan University, Mardan-23200, Pakistan.
fDepartment of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC),
Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia
Abstract: Current study is based on the sequential conversion of indolyl butanoic acid (1) into
ethyl indolyl butanoate (2), indolyl butanohydrazide (3), and 1,3,4-oxadiazole-2-thiol analogs (4)
by adopting chemical transformations. In a parallel series of reactions, 2-bromo-N-
phenyl/arylacetamides (7a-l) were synthesized by reacting different amines derivatives (5a-l)
with 2-bromoacetyl bromide (6) to serve as electrophile. Then, the synthesized electrophiles (7a-
l) were treated with nucleophilic 1,3,4-oxadiazole-2-thiol analog (4) to afford a range of N-
substituted derivatives (8a-l). The structural confirmation of all the synthetic compounds was
carried out by IR, 1H-, 13C-NMR, EI-MS, and CHN analysis data. All synthesized molecules (8a-
l) were tested for their antidiabetic potential via inhibition of theα-glucosidase enzyme followed
by their in silico study. Their cytotoxicity profile was also ascertained via hemolytic activity and
all of them possessed very low cytotoxicity. Compounds 8h and 8l were found most active
having IC50 values 9.46 ± 0.03 µM and 9.37 ± 0.03 µM, respectively. However, all other
molecules also exhibited good to moderate inhibition potential with IC50 values between 12.68 ±
0.04 - 37.82 ± 0.07, compared to standard acarbose (IC50 = 37.38 ± 0.12 µM), hence can be used
as lead molecules for further research in order to get better antidiabetic agents.
Keywords: Indole; oxadiazole; α-glucosidase; inhibitors; molecular docking; cytotoxicity
Corresponding Authors: Muhammad Athar Abbasi, E-mail: atrabbasi@yahoo.com; abbasi@gcu.edu.pk; Tel:
(+92)-42-111000010 (Ext. 266); Khalid M. Khan, E-mail: khalid.khan@iccs.edu; Tel: (+92)-21-34824910
1

Introduction
α-Glucosidase enzyme (EC 3.2.1.20) belongs to the hydrolase family, found in the brush border
surface membrane of small intestinal cells [1]. α-Glucosidase is one of the prime target for the
development of anti-diabetic drugs for the patients suffering from type-2 diabetic mellitus. It is a
fact that post-prandial hyperglycemia leads to the development of type-2 diabetes mellitus and
complications associated with it such as neuropathy, nephropathy, micro and macroangiopathies
[2].
Acarbose, voglibose, and miglitol are the α-glucosidase inhibitors which are being clinically
used to treat the patients of type-2 diabetic mellitus and also used as anticancer and anti-HIV
agents. Regrettably, some side effects such as diarrhea, abdominal discomfort, and flatulence are
also linked to them. That’s why, these clinical inhibitors are 50% less operative than other
antidiabetic agents including metformin and sulfonylurea. Consequently, these drugs oftenly use
in combination with other antidiabetic agents to improve the efficacy [3-9]. Identification of new
therapies with no or lesser risk of side effects for the cure of type-2 diabetic mellitus is an
appealing and interesting area of research for the medicinal chemist.
Indole is an aromatic heterocyclic compound, composed of a benzo-pyrrole scaffold in which the
benzene ring fused with the 2- and 3-positions of pyrrole ring. Indole exhibits a distinctive
reactivity and can be deprotonated at nitrogen of pyrrole ring. The resulting salts has proved to
be good nucleophiles. Indole ring is found in many fungal metabolites, indole alkaloids, and
marine natural products. Highly ionic salts (e.g. Li+, K+) favor the N-substitutions and softer
counter ions favor C-3 substitution [10]. Indole is a highly conserved heterocyclic aromatic
molecule, acts as a free radical scavenger. Indole analogs have a broad-spectrum of antioxidant
activities. It also play crucial roles in the biological systems in the form of amino acid, alkaloids,
and growth hormones. Many recent drugs used as antineoplastic, antihypertensive, and
antimitotic agents, have indole ring as core scaffold. These drugs also have utilization for the
treatment of chemotherapy-induced vomiting and nausea, and cluster headache [11-13].
1,3,4-Oxadiazole ring has a crucial important in heterocyclic chemistry and have extensive
utilization in organic synthesis [14,15]. 1,3,4-Oxadiazole containing compounds have been
gained considerable attention in pharmaceutical field due to their remarkable bioactivities. These
2

compounds are effectively being utilized as antibacterial agents, anticancer, anti-Parkinson, anti-
HIV, and anti-proliferative agents [16-21].
Our group has already reported lead compounds based on indole and oxadiazole scaffold as
potent α-glucosidase inhibitors [22-28]. It is noteworthy that hybrid scaffold of indole with
oxadiazole were also identified as significant inhibitors [25] (Figure-1). Therefore, we decided
to expand this study and further evaluate this class of compounds in order to get new and more
powerful inhibitors. In the present investigation, the designed hybrid molecules were screened to
explore their enzyme inhibitory potential against α-glucosidase enzyme. In silico studies were
also carried out to ascertain various kinds of interactions with active pocket of α-glucosidase
enzyme. Moreover, their cytotoxicity was also assessed to find their utility as possible drug
candidates in drug discovery and development.
Figure-1: Rationale of the current study
3

Results and Discussion
Chemistry
First, the indolyl butanoic acid (1) was esterified by ethanol in the presence of catalytic volume
of concentrated sulfuric acid. Ethanol was used as reactant and solvent in order to push the
equilibrium towards product side, as it was a reversible reaction. The product was collected by
solvent extraction after the addition of a weak base and excess of water. The base was added to
neutralize the catalytic sulfuric acid and the unreacted carboxylic acid. During solvent extraction,
salts of these acids were transferred to the aqueous layer while the resulted ester to the organic
phase. Thus, ethyl indolyl butanoate (2) was obtained as brownish liquid (solid at refrigeration).
The second step was performed to convert this ethyl ester to respective carbohydrazide (3), in the
presence of hydrazine hydrate in methanol under reflux for 14 h. Thus, indolyl butanohydrazide
(3) was obtained as a light brown solid. The third step was a cyclization to form heterocyclic ring
by reaction with CS2 in a basic alcoholic medium. The resulting product 1,3,4-oxadiazole-2-thiol
analog (4) have a mercapto group at its second carbon. In a parallel sequence of reactions,
different electrophiles were synthesized by reacting different amines derivatives (5a-l) with 2-
bromoacetyl bromide (6) to afford 2-bromo-N-phenyl/arylacetamides (7a-l). Finally, in the last
step, 1,3,4-oxadiazole-2-thiol analog (4) was reacted with the synthesized electrophiles (7a-l)
(one in each reaction), in the presence of LiH using aprotic polar medium to get required
derivatives (8a-l) (Scheme-1, Table-1).
Scheme-1: Reaction scheme for the synthesis of compounds (8a-l)
4

Spectral Studies of Representative Compound 8f
The molecule 8f was obtained as light yellow solid. Formation of the desired compound was
confirmed by molecular ion peak at m/z 450 in EI-MS spectrum. Further, structural confirmation
1
was done by H- and 13C-NMR. The CHN analysis data was also in agreement with the
calculated values. Different Functional groups in the molecule were depicted by absorption
bands in IR spectrum at υ3274 (str., N-H), 2953 (aromatic str., C-H), 1761 (C=O ester str.),
1671 (C=O amide str.), 1650 (C=N str.), 1590 (aromatic str., C=C), 1531, 1489, 1452 (str. for
oxadiazole), 1159 (str., C-O-C), 666 (str., C-S) cm-1.
1
In H-NMR spectrum, the most downfield signal was observed at δ 10.80 for NH of the indole
heterocyclic core. H-7 resonated at δ 7.48 as a doublet, showed ortho coupling (J = 7.8 Hz) with
H-6. Another doublet of H-4 was appeared at δ 7.34, showed ortho coupling (J = 8.0 Hz) with
H-5. A singlet for H-2 was resonated at δ 7.14. However, H-6 and H-5 resonated at δ 7.06 (J =
7.5 Hz) and δ 6.96 (J = 7.4 Hz), as triplets, respectively. Similarly, other aromatic protons also
resonated in the usual range such as H-6'''' and H-3'''' appeared at δ 8.24 (J = 8.3 Hz) and δ 7.91
(J = 7.8 Hz), as doublets, and showed ortho couplings with H-5'''' and H-4'''', respectively. The
remaining protons H-5'''' and H-4'''' also appeared as triplets at δ 7.61 (J = 7.8 Hz) and δ 7.22 (J
= 7.5 Hz), respectively. The OCH3-7'''' signal resonated as singlet at δ 3.80. The C- and N-
substituted acetamides group was identified by two signals at δ 11.06 and δ 4.28. In the up-field
region of spectrum, the signals of three intervening methylene groups were appeared including
CH2-1' and CH2-3' at δ 2.75 (J = 7.3 Hz) and δ 2.87 (J = 7.4 Hz), respectively, as triplet,
however, CH2-2' (J = 7.4 Hz) resonated at δ 2.04 as quintet (Figure-2A).
Figure-2: 1H- (A) and 13C-NMR (B) chemical shifts of compound 8f
5

The carbon skeleton of this molecule was also fully supported by its 13C-NMR spectrum
(Figure-2B). The 13C-NMR spectrum depicted the signals of all the twenty three carbons, where
the most downfield quaternary carbons signals at δ 165.42 (C-5'') and 162.19 (C-2'') belonged to
the cyclized 1,3,4-oxadiazole ring, thus confirming the formation of this ring. The other three
quaternary carbons appearing at δ 136.29 (C-8), 127.00 (C-9), and 113.23 (C-3) ppm, were
attribute of the indole core. The methine carbon resonances appeared at δ 122.46 (C-2), 120.85
(C-6), 118.17 (C-4), 118.15 (C-5), and 111.33 (C-7) were also coherent with the indole moiety.
The C and N-substituted acetamido group was confirmed by two discrete resonances, one for a
carbonyl group at δ 168.08 (C-1''') and other for a methylene group at δ 36.47 (C-2'''). The 2-
methoxycarbonylphenyl group attached with a nitrogen atom was thoroughly corroborated by
three quaternary signals at δ 167.25 (C-7''''), 138.89 (C-1''''), and 118.02 (C-2''''), four methine
signals at δ 133.96 (C-3''''), 130.57 (C-4''''), 123.77 (C-5''''), 121.23 (C-6''''), and a methoxyl
signal at δ 52.37 (C-8''''). In the up-field region of the spectrum, three signals at δ 26.5 (C-1'),
24.28 (C-3'), and 23.8 (C-2') were characteristic for three connected methylenes which were
joining the indole moiety with heterocyclic oxadiazole core in the molecule. So, on the basis of
aforesaid spectroscopic evidences, the structure of 8f was confirmed and named as 2-({5-[3-(1H-
indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}sulfanyl)-N-(2-methoxycarbonylphenyl) acetamide. A
similar approach was adopted for the complete structural characterization of other synthetic
derivatives.
Mass Spectrometry
The parent molecular ion observed at m/z 450 cleaved in three ways (A-C).
(A)
(B)
(C)
Molecular radical cation m/z 450 cleaved with the loss of an overall neutral 3-vinyl-1H-
indole molecule to give another radical cation at m/z 307.
Parent radical cation at m/z 450 was fragmented by the cleavage of a sigma bond to
afford 3-methylene-1H-indole cation at m/z 130.
At another sigma bond, the radical cation at m/z 450 was cleaved to afford a cation at m/z
144 which unexpectedly by the loss H-radical gave a radical cation at m/z 143, furnishing
the base peak. The key fragments are showed in Figure-3.
6

Figure-3: EI-MS key fragmentation pattern of compound 8f.
α-Glucosidase Inhibitory Activity
The synthetic molecules (8a-l) were screened against α-glucosidase enzyme and found to have
potent inhibitory potential against this enzyme, evident from their IC50 (M) values as compared
to the standard acarbose (Table-1). The compounds, 8l, 8h, 8c, 8e, 8d, and 8f showed excellent
inhibition with IC50 values of 9.37 ± 0.03, 9.46 ± 0.03, 12.68 ± 0.04, 14.35 ± 0.02, 21.49 ± 0.04,
and 21.64 ± 0.04 µM which were even lower and much better than the standard acarbose (IC50 of
37.38 ± 0.12 µM). Although the observed activity is the resultant of the whole molecules, but a
limited structure-activity relationship (SAR) was rationalized by analyzing the effect of different
“R” group on the inhibitory potential.
7

Table-1: α-Glucosidase inhibition studies and cytotoxic potential through hemolytic activity
of synthetic derivatives (8a-l).
α-Glucosidase Inhibition
Compounds
-R
Hemolysis
Inhibition (%)
at 0.5 mM
IC50 (μM) ± SEMa
92.37 ± 0.12
36.57 ± 0.09
8.95
8a
-
-
5.26
8b
94.47 ± 0.12
95.27 ± 0.12
94.86 ± 0.13
12.68 ± 0.04
21.49 ± 0.06
14.35 ± 0.02
6.42
7.47
7.89
8c
8d
8e
93.67 ± 0.14
92.83 ± 0.15
93.67 ± 0.11
21.64 ± 0.04
35.62 ± 0.04
9.46 ± 0.03
7.47
6.84
8.95
8f
8g
8h
92.74 ± 0.12
92.48 ± 0.14
35.53 ± 0.04
37.82 ± 0.07
9.47
7.68
8i
8j
8

92.38 ± 0.12
94.74 ± 0.11
35.27 ± 0.02
9.37 ± 0.03
9.68
8k
8l
10.95
Triton X =
89.00
PBS Hemolysis
(%) = 1.03
Acarbose
92.23 ± 0.16
Acarbose
37.38 ± 0.12
Standards
(Mean ± SEM a (Standard error mean), n = 3). Compound 8b was not assayed.
Structure-Activity Relationship (SAR)
Compound 8a (IC50 = 36.57 ± 0.09 µM) having unsubstituted phenyl ring showed comparable
activity with the standard acarbose (IC50 = 37.38 ± 0.12 µM). Compound 8k (IC50 = 35.27 ± 0.02
µM) possessing an ethyl benzene ring also showed the similar activity as compared to compound
8a which showed that phenyl ring either attached directly to nitrogen or separated through an
additional ethyl group behave almost similarly with the active site of enzyme. However,
compound 8l bearing the methyl substituted pyridine ring showed excellent inhibitory potential
and was found to be most active among all synthetic derivatives having (IC50 = 9.37 ± 0.03 µM)
this may be due to the interaction of methyl substituted pyridine ring with the active site of
enzyme (Figure-4).
Figure-4: Structure-activity relationship of compounds 8a, 8k, and 8l
Compound 8g (IC50 = 35.62 ± 0.04 µM) with methyl group at ortho position showed comparable
activity with that of standard. Interestingly, the activity of compound 8c (IC50 = 12.68 ± 0.04
µM) was increased up to three folds when methyl group was replaced with ethyl. It means that
ethyl group at para position is more efficiently interacting with enzyme as compared to methyl
9

group at ortho position. However, compound 8f (IC50 = 21.64 ± 0.04 µM) with methyl ester
group at ortho position showed better potential then 8g might be due to the interaction of
carbonyl group with the enzyme (Figure-5).
Figure-5: Structure-activity relationship of compounds 8g, 8c, and 8f
Among dimethyl substituted derivatives, compound 8h (IC50 = 9.46 ± 0.03 µM) with two methyl
groups adjacent to each other was the second most active compound of the series. However,
shifting the positions of methyl groups resulted in decreased activity in structurally similar
analogues 8i and 8j having (IC50 = 35.53 ± 0.04 µM) and (IC50 = 37.82 ± 0.07 µM), respectively
(Figure-6).
Figure-6: Structure-activity relationship of compounds 8h, 8i, and 8j
Compounds 8d (IC50 = 14.35 ± 0.02 µM) and 8e (IC50 = 21.49 ± 0.06 µM) with ethoxy groups at
ortho and para positions, respectively, showed potent inhibitory activity. Compound 8e with
ethoxy group at para position had greater activity as compared to the standard, however, a
decrease in the activity was observed when the position of ethoxy was shifted from para to ortho
in 8d may be due to the increased steric factors (Figure-7).
10

Figure-7: Structure-activity relationship of compounds 8d and 8e
All the synthesized compounds 8a-l, were also subjected to hemolytic assay to find out their
cytotoxicity profile. Results of percentage hemolysis (%) are shown in Table-1. Our results
showed that all compounds of this series have low toxicity towards red blood cell membrane.
Maximum membrane toxicity was shown by the compound 8l (10.95%) while minimum toxicity
was recorded in 8b (5.26%). Precisely, a low toxicity was observed for molecule 8c (6.42%), 8g
(6.84%), 8d (7.47%), 8f (7.47%), 8j (6.68%), 8e (6.89%), 8a (8.95%), 8h (8.95%), 8i (9.47%),
and 8k (9.68%) relative to Triton-X having % hemolysis of 89.00 (%).
Molecular Docking Studies
It was also cleared from the molecular docking results that compound 8h was strongly bound in
the active site of enzyme by making very strong polar and acidic interactions with Asp73 and
Arg404 through its indolic-NH proton and carbonyl oxygen of acetamidic moiety. The estimated
bond lengths were 1.80 and 2.01 angstroms, respectively (Figure-8A and -8B). From the
Figure-9 (A and B), it was rationalized that strong acidic and polar interactions were established
among Asp420, Lys422 and carbonyl oxygen of acetamidic moiety and indolic-NH proton of
ligand 8l at bond distances of 2.15Å and 2.25Å respectively. A weak arene-cation interaction
was also found between Arg404 and oxadiazole ring of the same ligand showing an average
bond length of 3.80Å.
11

Figure-8 (A): 2D interacted image of α- Figure-8 (B): 3D interacted image of α-
glucosidase with the docked ligand, 8h, after glucosidase with the docked ligand, 8h, after
docking.
docking.
Figure-9 (A): 2D interacted image of α- Figure-9 (B): 3D interacted image of α-
glucosidase with the docked ligand, 8l, after glucosidase with the docked ligand, 8l, after
docking.
docking.
Conclusion
The targeted indole based hybrid oxadiazole scaffolds with N-substituted acetamides (8a-l) were
synthesized in good yields and all these molecules exhibited potent inhibition of yeast
-
glucosidase enzyme with IC50 even lower than that of the standard. The enzyme inhibitory data
was also in agreement with the in silico study of these molecules. Furthermore, all molecules
12

encompassed low cytotoxicity. Therefore, it was concluded from the present study that these
molecules might serve as potent anti-diabetic agents.
Experimental
Materials and Methods
All the chemicals, along with analytical grade solvents, were purchased from Sigma Aldrich,
Alfa Aesar (Germany), or Merck through local suppliers. Pre-coated silica gel Al-plates were
used for TLC with ethyl acetate and n-hexane as solvent system (30:70). Spots were detected by
UV254. Gallonkamp apparatus was used to measure melting points (uncorrected) in capillary
tubes. IR spectra (ν, cm–1) were recorded by KBr pellet method in the Jasco-320-A
1
spectrophotometer. H-NMR spectra (δ, ppm) were recorded at 600 MHz (13C-NMR spectra, at
150 MHz) in DMSO-d6 using the Bruker Advance III 600 As-cend spectrometer using BBO
probe. Elemental analyses were performed on a Foss Heraeus CHN-O-Rapid instrument and
were within ± 0.4% of the theoretical values. EI-MS spectra were measured on a JEOL JMS-
600H instrument with data processing system. The coupling constant (J) is given in Hz and
1
chemical shift ( ) in ppm. The abbreviations used in interpretation of H NMR spectra are as
follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; br.t, broad triplet; q, quartet;
quint, quintet; sex, sextet; sep, septet; m, multiplet; dist., distorted.
Synthesis of ethyl 4-(1H-indol-3-yl)butanoate (2)
4-(1H-Indol-3-yl)butanoic acid (0.2 mol; 1) was dissolved in absolute ethanol (70 mL) taken in a
500 mL round-bottomed flask. Catalytic volume of conc. sulfuric acid (20 mL) was added into it
and refluxed for 8 h. Maximum completion of reaction was monitored through TLC analysis.
After completion, reaction mixture was neutralized with 10% aqueous sodium carbonate (40
mL). The product was isolated by solvent extraction by chloroform (50 mL × 3). The solvent was
distilled off and the required ester (2) was obtained as reddish brown liquid. 1H-NMR (600 MHz,
DMSO-d6, δ/ppm): 10.76 (s, 1H, NH-1), 7.49 (d, J7,6 = 7.8 Hz, 1H, H-7), 7.32 (d, J4,5 = 8.1 Hz,
1H, H-4), 7.10 (d, J2,NH = 1.8 Hz, 1H, H-2), 7.05 (dt, J6,4 = 1.0 Hz, J6,5/6,7 = 8.0 Hz, 1H, H-6),
6.96 (dt, J5,7 = 0.9 Hz, J5,4/5,6 = 7.8 Hz, 1H, H-5), 4.04 (q, J1ʺ,2ʺ = 7.1 Hz, 2H, OCH2-1''), 2.69 (t,
J3ʹ,2ʹ = 7.6 Hz, 2H, CH2-3'), 2.33 (t, J1ʹ,2ʹ = 7.6 Hz, 2H, CH2-1'), 1.89 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.5 Hz,
2H, CH2-2'), 1.16 (t, J2ʺ,1ʺ = 7.1 Hz, 3H, OCH2CH3-2''); 13C-NMR (150 MHz, DMSO-d6, δ/ppm):
13

172.8 (C-4'), 136.2 (C-8), 127.0 (C-9), 122.3 (C-2), 120.7 (C-6), 118.1 (C-7), 118.0 (C-5), 113.6
(C-3), 111.3 (C-4), 59.6 (C-1''), 32.9 (C-2'), 25.3 (C-4'), 23.9 (C-3'), 14.0 (C-2'').
Synthesis of 4-(1H-indol-3-yl)butanehydrazide (3)
4-(1H-Indol-3-yl)butanoate (0.15 mol; 2) and hydrazine monohydrate (80%; 25 mL) in 60 mL
methanol were taken in a 500 mL round-bottommed flask. The reaction mixture was stirred for
14 h at room temperature (RT). After completion, the acid hydrazide was obtained by distilling
methanol off from the reaction mixture. The precipitates were filtered, washed with cold n-
1
hexane, and air-dried to get pure 4-(1H-indol-3-yl)butanohydrazide (3). H-NMR (600 MHz,
DMSO-d6, δ/ppm): 10.70 (s, 1H, NH-1), 9.90 (s, 1H, CONH), 8.96 (s, 2H, CONH-NH2), 7.49 (d,
J7,6 = 7.5 Hz, 1H, H-7), 7.32 (d, J4,5 = 8.0 Hz, 1H, H-4), 7.09 (s, 1H, H-2), 7.05 (t, J6,5/6,7 = 7.6
Hz, 1H, H-6), 6.95 (t, J5,4/5,6 = 7.3 Hz, 1H, H-5), 2.65 (t, J3ʹ,2ʹ = 7.6 Hz, 2H, CH2-3'), 2.08 (t, J1ʹ,2ʹ
13
= 7.4 Hz, 2H, CH2-1'), 1.86 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.5 Hz, 2H, CH2-2'); C-NMR (150 MHz,
DMSO-d6, δ/ppm): 171.5 (C-1'), 136.2 (C-8), 127.1 (C-9), 122.1 (C-2), 120.7 (C-6), 118.2 (C-7),
118.0 (C-5), 114.0 (C-3), 111.2 (C-4), 33.2 (C-2'), 26.0 (C-4'), 24.3 (C-3').
Synthesis of 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazole-2-thiol (4)
4-(1H-Indol-3-yl)butanehydrazide (0.13 mol; 3) and KOH (0.13 mol) in absolute ethanol (30
mL) were taken in a round-bottomed flask. Carbon disulfide (0.26 mol.) was added
subsequently. Mixture was refluxed for 16 h. On completion of the reaction, excess chilled
distilled water and dil. HCl was added to adjust pH 5-6. The precipitates were filtered, washed,
1
and dried to get desired cyclized product (4). H-NMR (600 MHz, DMSO-d6, δ/ppm): 10.80 (s,
1H, NH-1), 7.52 (d, J7,6 = 7.8 Hz, 1H, H-7), 7.35 (d, J4,5 = 8.1 Hz, 1H, H-4), 7.15 (d, J2,NH = 1.9
Hz, 1H, H-2), 7.07 (t, J6,5/6,7 = 7.3 Hz, 1H, H-6), 6.98 (t, J5,4/5,6 = 7.2 Hz, 1H, H-5), 2.79 (t, J3ʹ,2ʹ
= 7.4 Hz, 2H, CH2-3'), 2.76 (t, J1ʹ,2ʹ = 7.4 Hz, 2H, CH2-1'), 2.02 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.3 Hz, 2H,
CH2-2'); 13C-NMR (150 MHz, DMSO-d6, δ/ppm): 177.7 (C-2''), 164.1 (C-5''), 136.3 (C-8), 127.0
(C-9), 122.4 (C-2), 120.8 (C-6), 118.1 (C-7), 118.0 (C-5), 113.2 (C-3), 111.3 (C-4), 25.8 (C-1'),
24.5 (C-3'), 23.7 (C-2').
14

Preparation of 2-bromo-N-(un/substituted-phenyl)acetamides (7a-l)
Preparation of various 2-bromo-phenyl/arylacetamides (7a-l) was carried out by reaction of
various aryl/alkyl amines (5a-l) with 2-bromoacetyl bromide (6) in equimolar quantities (0.001
mol) and shaking manually in 10% aqueous Na2CO3 solution. Solid precipitates were formed
after 20-30 min, which were filtered and washed with cold distilled water to obtain the desired
electrophiles (7a-l).
Synthesis of 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazole-2-thiol derivatives (8a-l)
5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazole-2-thiol (0.2 g, 4) was dissolved in DMF (5 mL)
contained in a 250 mL round-bottommed flask at room temperature, added one pinch of LiH and
stirred for 30 min. Then different 2-bromo-N-(un/substituted-phenyl)acetamides (7a-l) were
added in equimolar amounts separately in each respective reaction and stirred for 6-8 h. The
completion of the reaction was monitored by TLC and after its completion; the reaction mixture
was quenched with ice cold water (100 mL). The respective derivatives (8a-l) were collected
through filtration or solvent extraction according to nature of the product.
2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-phenylacetamide (8a)
Yellow colored amorphous powder; Yield: 72%; Melting Point 141-143 ˚C; Mol. Formula:
C21H20N4SO2; Mol. Weight: 392 g/mol; IR (KBr, cm-1): υ 3310 (N-H str.), 2955 (C-H AR-
aromatic str.), 1674 (C=O str.), 1643 (C=N str.), 1595 (C=C aromatic str.), 1525, 1481, 1445
1
(Str. for Oxadiazole), 1151 (C-O-C str.), 685 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6,
δ/ppm): 10.80 (s, 1H, NH-1), 10.38 (s, 1H, CONH), 7.51 (d, J7,6 = 7.8 Hz, 1H, H-7), 7.57 (d,
J2ʹʹʹʹ,3ʹʹʹʹ = J6ʹʹʹʹ,5ʹʹʹʹ = 7.8 Hz, 2H, H-2'''' and 6''''), 7.34 (d, J4,5 = 8.1 Hz, 1H, H-4), 7.32 (t, J3ʹʹʹʹ,2ʹʹʹʹ
=
J5ʹʹʹʹ,6ʹʹʹʹ = 7.7 Hz, 2H, H-3'''' and 5''''), 7.13 (s, 1H, H-2), 7.09-7.05 (m, 2H, H-6 and H-4''''), 6.97 (t,
J5,4/5,6 = 7.8 Hz, 1H, H-5), 4.25 (s, 2H, CH2-2'''), 2.87 (t, J3ʹ,2ʹ = 7.4 Hz, 2H, CH2-3'), 2.76 (t, J1ʹ,2ʹ
13
= 7.3 Hz, 2H, CH2-1'), 2.04 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.4 Hz, 2H, CH2-2'); C-NMR (150 MHz,
DMSO-d6, δ/ppm): 167.9 (C-1'''), 164.8 (C-5''), 162.5 (C-2''), 138.6 (C-1''''), 136.2 (C-8), 128.8
(C-3'''' and 5''''), 127.0 (C-9), 123.6 (C-4''''), 122.4 (C-2), 120.8 (C-6), 119.1 (C-2'''' and 6''''),
118.2 (C-7), 118.1 (C-5), 113.2 (C-3), 111.3 (C-4), 36.7 (C-2'''), 26.5 (C-1'), 24.2 (C-3'), 23.7 (C-
2'); Anal. Calc. for C21H20N4SO2 (392.13): C, 64.27; H, 5.14; N, 14.28. Found: C, 64.25; H,
15

5.12; N, 14.26; EI-MS m/z (% rel. abund.): 392 (M+, 49) 318 (20), 249 (96), 207 (70), 200 (7),
186 (18), 175 (100), 156 (9), 143 (79), 130 (71), 93 (15), 77 (18).
2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-(2-ethyl-6-
methylphenyl)acetamide (8b)
Light yellow colored amorphous powder; Yield: 91%; Melting Point 127-129 ˚C; Mol. Formula:
C24H26N4SO2; Mol. Weight: 434 g/mol; IR (KBr, cm-1): υ 3286 (N-H str.), 2945 (C-H aromatic
str.), 1672 (C=O str.), 1644 (C=N str.), 1599 (C=C aromatic str.), 1517, 1478, 1441 (Str. for
1
Oxadiazole), 1159 (C-O-C str.), 689 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6, δ/ppm):
10.80 (s, 1H, NH-1), 9.65 (s, 1H, CONH), 7.52 (d, J7,6= 7.8 Hz, 1H, H-7), 7.34 (d, J4,5 = 8.1 Hz,
1H, H-4), 7.14 (d, J2,NH = 1.6 Hz, 1H, H-2), 7.13 (d, J5ʹʹʹʹ,4ʹʹʹʹ = 7.5 Hz, 1H, H-5''''), 7.08-7.06 (m,
3H, H-6, H-3'''' and H-4''''), 6.96 (dt, J5,7 = 0.8 Hz, J5,4/5,6 = 7.8 Hz, 1H, H-5), 4.25 (s, 2H, CH2-
2'''), 2.88 (t, J3ʹ,2ʹ = 7.4 Hz, 2H, CH2-3'), 2.79 (t, J1ʹ,2ʹ = 7.4 Hz, 2H, CH2-1'), 2.52 (q, J8ʹʹʹʹ,9ʹʹʹʹ = 7.5
Hz, 2H, OCH2-8''''), 2.10 (s, 3H, CH2-7''''), 2.07 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.4 Hz, 2H, CH2-2'), 1.05 (t,
J9ʹʹʹʹ,8ʹʹʹʹ = 7.5 Hz, 3H, CH3-9''''); 13C-NMR (150 MHz, DMSO-d6, δ/ppm): 167.8 (C-1'''), 165.0 (C-
5''), 162.5 (C-2''), 141.0 (C-1''''), 136.3 (C-8), 135.5 (C-2''''), 133.9 (C-6''''), 127.6 (C-4''''), 127.0
(C-9), 126.9 (C-5''''), 126.0 (C-3''''), 122.4 (C-2), 120.8 (C-6), 118.2 (C-7), 118.1 (C-5), 113.2 (C-
3), 111.3 (C-4), 35.5 (C-2'''), 26.5 (C-1'), 24.2 (C-3'), 24.1 (C-8''''), 23.7 (C-2'), 17.9 (C-7''''), 14.5
(C-9''''); Anal. Calc. for C24H26N4SO2 (434.18): C, 66.33; H, 6.03; N, 12.89. Found: C, 66.31; H,
6.02; N, 12.86; EI-MS m/z (% rel. abund.): 434 (M+, 21) 291 (31), 258 (10), 200 (5), 184 (11),
175 (18), 162 (22), 156 (13), 143 (100), 134 (28), 130 (93), 120 (18), 77 (11).
2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-(4-ethylphenyl)acetamide (8c)
Light yellow colored amorphous powder; Yield: 96%; Melting Point 130-132 ˚C; Mol. Formula:
C23H24N4SO2; Mol. Weight: 420 g/mol; IR (KBr, cm-1): υ 3298 (N-H str.), 2961 (C-H aromatic
str.), 1673 (C=O str.), 1651 (C=N str.), 1581 (C=C aromatic str.), 1527, 1483, 1441 (Str. for
1
Oxadiazole), 1157 (C-O-C str.), 689 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6, δ/ppm):
10.80 (s, 1H, NH-1), 10.29 (s, 1H, CONH), 7.51 (d, J7,6 = 7.8 Hz, 1H, H-7), 7.46 (d, J2ʹʹʹʹ,3ʹʹʹʹ
J6ʹʹʹʹ,5ʹʹʹʹ = 8.4 Hz, 2H, H-2'''' and 6''''), 7.34 (d, J4,5 = 8.1 Hz, 1H, H-4), 7.15 (d, J3ʹʹʹʹ,2ʹʹʹʹ = J5ʹʹʹʹ,6ʹʹʹʹ
=
=
8.6 Hz, 2H, H-3'''' and 5''''), 7.13 (d, J2,NH = 2.4 Hz, 1H, H-2), 7.06 (dt, J6,4 = 1.0 Hz, J6,5/6,7 = 7.9
Hz, 1H, H-6), 6.97 (dt, J5,7 = 1.0 Hz, J5,4/5,6 = 7.8 Hz, 1H, H-5), 4.23 (s, 2H, CH2-2'''), 2.88 (t,
16

J3ʹ,2ʹ = 7.5 Hz, 2H, CH2-3'), 2.76 (t, J1ʹ,2ʹ = 7.4 Hz, 2H, CH2-1'), 2.52 (q, J7ʹʹʹʹ,8ʹʹʹʹ = 7.6 Hz, 2H,
CH3CH2-7''''), 2.04 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.4 Hz, 2H, CH2-2'), 1.15 (t, J8ʹʹʹʹ,7ʹʹʹʹ = 7.6 Hz, 3H, -
13
CH2CH3-8''''); C-NMR (150 MHz, DMSO-d6, δ/ppm): 167.9 (C-1'''), 165.5 (C-5''), 162.5 (C-
2''), 139.0 (C-4''''), 136.3 (C-1''''), 136.2 (C-8), 127.9 (C-3'''' and 5''''), 127.0 (C-9), 122.4 (C-2),
120.8 (C-6), 119.2 (C-2'''' and 6''''), 118.2 (C-7), 118.1 (C-5), 113.2 (C-3), 111.3 (C-4), 36.6 (C-
2'''), 27.5 (C-7''''), 26.5 (C-1'), 24.2 (C-3'), 23.7 (C-2'), 15.6 (C-8''''); Anal. Calc. for C23H24N4SO2
(420.16): C, 65.69; H, 5.75; N, 13.32. Found: C, 65.67; H, 5.73; N, 13.30; EI-MS m/z (% rel.
abund.): 420 (M+, 22), 346 (4), 277 (47), 258 (5), 235 (33), 203 (88), 186 (9), 184 (9), 161 (22),
156 (12), 143 (93), 130 (100), 120 (11), 106 (22), 91 (7), 77 (19).
2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-(2-ethoxyphenyl)acetamide
(8d)
Light yellow colored amorphous powder; Yield: 82%; Melting Point 114-116 ˚C; Mol. Formula:
C23H24N4SO3; Mol. Weight: 436 g/mol; IR (KBr, cm-1): υ 3292 (N-H str.), 2949 (C-H aromatic
str.), 1676 (C=O str.), 1651 (C=N str.), 1599 (C=C aromatic str.), 1528, 1487, 1449 (Str. for
1
Oxadiazole), 1159 (C-O-C str.), 688 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6, δ/ppm):
10.80 (s, 1H, NH-1), 9.46 (s, 1H, CONH), 7.95 (d, J2ʹʹʹʹ,3ʹʹʹʹ = 7.2 Hz, 1H, H-2''''), 7.51 (d, J7,6
=
7.9 Hz, 1H, H-7), 7.34 (d, J4,5 = 8.1 Hz, 1H, H-4), 7.13 (d, J2,NH = 2.1 Hz, 1H, H-2), 7.08-7.03
(m, 3H, H-6, H-3'''' and H-5''''), 6.96 (dt, J5,7 = 0.8 Hz, J5,4/5,6 = 7.8 Hz, 1H, H-5), 6.89 (dt, J4ʹʹʹʹ,2ʹʹʹʹ
= 1.2 Hz, J4ʹʹʹʹ,3ʹʹʹʹ/4ʹʹʹʹ,5ʹʹʹʹ = 7.9 Hz, 1H, H-4''''), 4.31 (s, 2H, CH2-2'''), 4.09 (q, J7ʹʹʹʹ,8ʹʹʹʹ = 6.9 Hz, 2H,
OCH2-7''''), 2.87 (t, J3ʹ,2ʹ = 7.4 Hz, 2H, CH2-3'), 2.76 (t, J1ʹ,2ʹ = 7.4 Hz, 2H, CH2-1'), 2.04 (quintet,
J2ʹ,1ʹ/2ʹ,3ʹ = 7.4 Hz, 2H, CH2-2'), 1.36 (t, J8ʹʹʹʹ,7ʹʹʹʹ = 6.9 Hz, 3H, -CH2CH3-8''''); 13C-NMR (150 MHz,
DMSO-d6, δ/ppm): 167.9 (C-1'''), 165.0 (C-5''), 162.5 (C-2''),148.5 (C-2''''), 136.2 (C-8), 127.0
(C-1''''), 127.1 (C-9), 124.6 (C-4''''), 122.4 (C-2), 121.3 (C-6''''), 120.8 (C-6), 120.2 (C-5''''), 118.2
(C-7), 118.1 (C-5), 113.2 (C-3), 112.3 (C-3''''), 111.3 (C-4), 63.9 (C-7''''), 36.4 (C-2'''), 26.5 (C-
1'), 24.2 (C-3'), 23.7 (C-2'), 14.4 (C-8''''); Anal. Calc. for C23H24N4SO3 (436.16): C, 63.28; H,
5.54; N, 12.83. Found: C, 63.25; H, 5.51; N, 12.80; EI-MS m/z (% rel. abund.): 436 (M+, 26),
362 (3), 293 (40), 258 (7), 219 (49), 200 (4), 186 (6), 184 (10), 179 (35), 156 (15), 143 (100),
136 (11), 130 (87), 120 (8), 77 (9).
17

2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-(4-ethoxyphenyl)acetamide
(8e)
Reddish brown colored amorphous powder; Yield: 93%; Melting Point 142-144 ˚C; Mol.
Formula: C23H24N4SO3; Mol. Weight: 436 g/mol; IR (KBr, cm-1): υ 3296 (N-H str.), 2958 (C-H
aromatic str.), 1672 (C=O str.), 1649 (C=N str.), 1591 (C=C aromatic str.), 1531, 1489, 1444
1
(Str. for Oxadiazole), 1155 (C-O-C str.), 687 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6,
δ/ppm): 10.80 (s, 1H, NH-1), 10.21 (s, 1H, CONH), 7.51 (d, J7,6 = 7.8 Hz, 1H, H-7), 7.45 (d,
J2ʹʹʹʹ,3ʹʹʹʹ = J6ʹʹʹʹ,5ʹʹʹʹ = 7.0 Hz, 2H, H-2'''' and 6''''), 7.34 (d, J4,5 = 8.1 Hz, 1H, H-4), 7.13 (d, J2,NH
=
2.0 Hz, 1H, H-2), 7.06 (dt, J6,4 = 0.8 Hz, J6,5/6,7 = 7.8 Hz, 1H, H-6), 6.97 (dt, J5,7 = 0.8 Hz, J5,4/5,6
= 7.8 Hz, 1H, H-5), 6.87 (d, J3ʹʹʹʹ,2ʹʹʹʹ = J5ʹʹʹʹ,6ʹʹʹʹ = 7.0 Hz, 2H, H-3'''' and 5''''), 4.21 (s, 2H, CH2-2'''),
3.98 (q, J7ʹʹʹʹ,8ʹʹʹʹ = 6.9 Hz, 2H, CH2-7''''), 2.87 (t, J3ʹ,2ʹ =7.5 Hz, 2H, CH2-3'), 2.76 (t, J1ʹ,2ʹ = 7.4 Hz,
2H, CH2-1'), 2.04 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.4 Hz, 2H, CH2-2'), 1.30 (t, J8ʹʹʹʹ,7ʹʹʹʹ = 6.9 Hz, 3H, CH3-8'''');
13C-NMR (150 MHz, DMSO-d6, δ/ppm): 167.8 (C-1'''), 164.2 (C-5''), 162.5 (C-2''), 154.7 (C-
4''''), 136.2 (C-8), 131.6 (C-1''''), 127.0 (C-9), 122.4 (C-2), 120.8 (C-6), 120.7 (C-2'''' and 6''''),
118.2 (C-7), 118.1 (C-5), 114.4 (C-3'''' and 5''''), 113.2 (C-3), 111.3 (C-4), 63.0 (C-7''''), 36.6 (C-
2'''), 26.5 (C-1'), 24.2 (C-3'), 23.7 (C-2'), 14.6 (C-8'''); Anal. Calc. for C23H24N4SO3 (436.16): C,
63.28; H, 5.54; N, 12.83. Found: C, 63.25; H, 5.52; N, 12.81; EI-MS m/z (% rel. abund.): 436
(M+, 18), 362 (11), 293 (64), 259 (5), 251 (34), 200 (6), 186 (13), 184 (11), 179 (13), 158 (6),
143 (60), 136 (17), 130 (100), 120 (5), 108 (25), 77 (8).
Methyl 2-[2-({5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)acetamido]benzoate (8f)
Light yellow colored amorphous powder; Yield: 72%; Melting Point 124-126 ˚C; Mol. Formula:
C23H22N4SO4; Mol. Weight: 450 g/mol; IR (KBr, cm-1): υ 3274 (N-H str.), 2953 (C-H aromatic
str.), 1761 (C=O ester str.), 1671 (C=O amide str.), 1650 (C=N str.), 1590 (C=C aromatic str.),
1
1531, 1489, 1452 (Str. for Oxadiazole), 1159 (C-O-C str.), 666 (C-S str.) cm-1; H-NMR (600
MHz, DMSO-d6, δ/ppm): 11.06 (s, 1H, NH-1), 10.80 (s, 1H, CONH), 8.24 (d, J6ʹʹʹʹ,5ʹʹʹʹ = 8.3 Hz,
1H, H-6''''), 7.91 (d, J3ʹʹʹʹ,4ʹʹʹʹ = 7.8 Hz, 1H, H-3''''), 7.61 (t, J5ʹʹʹʹ,4ʹʹʹʹ/5ʹʹʹʹ,6ʹʹʹʹ = 7.8 Hz, 1H, H-5''''), 7.48
(d, J7,6 = 7.8 Hz, 1H, H-7), 7.34 (d, J4,5 = 8.0 Hz, 1H, H-4), 7.22 (t, J4ʹʹʹʹ,3ʹʹʹʹ/4ʹʹʹʹ,5ʹʹʹʹ = 7.5 Hz, 1H, H-
4''''), 7.13 (s, 1H, H-2), 7.06 (t, J6,5/6,7 = 7.5 Hz, 1H, H-6), 6.97 (t, J5,4/5,6 = 7.4 Hz, 1H, H-5), 4.28
(s, 2H, CH2-2'''), 3.80 (s, 3H, OCH3-7''''), 2.87 (t, J3ʹ,2ʹ = 7.4 Hz, 2H, CH2-3'), 2.75 (t, J1ʹ,2ʹ = 7.3
Hz, 2H, CH2-1'), 2.04 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.3 Hz, 2H, CH2-2'); 13C-NMR (150 MHz, DMSO-d6,
18

δ/ppm): 168.0 (C-1'''), 167.2 (C-7''''), 165.4 (C-5''), 162.1 (C-2''), 138.8 (C-1''''), 136.2 (C-8),
133.9 (C-3''''), 130.5 (C-4''''), 127.0 (C-9), 123.7 (C-5''''), 122.4 (C-2), 121.2 (C-6''''), 120.8 (C-6),
118.1 (C-7), 118.1 (C-5), 118.0 (C-2''''), 113.2 (C-3), 111.3 (C-4), 52.3 (C-9''''), 36.4 (C-2'''), 26.5
(C-1'), 24.2 (C-3'), 23.7 (C-2'); Anal. Calc. for C23H22N4SO4 (450.14): C, 61.32; H, 4.92; N,
12.44. Found: C, 61.30; H, 4.90; N, 12.41; EI-MS m/z (% rel. abund.): 450 (M+, 58), 418 (5),
307 (50), 275 (28), 258 (10), 200 (5), 193 (11), 186 (3), 184 (8), 161 (47), 158 (3), 151 (27), 143
(100), 130 (90), 77 (7).
2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-(o-tolyl)acetamide (8g)
Light yellow colored amorphous powder; Yield: 75%; Melting Point 146-148 ˚C; Mol. Formula:
C22H22N4SO2; Mol. Weight: 406 g/mol; IR (KBr, cm-1): υ 3317 (N-H str.), 2955 (C-H aromatic
str.), 1674 (C=O str.), 1653 (C=N str.), 1599 (C=C aromatic str.), 1535, 1484, 1449 (Str. for
1
Oxadiazole), 1155 (C-O-C str.), 681 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6, δ/ppm):
10.80 (s, 1H, NH-1), 9.71 (s, 1H, CONH), 7.51 (d, J7,6 = 7.9 Hz, 1H, H-7), 7.38 (d, J6ʹʹʹʹ,5ʹʹʹʹ = 7.9
Hz, 1H, H-6''''), 7.33 (d, J4,5 = 8.0 Hz, 1H, H-4), 7.21 (d, J3ʹʹʹʹ,4ʹʹʹʹ = 7.3 Hz, 1H, H-3''''), 7.16 (dt,
J5ʹʹʹʹ,3ʹʹʹʹ = 6.5 Hz, J5ʹʹʹʹ,4ʹʹʹʹ/5ʹʹʹʹ,6ʹʹʹʹ = 8.1 Hz, 1H, H-5''''), 7.13 (d, J2,NH = 2.2 Hz, 1H, H-2), 7.11-7.08
(m, 1H, H-4''''), 7.07 (dt, J6,4 = 1.4 Hz, J6,5/6,7 = 8.0 Hz, 1H, H-6), 6.97 (dt, J5,7 = 1.0 Hz, J5,4/5,6
=
7.8 Hz, 1H, H-5), 4.27 (s, 2H, CH2-2'''), 2.88 (t, J3ʹ,2ʹ = 7.4 Hz, 2H, CH2-3'), 2.77 (t, J1ʹ,2ʹ = 7.5
13
Hz, 2H, CH2-1'), 2.18 (s, 3H, CH3-7''''), 2.05 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.4 Hz, 2H, CH2-2'); C-NMR
(150 MHz, DMSO-d6, δ/ppm): 168.4 (C-1'''), 165.5 (C-5''), 163.0 (C-2''), 136.8 (C-1''''), 136.2
(C-8), 132.1 (C-2''''), 130.8 (C-3''''), 127.5 (C-9), 126.4 (C-5''''), 125.9 (C-4''''), 125.2 (C-6''''),
122.9 (C-2), 121.3 (C-6), 118.6 (C-7), 118.6 (C-5), 113.7 (C-3), 111.8 (C-4), 36.6 (C-2'''), 27.0
(C-1'), 24.7 (C-3'), 24.2 (C-2'), 18.1 (C-7''''); Anal. Calc. for C22H22N4SO2 (406.15): C, 65.00; H,
5.46; N, 13.76. Found: C, 64.98; H, 5.43; N, 13.74; EI-MS m/z (% rel. abund.): 406 (M+, 28),
332 (3), 263 (48), 258 (8), 221 (22), 200 (5), 189 (74), 186 (8), 184 (10), 158 (7), 149 (9), 143
(100), 134 (5), 130 (99), 106 (24), 91 (14), 77 (18).
19

2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-(2,3-dimethylphenyl)acetamide
(8h)
Dark brown colored amorphous powder; Yield: 58%; Melting Point 81-83 ˚C; Mol. Formula:
C23H24N4SO2; Mol. Weight: 420 g/mol; IR (KBr, cm-1): υ 3286 (N-H str.), 2957 (C-H aromatic
str.), 1676 (C=O str.), 1654 (C=N str.), 1599 (C=C aromatic str.), 1527, 1481, 1441 (Str. for
1
Oxadiazole), 1141 (C-O-C str.), 677 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6, δ/ppm):
10.80 (s, 1H, NH-1), 9.77 (s, 1H, CONH), 7.52 (d, J7,6 = 7.1 Hz, 1H, H-7), 7.34 (d, J4,5 = 7.3 Hz,
1H, H-4), 7.26 (d, J6ʹʹʹʹ,5ʹʹʹʹ = 7.4 Hz, 1H, H-6''''), 7.25 (t, J5ʹʹʹʹ,4ʹʹʹʹ/5ʹʹʹʹ,6ʹʹʹʹ = 7.6 Hz, 1H, H-5''''), 7.14 (s,
1H, H-2), 7.08-7.03 (m, 2H, H-4'''' and H-6), 6.98 (t, J5,4/5,6 = 7.2 Hz, 1H, H-5), 4.26 (s, 2H, CH2-
2'''), 2.88 (t, J3ʹ,2ʹ = 7.6 Hz, 2H, CH2-3'), 2.78 (t, J1ʹ,2ʹ = 7.2 Hz, 2H, CH2-1'), 2.24 (s, 3H, CH3-
13
8''''), 2.13 (m, 2H, CH2-2'), 2.02 (s, 3H, CH3-7''''); C-NMR (150 MHz, DMSO-d6, δ/ppm):
167.9 (C-1'''), 165.1 (C-5''), 162.6 (C-2''), 137.0 (C-3''''), 136.3 (C-8), 135.5 (C-1''''), 128.8 (C-
2''''), 127.0 (C-9), 126.2 (C-4''''), 125.2 (C-5''''), 122.4 (C-2), 122.2 (C-6''''), 120.8 (C-6), 118.1
(C-7), 118.0 (C-5), 113.2 (C-3), 111.3 (C-4), 36.0 (C-2'''), 26.5 (C-1'), 24.2 (C-3'), 23.8 (C-2'),
20.0 (C-8''''), 13.7 (C-7''''); Anal. Calc. for C23H24N4SO2 (420.16): C, 65.69; H, 5.75; N, 13.32.
Found: C, 65.66; H, 5.72; N, 13.30; EI-MS m/z (% rel. abund.): 420 (M+, 21), 302 (3), 277 (57),
258 (5), 235 (39), 203 (52), 200 (5), 186 (18), 184 (10), 163 (10), 158 (7), 156 (16), 148 (9), 143
(81), 130 (100), 120 (18), 103 (15), 77 (20).
2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-(2,4-dimethylphenyl)acetamide
(8i)
Light Yellow colored amorphous powder; Yield: 83%; Melting Point 137-139 ˚C; Mol. Formula:
C23H24N4SO2; Mol. Weight: 420 g/mol; IR (KBr, cm-1): υ 3293 (N-H str.), 2966 (C-H aromatic
str.), 1672 (C=O str.), 1648 (C=N str.), 1598 (C=C aromatic str.), 1529, 1488, 1447 (Str. for
1
Oxadiazole), 1153 (C-O-C str.), 687 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6, δ/ppm):
10.80 (s, 1H, NH-1), 9.62 (s, 1H, CONH), 7.52 (d, J7,6 = 7.7 Hz, 1H, H-7), 7.34 (d, J4,5 = 8.0 Hz,
1H, H-4), 7.23 (d, J6ʹʹʹʹ,5ʹʹʹʹ = 8.0 Hz, 1H, H-6''''), 7.14 (s, 1H, H-2), 7.13 (d, J2,NH = 2.1 Hz, 1H, H-
2), 7.07 (t, J6,5/6,7 = 7.9 Hz, 1H, H-6), 7.01 (s, 1H, H-3''''), 6.98-6.94 (m, 2H, H-5 and H-5''''),
4.26 (s, 2H, CH2-2'''), 2.88 (t, J3ʹ,2ʹ = 7.5 Hz, 2H, CH2-3'), 2.78 (t, J1ʹ,2ʹ = 7.4 Hz, 2H, CH2-1'),
13
2.25 (s, 3H, CH3-8''''), 2.04 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.4 Hz, 2H, CH2-2'), 2.14 (s, 3H, CH3-7''''); C-
NMR (150 MHz, DMSO-d6, δ/ppm): 167.9 (C-1'''), 164.9 (C-5''), 162.5 (C-2''), 136.3 (C-8),
20

134.5 (C-1''''), 133.1 (C-2''''), 130.8 (C-5''''), 128.4 (C-4''''), 127.0 (C-9), 126.4 (C-3''''), 124.7 (C-
6''''), 122.4 (C-2), 120.8 (C-6), 118.1 (C-7), 118.0 (C-5), 113.2 (C-3), 111.2 (C-4), 36.1 (C-2'''),
26.5 (C-1'), 24.2 (C-3'), 23.8 (C-2'), 20.4 (CH3-8'''), 17.5 (CH3-7'''); Anal. Calc. for C23H24N4SO2
(420.16): C, 65.69; H, 5.75; N, 13.32. Found: C, 65.66; H, 5.73; N, 13.30; EI-MS m/z (% rel.
abund.): 420 (M+, 24), 346 (7), 302 (3), 277 (83), 262 (5), 259 (5), 235 (72), 200 (6), 186 (25),
184 (12), 163 (13), 156 (16), 148 (8), 146 (20), 143 (72), 130 (86), 120 (24), 103 (12), 91 (6), 77
(18).
2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-(2,5-dimethylphenyl)acetamide
(8j)
Light yellow colored amorphous powder; Yield: 92%; Melting Point 155-157 ˚C; Mol. Formula:
C23H24N4SO2; Mol. Weight: 420 g/mol; IR (KBr, cm-1): υ 3282 (N-H str.), 2945 (C-H aromatic
str.), 1664 (C=O str.), 1649 (C=N str.), 1599 (C=C aromatic str.), 1535, 1473, 1456 (Str. for
1
Oxadiazole), 1155 (C-O-C str.), 689 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6, δ/ppm):
10.80 (s, 1H, NH-1), 9.64 (s, 1H, CONH), 7.51 (d, J7,6 = 7.8 Hz, 1H, H-7), 7.34 (d, J4,5 = 8.1 Hz,
1H, H-4), 7.22 (s, 1H, H-6''''), 7.13 (d, J2,NH = 2.1 Hz, 1H, H-2), 7.07 (t, J6,5/6,7 = 7.1 Hz, 1H, H-
6), 7.05 (d, J3ʹʹʹʹ,4ʹʹʹʹ = 8.0 Hz, 1H, H-3''''), 6.98 (dt, J5,7 = 1.0 Hz, J5,4/5,6 = 7.9 Hz, 1H, H-5), 6.92
(d, J4ʹʹʹʹ,3ʹʹʹʹ = 7.6 Hz, 1H, H-4''''), 4.25 (s, 2H, CH2-2'''), 2.88 (t, J3ʹ,2ʹ = 7.5 Hz, 2H, CH2-3'), 2.78 (t,
J1ʹ,2ʹ = 7.4 Hz, 2H, CH2-1'), 2.23 (s, 3H, CH3-8''''), 2.04 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.4 Hz, 2H, CH2-2'),
13
2.13 (s, 3H, CH3-7''''); C-NMR (150 MHz, DMSO-d6, δ/ppm): 167.9 (C-1'''), 164.9 (C-5''),
162.5 (C-2''), 136.3 (C-8), 135.5 (C-1''''), 135.0 (C-5''''), 130.1 (C-2''''), 128.4 (C-3''''), 127.0 (C-
9), 126.1 (C-4''''), 125.2 (C-6''''), 122.4 (C-2), 120.8 (C-6), 118.2 (C-7), 118.1 (C-5), 113.2 (C-3),
111.3 (C-4), 36.1 (C-2'''), 26.5 (C-1'), 24.2 (C-3'), 23.7 (C-2'), 20.5 (C-8''''), 17.2 (C-7''''); Anal.
Calc. for C23H24N4SO2 (420.16): C, 65.69; H, 5.75; N, 13.32. Found: C, 65.66; H, 5.73; N,
13.29; EI-MS m/z (% rel. abund.): 420 (M+, 29), 346 (3), 302 (3), 277 (67), 258 (8), 235 (46),
219 (6), 200 (6), 186 (14), 184 (10), 163 (11), 161 (16), 156 (13), 148 (5), 143 (100), 130 (98),
120 (19), 103 (12), 77 (16).
2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-phenethylacetamide (8k)
Light yellow colored amorphous powder; Yield: 95%; Melting Point 119-121 ˚C; Mol. Formula:
C23H24N4SO2; Mol. Weight: 420 g/mol; IR (KBr, cm-1): υ 3250 (N-H str.), 2956 (C-H aromatic
21

str.), 1674 (C=O str.), 1652 (C=N str.), 1591 (C=C aromatic str.), 1508, 1471, 1433 (Str. for
1
Oxadiazole), 1157 (C-O-C str.), 696 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6, δ/ppm):
10.80 (s, 1H, NH-1), 8.36 (s, 1H, CONH), 7.52 (d, J7,6 = 7.8 Hz, 1H, H-7), 7.34 (d, J4,5 = 8.1 Hz,
1H, H-4), 7.28 (d, J2ʹʹʹʹ,3ʹʹʹʹ = J6ʹʹʹʹ,5ʹʹʹʹ = 7.5 Hz, 2H, H-2'''' and 6''''), 7.2-7.18 (m, 3H, H-3'''', H-4''''
and 5''''), 7.14 (d, J2,NH = 2.1 Hz, 1H, H-2), 7.06 (dt, J6,4 = 1.0 Hz, J6,5/6,7 = 8.0 Hz, 1H, H-6),
6.97 (dt, J5,7 = 1.0 Hz, J5,4/5,6 = 7.8 Hz, 1H, H-5), 3.98 (s, 2H, CH2-2'''), 3.30 (t, J8ʹʹʹʹ,7ʹʹʹʹ = 7.1 Hz,
2H, CH2-8''''), 2.87 (t, J3ʹ,2ʹ = 7.4 Hz, 2H, CH2-3'), 2.76 (t, J1ʹ,2ʹ = 7.4 Hz, 2H, CH2-1'), 2.70 (t,
13
J7ʹʹʹʹ,8ʹʹʹʹ = 7.1 Hz, 2H, CH2-7''''), 2.04 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 7.4 Hz, 2H, CH2-2'); C-NMR (150
MHz, DMSO-d6, δ/ppm): 167.8 (C-1'''), 165.8 (C-5''), 162.6 (C-2''), 139.1 (C-1''''), 136.2 (C-8),
128.5 (C-2'''' and 6''''), 128.2 (C-3'''' and 5''''), 127.0 (C-9), 126.0 (C-4''''), 122.4 (C-2), 120.8 (C-
6), 118.2 (C-7), 118.1 (C-5), 113.2 (C-3), 111.3 (C-4), 40.6 (C-2'''), 35.6 (C-7''''), 34.8 (C-8''''),
26.5 (C-1'), 24.2 (C-3'), 23.8 (C-2'); Anal. Calc. for C23H24N4SO2 (420.16): C, 65.69; H, 5.75; N,
13.32. Found: C, 65.67; H, 5.73; N, 13.30; EI-MS m/z (% rel. abund.): 420 (M+, 4), 346 (13),
277 (4), 203 (100), 200 (14), 186 (3), 184 (3), 163 (4), 156 (5), 143 (67), 130 (53), 105 (12),
91(12), 77 (7).
2-({5-[3-(1H-Indol-3-yl)propyl]-1,3,4-oxadiazol-2-yl}thio)-N-(4-methylpyridin-2-
yl)acetamide (8l)
Reddish orange colored amorphous powder; Yield: 76%; Melting Point 169-171 ˚C; Mol.
Formula: C21H21N5SO2; Mol. Weight: 407 g/mol; IR (KBr, cm-1): υ 3295 (N-H str.), 2947 (C-H
aromatic str.), 1674 (C=O str.), 1647 (C=N str.), 1586 (C=C aromatic str.), 1519, 1477, 1439
1
(Str. for Oxadiazole), 1146 (C-O-C str.), 680 (C-S str.) cm-1; H-NMR (600 MHz, DMSO-d6,
δ/ppm): 10.80 (s, 1H, NH-1), 9.51 (s, 1H, CONH), 7.51 (d, J7,6 = 7.5 Hz, 1H, H-7), 7.33 (d, J4,5
= 7.6 Hz, 1H, H-4), 7.13 (s, 1H, H-2), 7.11-7.05 (m, 4H, H-6, 3'''', 4'''' and 6''''), 6.97 (t, J5,4/5,6
=
7.0 Hz, 1H, H-5), 4.66 (s, 2H, CH2-2'''), 2.87 (t, J3ʹ,2ʹ = 6.8 Hz, 2H, CH2-3'), 2.76 (t, J1ʹ,2ʹ = 6.8
13
Hz, 2H, CH2-1'), 2.42 (s, 3H, CH3-7''''), 2.04 (quintet, J2ʹ,1ʹ/2ʹ,3ʹ = 6.4 Hz, 2H, CH2-2'); C-NMR
(150 MHz, DMSO-d6, δ/ppm): 176.0 (C-1'''), 167.7 (C-5''), 163.1 (C-2''), 159.9 (C-1''''), 145.8
(C-5''''), 137.3 (C-3''''), 136.2 (C-8), 128.2 (C-4''''), 127.0 (C-9), 122.4 (C-2), 120.8 (C-6), 118.1
(C-7), 118.1 (C-5), 113.3 (C-3), 111.3 (C-4), 102.6 (C-6''''), 36.5 (C-2'''), 26.5 (C-1'), 24.2 (C-3'),
23.7 (C-2'); Anal. Calc. for C21H21N5SO2 (407.14): C, 61.90; H, 5.19; N, 17.19. Found: C, 61.87;
22

H, 5.16; N, 17.17; EI-MS m/z (% rel. abund.): 373 (4), 332 (5), 304 (4), 262 (4), 259 (58), 230
(25), 186 (4), 184 (8), 148 (37), 143 (44), 135 (4), 130 (100), 93 (14), 77 (8).
In vitro α-glucosidase assay
The enzyme inhibition activity against baker’s yeast α-glucosidase was performed according to
the cited method [29]. Phosphate buffer saline (50 mM, pH 6.8, 70 µL), test compound (0.5 mM,
10 µL) and enzyme (0.057 units, 10 µL) were taken to make total volume of 100 µL, mixed well
and pre-incubated for 10 min at 37 ˚C and absorbance was taken at 400 nm. Ten µL of substrate
p-nitrophenyl glucopyranoside (0.5 mM) was added to start the reaction and after incubation for
30 min at 37 ˚C, absorbance was noted again at 400 nm at microplate reader (Synergy HT). The
change in absorbance was used an index for the measurement of percentage inhibition. Acarbose
was used as positive control. All the experiments were performed in triplicates. The inhibition
(%) was calculated by the following equation:
% age Inhibition = Control – Test/Control x 100
Serial dilutions of the active compounds from 0.5 to 0.015625 mM were employed for
determination of IC50 value by EZ-Fit Enzyme Kinetics Software (Perrella Scientific.Inc.
Amherst, USA) software.
Hemolytic activity
Bovine blood samples was collected in EDTA that was diluted with saline (0.9% NaCl), and
centrifuge at 1000 xg for 10 min. Erythrocytes were separated and diluted in phosphate buffer
saline (PBS) of pH 7.4 and a suspension was made. Test compound solution (20 µL, 10 mg/mL)
was mixed with 180 µL of RBCs suspension and incubate for 30 min at room temperature. PBS
was used as negative control and Triton 100-X was taken as positive control [30,31]. The % age
of hemolysis was taken as by using formula:
(%) of Hemolysis = (Absorbance of Sample – Absorbance of Negative Control/ Absorbance of
Positive Control) x 100
23

Molecular Docking
In order to predict the bioactive conformations, various synthesized ligands were docked into the
active pockets of the α-glucosidase enzyme by using the default parameters of MOE-Dock
program. Prior to dock the ligands in protein molecules, MOE 2009-10 Build program was used
to sketch the structures of synthesized compounds. Energy minimization was carried out up to
0.05 gradients by using MMFF94x force field through the default parameter of MOE energy
minimization algorithm. Database was created in which all the ligands were saved in their 3D
structures in the mdb file format. The protein molecules of baker’s yeast α-glucosidase (PDB ID
code: 3N04) and Jack bean Urease (PDB ID code: 4UBP) were retrieved from Protein Data
Bank. All water molecules were released from the receptor enzymes and 3D protonation was
carried out by using Protonate 3D Option. The energies of protein molecules were also
minimized by using the default parameters of MOE 2009-10 energy minimization algorithm
(gradient: 0.05, Force Field: Amber99). Then all the ligands were docked into the binding
pockets (selective residues/amino acids) of the above proteins using default parameters of MOE-
Dock Program. A maximum of 30 conformations were given for each compound in order to use
the default parameters of MOE (Placement: Triangle Matcher, Rescoring 1: London dG,
Refinement: Force field, Rescoring 2: GBVI/WSA dG). Re-docking was also carried to validate
the accuracy of docking protocol [32]. At the end of docking, all the 2D and 3D images were
analyzed for the types of interactions and bond lengths.
Statistical analysis
All the measurements were carried out in triplicate and statistical analysis was performed by
Microsoft Excel 2010. The results are presented as mean ± SEM with 96 % CL.
Acknowledgement
The Higher Education Commission (HEC) of Pakistan is highly acknowledged by the authors for
financial support regarding the spectral analysis.
24

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26

Graphical abstract
27

Highlights:

Synthesis of new indole based hybrid oxadiazole scaffolds with N-substituted
acetamides by multiple chemical transformations.





Structural characterization of compounds by various spectroscopic techniques.
Evaluation of compounds 8a-8l for in vitro α-glucosidase inhibitory activity.
Cytotoxicity evaluation of compounds 8a-8l by hemolytic activity.
Limited structure-activity relationship (SAR).
Assessment of ligand-enzyme binding interactions by in silico study.
28