Iodine-mediated one-pot intramolecular decarboxylation domino reaction for accessing functionalised 2-(1,3,4-oxadiazol-2-yl)anilines with carbonic anhydrase inhibitory action

Article abstract of DOI:10.1080/14756366.2018.1443447

A practical and transition metal-free one-pot domino synthesis of diversified (1,3,4-oxadiazol-2-yl)anilines has been developed employing isatins and hydrazides as the starting materials, in the presence of molecular iodine. The prominent feature of this domino process involves consecutive condensation, hydrolytic ring cleavage, and an intramolecular decarboxylation, in a one-pot process that leads to the oxidative formation of a C–O bond. Fluorescence properties of some of the representative molecules obtained in this way were studied. The synthesised 2-(1,3,4-oxadiazolo-2-yl)aniline-benzene sulphonamides (8a–o) were screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity. Most of the compounds exhibited low micromolar to nanomolar activity against human (h) isoforms hCA I, hCA II, hCA IV, and XII, with some compounds displaying selective CA inhibitory activity towards hCA II with K_Is of 6.4–17.6 nM.

Full text of DOI:10.1080/14756366.2018.1443447

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Iodine-mediated one-pot intramolecular
decarboxylation domino reaction for accessing
functionalised 2-(1,3,4-oxadiazol-2-yl)anilines with
carbonic anhydrase inhibitory action
Srinivas Angapelly, P. V. Sri Ramya, Rohini Sodhi, Andrea Angeli, Krishnan
Rangan, Narayana Nagesh, Claudiu T. Supuran & Mohammed Arifuddin
To cite this article: Srinivas Angapelly, P. V. Sri Ramya, Rohini Sodhi, Andrea Angeli, Krishnan
Rangan, Narayana Nagesh, Claudiu T. Supuran & Mohammed Arifuddin (2018) Iodine-mediated
one-pot intramolecular decarboxylation domino reaction for accessing functionalised 2-(1,3,4-
oxadiazol-2-yl)anilines with carbonic anhydrase inhibitory action, Journal of Enzyme Inhibition and
Medicinal Chemistry, 33:1, 615-628, DOI: 10.1080/14756366.2018.1443447
To link to this article: https://doi.org/10.1080/14756366.2018.1443447
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2018 The Author(s). Published by Informa
Published online: 14 Mar 2018.
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2018
VOL. 33, NO. 1, 615–628
https://doi.org/10.1080/14756366.2018.1443447
RESEARCH PAPER
Iodine-mediated one-pot intramolecular decarboxylation domino reaction for
accessing functionalised 2-(1,3,4-oxadiazol-2-yl)anilines with carbonic anhydrase
inhibitory action
a
a
a
b
c
d
Srinivas Angapelly , P. V. Sri Ramya , Rohini Sodhi , Andrea Angeli , Krishnan Rangan , Narayana Nagesh ,
b
a
Claudiu T. Supuran and Mohammed Arifuddin
a
b
National Institute of Pharmaceutical Education and Research (NIPER) – Hyderabad, Hyderabad, India; Neurofarba Department, Sezione di
c
Scienze Farmaceutiche e Nutraceutiche, University of Florence, Florence, Italy; Birla Institute of Technology & Science, Pilani, Hyderabad, India;
d
Center for Cellular and Molecular Biology (CCMB), Hyderabad, India
ABSTRACT
ARTICLE HISTORY
A practical and transition metal-free one-pot domino synthesis of diversified (1,3,4-oxadiazol-2-yl)anilines
has been developed employing isatins and hydrazides as the starting materials, in the presence of molecu-
lar iodine. The prominent feature of this domino process involves consecutive condensation, hydrolytic
ring cleavage, and an intramolecular decarboxylation, in a one-pot process that leads to the oxidative for-
mation of a C–O bond. Fluorescence properties of some of the representative molecules obtained in this
way were studied. The synthesised 2-(1,3,4-oxadiazolo-2-yl)aniline-benzene sulphonamides (8a–o) were
screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity. Most of the compounds exhibited
low micromolar to nanomolar activity against human (h) isoforms hCA I, hCA II, hCA IV, and XII, with some
Received 31 January 2018
Accepted 18 February 2018
KEYWORDS
Domino synthesis; 1,3,4-
oxadiazole; carbonic
anhydrase; sulphonamide;
iodine
compounds displaying selective CA inhibitory activity towards hCA II with K s of 6.4–17.6 nM.
I
Introduction
heterocycles (quinazoline, oxazole, and pyridine) through the tan-
dem oxidative coupling reactions using iodine as catalyst and tert-
Construction of O–heterocyclic ring systems via intramolecular
C–O bond formation has become an emerging tool in drug discov-
ery. Accordingly, many efforts have been devoted to this activity,
and remarkable results have been achieved to date. Among these,
the traditional intramolecular Pd-catalysed Hartwig–Buchwald and
copper-catalysed Ullmann-type C–O coupling of aryl halides with
8
butyl-hydroperoxide (TBHP) as the oxidant . Furthermore, Ma et al.
proposed the synthesis of imidazo[1,2-a]pyridines via oxidative
coupling of 2-aminopyridine with 1,3-diketones in the presence of
9
tetra-butylammonium iodide (TBAI), TBHP, and BF ꢀetherate . Very
1
3
recently Tang et al. reported iodine-catalysed radical oxidative
annulation for the synthesis of dihydrofurans and indolisines .
2
10
hydroxyl moieties, and in an alternative approach, the direct dehy-
drogenative coupling occurs between C–H and O–H bonds , lead-
2
Interestingly, I (or hypervalent iodine derivatives) also promoted
3
the oxidative decarboxylation of amino acids and b,c-unsaturated
ing to various functionalised compounds. In most cases, these
elaborative designs implied complex catalytic systems (based on
Pd(II), Cu(II), Rh(III), and Ru(III) derivatives) and multi-step processes
for the preparation of diversely functionalised derivatives, such as,
furan, pyrrole, pyrazole, isoquinoline, indole, benzoxazole, and car-
11
carboxylic acids . Intrigued by these advances, herein we envi-
sioned a metal-free, iodine-mediated domino strategy involving
intramolecular decarboxylative coupling of isatins, and hydrazides
for the synthesis of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives
(
Scheme 1).
,3,4-Oxadiazole motif is an important five-membered aromatic
4
bazole ring systems . However, oxidative decarboxylation leading
1
to construction of C–heteroatom bonds, particularly the C–O and
the C–N bonds, has received significantly less attention. In recent
years, in the perspective of green chemistry, most of the organic
chemists have switched to metal-free reactions to reduce the bur-
den of toxicity. In this context, iodine and hypervalent iodine
reagents have emerged as inexpensive, versatile, and environmen- moieties are depicted in Figure 1. Apart from biology, their appli-
tally more friendly reagents . Structural features and the reactivity cations have also been extended to material chemistry due to
12,13
heterocyclic ring present in many bioactive molecules
ing anticancer, antibacterial, anti-inflammatory, anti-diabetic, anti-
viral, anticonvulsant, analgesic, and antifungal agents
, includ-
1
2,13
. Some of
the drugs and drug candidates, such as raltegravir, zibotentan,
furamizole, and ABT-751-oxadiazole possessing 1,3,4-oxadiazole
5
1
4
pattern of these iodine compounds in many aspects are similar to their unique optoelectronic properties .
those of the transition metal compounds applied for such pur-
To date, a number of synthetic protocols have been described
poses. Up until now, many efforts have been made to directly in the literature to access 1,3,4-oxadiazoles1
5–17
. They include: (i)
functionalise C–H bonds for the construction of C–C and oxidative cyclisation of N-acylhydrazones with FeCl , CAN, PbO ,
3
2
C–heteroatoms bonds by employing iodine or hypervalent iodine hypervalent iodines, chloramine T, KMnO , Br , HgO/I ; (ii) From
4
2
2
6
,7
reagents . Wang et al. demonstrated a facile access to various 1,2-diacylhydrazones via cyclodehydration by employing PPA,
CONTACT Mohammed Arifuddin
00037, India; Claudiu T. Supuran
arif@niperhyd.ac.in
claudiu.supuran@unifi.it
National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, Hyderabad
Birla Institute of Technology & Science, Pilani, Hyderabad Campus, Hyderabad 500078, India
5
ß 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

6
16
S. ANGAPELLY ET AL.
POCl
,3,4-oxadiazoles through C–H activation . Additionally, Guin et al. aniline derivatives (3a–u), (6a–g), and (8a–o)
successfully accomplished 2,5-disubstituted 1,3,4-oxadiazoles from A glass tube charged with a mixture of the desired isatin
3 2 2 4
, SOCl , and H SO ; (iii) Arylation of preformed 2-substituted General procedure for the preparation of 2–(1,3,4-oxadiazol-2-yl)
1
8
1
1
9
N-arylidenearoyl hydrazides using Cu(OTf)
2
. Recently, Xu et al. (0.5 mmol), aryl or heteroaryl hydrazide (0.5 mmol), I2 (100 mol%),
demonstrated an easy access to synthesise 2-(1,3,4-oxadiazol-2- K CO (1.5 equiv.), and then 3 ml of DMSO at room temperature,
2
3
2
0
yl)anilines by employing CuI as the catalyst . Nevertheless, the was sealed and the resulting mixture was stirred under microwave
problems associated with these protocols, including the use of irradiation at 160 C until the disappearance of the reactants
ꢁ
expensive, hazardous materials, or inefficient multi-step processes (monitored by TLC in 20% EtOAc and hexane). Iodine was then
endowed them with a limited applicability. Therefore, more gen- quenched by the addition of 10% aqueous Na
eral and eco-friendly strategies for the synthesis of functionalised uct was extracted with EtOAc (3 ꢂ 25 ml). The combined extract
,3,4-oxadiazoles from easily available starting materials are still was washed with brine, dried over anhydrous Na SO and was
highly desirable. This prompted us to explore a simpler and more concentrated under reduced pressure. The residue was purified by
S O and the prod-
2 2 3
1
2
4
efficient protocol which is reported in this article.
column chromatography on 60–120 silica gel using a mixture of
ꢁ
ꢁ
EtOAc (bp 77 C) and petroleum ether (bp 42–60 C) as eluent to
afford the desired product (correspondingly, 3a–3u/6a–6g/8a–o)
as a yellow solid (yield, 69–92%).
Materials and methods
Chemistry
2-(5-(p-Tolyl)-1,3,4-oxadiazol-2-yl)aniline (3a)
ꢁ
1
Yellow solid, Yield: 114 mg (91%), m.p 174–175 C. H NMR
500 MHz, CDCl
All solvents were purified and dried using standard methods prior
to use. Commercially available reagents were used without further
purification. All reactions involving air- or moisture-sensitive com-
pounds were performed under a nitrogen atmosphere using dried
glassware and syringe techniques to transfer solutions. Analytical
thin-layer chromatography (TLC) was carried out on Merck silica
gel 60 F-254 aluminium plates. Melting points were determined on
Stuart digital melting-point apparatus/SMP 30 in open capillary
(
3
) d 8.02 (d, J ¼ 7.7 Hz, 2H), 7.85 (d, J ¼ 7.6 Hz, 1H),
7
2
1
.31 (dd, J ¼ 23.7, 7.5 Hz, 3H), 6.79 (dd, J ¼ 14.7, 7.7 Hz, 2H), 5.89 (s,
13
H), and 2.44 (s, 3H). C NMR (126 MHz, DMSO) d 164.5, 162.6,
48.2, 142.6, 132.9, 130.4, 128.2, 127.0, 120.9, 116.3, 116.1, 104.5,
þ
and 21.6. HRMS (ESI) m/z [M þ H] calculated for C15
14 3
H N O
2
52.1131, found 252.1136.
1
13
tubes and uncorrected. Nuclear magnetic resonance ( H-NMR, C-
NMR) spectra were recorded using an Avance Bruker 500 MHz,
2-(5-(4-Methoxy-2-methylphenyl)-1,3,4-oxadiazol-2-yl)aniline (3b)
ꢁ
1
Yellow solid, Yield: 126 mg (90%), m.p 148.5–150 C. H NMR
1
6
25 MHz spectrometer in DMSO-d . Chemical shifts reported in
(
1
2
500 MHz, DMSO) d 8.02 (d, J ¼ 8.7 Hz, 1H), 7.80 (dd, J ¼ 8.0, 1.4 Hz,
parts per million (ppm) with TMS as an internal reference, and the
coupling constants (J) expressed in hertz (Hz). Splitting patterns
are denoted as follows: s, singlet; d, doublet; t, triplet; m, multiplet; 3.84 (s, 3H), and 2.68 (s, 3H). C NMR (126 MHz, DMSO) d 163.8,
H), 7.31–7.25 (m, 1H), 7.03 (d, J ¼ 2.4 Hz, 1H), 6.99 (dd, J ¼ 8.7,
.6 Hz, 1H), 6.92 (d, J ¼ 8.3 Hz, 1H), 6.78 (s, 2H), 6.73–6.68 (m, 1H),
1
3
dd, doublet of doublet. HRMS were determined with Agilent QTOF 162.7, 161.8, 148.2, 140.30, 132.80, 131.13, 128.1, 117.3, 116.3,
þ
mass spectrometer 6540 series instrument and were performed in 116.0, 115.3, 112.6, 104.6, 55.8, and 22.3. HRMS (ESI) m/z: [M þ H]
the ESI techniques at 70 eV.
16 16 3 2
calculated for C H N O 282.1237, found 282.1240.
O
N
N
O
metal-free, base
air
R
2-(5-(3,4,5-Trimethoxyphenyl)-1,3,4-oxadiazol-2-yl)aniline (3c)
O
ꢁ
1
O
R
NHNH2
Yellow solid, Yield: 149 mg (91%), m.p 169–171 C. H NMR
(500 MHz, DMSO) d 7.94 (dd, J ¼ 8.0, 1.4 Hz, 1H), 7.39 (s, 2H), 7.30
(ddd, J ¼ 8.5, 7.2, 1.5 Hz, 1H), 6.93 (dd, J ¼ 8.3, 0.6 Hz, 1H), 6.79 (s,
N
H
NH2
R = aryl/heteroaryl
CO2
1
3
Scheme 1. Transition metal-free domino oxidative decarboxylation for the forma- 2H), 6.75–6.69 (ddd,.1H), 3.92 (s, 6H), 3.77 (s, 3H).
C NMR
tion of 1,3,4-oxadiazole.
(126 MHz, DMSO) d 164.7, 162.4, 153.9, 148.3, 141.0, 133.0, 128.4,
O
N
N
N
O
O
H
N
OH
NH
F
N
O
O
S
N
N
N
H
N
N
O
O
O
N
Raltegravir
Zibotentan
N
N
NH
N
N
O
NH2
O
O
O
O N
2
N
NH
O
O
N
Furamizole
ABT-751-oxadiazole
Figure 1. Some of the bioactive compounds containing 1,3,4-oxadiazole moiety.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
617
1
[
18.9, 116.3, 115.9, 104.5, 104.4, 60.7, and 56.6. HRMS (ESI) m/z: 4-Chloro-2-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)aniline (3k)
M þ H]þ calculated for C17
H
18
328.1292, found 328.1291.
ꢁ
1
3
F N
3
O
4
Yellow solid, Yield: 117 mg (81%), m.p 176–177.5 C. H NMR
(
500 MHz, DMSO) d 8.29–8.23 (m, 2H), 7.91 (d, J ¼ 2.5 Hz, 1H),
7
1
1
1
.50–7.44 (m, 2H), 7.31 (dd, J ¼ 8.9, 2.5 Hz, 1H), 6.96 (d, J ¼ 8.9 Hz,
2
-(5-(4-(Trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)aniline (3d)
13
H), 6.92 (s, 2H). C NMR (126 MHz, DMSO) d 165.67, 163.78,
ꢁ
1
Yellow solid, Yield: 129 mg (84%), m.p 195–197 C. H NMR
62.0, 147.1, 132.7, 130.0 (d, J ¼ 9.1 Hz), 127.1, 120.0 (d, J ¼ 3.1 Hz),
(
7
1
500 MHz, DMSO) d 8.34 (d, J ¼ 8.0 Hz, 2H), 7.98 (d, J ¼ 8.0 Hz, 2H),
þ
19.2, 118.2, 117.1, 116.9, and 105.4. HRMS (ESI) m/z: [M þ H] cal-
.88 (d, J ¼ 7.8 Hz, 1H), 7.30 (t, J ¼ 7.5 Hz, 1H), 6.93 (d, J ¼ 8.3 Hz,
13
culated for C H ClFN O 290.0941, found 290.0939.
1
4
10
3
H), 6.80 (s, 2H), and 6.72 (t, J ¼ 7.4 Hz, 1H). C NMR (126 MHz,
DMSO) d 165.3, 161.4, 148.5, 133.2, 128.3, 127.9, 126.7 (d,
J ¼ 3.7 Hz), 125.3, 123.1, 116.4, 116.0, and 104.1. HRMS (ESI) m/z: 2-(5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl)-4-chloroaniline (3l)
ꢁ
1
[
M þ H]þ calculated for C15
H
11
F
3
N
3
O 306.0849, found 306.0846.
Yellow solid, Yield: 145 mg (83%), m.p 196–197 C. H NMR
(
7
500 MHz, DMSO) d 8.17–8.13 (m, 2H), 7.93 (d, J ¼ 2.5 Hz, 1H),
.87–7.82 (m, 2H), 7.33 (dd, J ¼ 8.9, 2.5 Hz, 1H), 6.97–6.91 (m, 3H).
13
2
-(5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl)aniline (3e)
C NMR (126 MHz, DMSO) d 163.9, 162.2, 147.2, 132.9, 132.8,
ꢁ
1
Yellow solid, Yield: 106 mg (83%), m.p 170–172 C. H NMR
500 MHz, CDCl
) d 8.21–8.10 (m, 2H), 7.84 (dd, J ¼ 7.9, 1.3 Hz, 1H),
.32–7.27 (m, 1H), 7.26–7.19 (m, 2H), 6.80 (dd, J ¼ 15.8, 7.8 Hz, 2H),
1
[
29.2, 127.1, 126.1, 122.9, 119.2, 118.2, and 105.3. HRMS (ESI) m/z:
M þ H] calculated for C H BrClN O 349.9690, found 349.9698.
(
7
3
þ
1
4
10
3
1
3
and 5.83 (s, 2H).
C NMR (126 MHz, CDCl ) d 165.7, 163.77,
3
1
62.00, 147.1, 132.6, 129.20 (d, J ¼ 8.9 Hz), 127.7, 120.24 (d,
4
-Chloro-2-(5-(3,5-dichlorophenyl)-1,3,4-oxadiazol-2-yl)aniline (3m)
ꢁ
1
J ¼ 3.3 Hz), 116.8, 116.5, 116.3, and 105.61. HRMS (ESI) m/z:
Yellow solid, Yield: 137 mg (81%), m.p 229–231 C. H NMR
[
M þ H]þ calculated for C14
3
H11FN O 256.0881, found 256.0878.
(
500 MHz, DMSO) d 8.24 (d, J ¼ 1.8 Hz, 2H), 8.06 (d, J ¼ 2.5 Hz, 1H),
7
3
1
.92 (t, J ¼ 1.8 Hz, 1H), 7.32 (dd, J ¼ 8.9, 2.5 Hz, 1H), 6.97–6.92 (m,
13
H).
C NMR (126 MHz, DMSO) d 164.4, 160.8, 147.3, 135.6,
2
-(5-(4-Bbromophenyl)-1,3,4-oxadiazol-2-yl)aniline (3f)
33.06, 131.7, 127.4, 126.8, 125.75, 119.35, 118.2, and 105.06.
ꢁ
1
Yellow solid, Yield: 134 mg (85%), m.p 186–187 C. H NMR
500 MHz, DMSO) d 8.10–8.06 (m, 2H), 7.89–7.82 (m, 3H), 7.30 (ddd,
þ
HRMS (ESI) m/z: [M þ H] calculated for C H Cl N O 339.9806,
1
4
9
3 3
(
found 339.9811.
J ¼ 8.5, 7.2, 1.5 Hz, 1H), 6.93 (d, J ¼ 8.3 Hz, 1H), 6.79 (d, J ¼ 7.3 Hz,
1
3
2
H), and 6.74–6.69 (m, 1H). C NMR (126 MHz, DMSO) d 164.9,
1
61.8, 148.4, 133.1, 132.9, 129.0, 128.3, 125.9, 123.0, 116.4, 116.0,
4
-Chloro-2-(5-(5-methoxy-2-methylphenyl)-1,3,4-oxadiazol-2-yl)
aniline (3n)
Yellow solid, Yield: 140 mg (89%), m.p 158–15.5 C. H NMR
500 MHz, DMSO) d 8.08 (d, J ¼ 8.7 Hz, 1H), 7.79 (d, J ¼ 2.4 Hz, 1H),
.30 (dd, J ¼ 8.9, 2.5 Hz, 1H), 7.02 (d, J ¼ 2.1 Hz, 1H), 6.99–6.90 (m,
þ
and 104.3. HRMS (ESI) m/z: [M þ H] calculated for C14
3
H11BrN O
3
16.0080, found 316.0078.
ꢁ
1
(
7
2
-(5-(3,5-Dichlorophenyl)-1,3,4-oxadiazol-2-yl)aniline (3g)
1
3
ꢁ
1
4H), 3.84 (s, 3H), and 2.67 (s, 3H). C NMR (126 MHz, DMSO) d
Yellow solid, Yield: 126 mg (83%), m.p 210–212 C. H NMR
1
1
62.9, 162.74, 161.8, 147.0, 140.4, 132.4, 131.3, 126.9, 119.1, 118.1,
17.3, 115.1, 112.6, 105.6, 55.87, and 22.3. HRMS (ESI) m/z:
(
1
500 MHz, DMSO) d 8.16 (d, J ¼ 1.9 Hz, 2H), 7.98 (dd, J ¼ 8.0, 1.5 Hz,
H), 7.92 (t, J ¼ 1.9 Hz, 1H), 7.30 (ddd, J ¼ 8.5, 7.1, 1.6 Hz, 1H), 6.92
þ
1
3
[M þ H] calculated for C H ClN O 316.0847, found 316.0844.
1
6
15
3 2
(
dd, J ¼ 8.4, 0.7 Hz, 1H), 6.79 (s, 2H), and 6.73–6.68 (m, 1H).
C
NMR (126 MHz, DMSO) d 165.4, 160.5, 148.5, 135.6, 133.3, 131.64,
1
[
28.7, 127.0, 125.5, 116.3, 116.0, and 104.0. HRMS (ESI) m/z
M þ H]þ calculated for C H Cl N O 306.0915, found 306.0918.
4-Bromo-2-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)
aniline (3o)
1
4
10
2 3
ꢁ
1
Yellow solid, Yield: 157 mg (82%), m.p 167–168 C. H NMR
(500 MHz, DMSO) d 8.40 (d, J ¼ 7.4 Hz, 2H), 8.09–7.93 (m, 3H), 7.42
2
-(5-(2-Methyl-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)aniline (3i)
1
1
3
ꢁ
Yellow solid, Yield: 120 mg (81%), m.p 186.5–188 C. H NMR (d, J ¼ 8.4 Hz, 1H), 6.97 (s, 2H), 6.91 (d, J ¼ 8.8 Hz, 1H). C NMR
(
(
500 MHz, DMSO) d 8.12 (d, J ¼ 8.3 Hz, 1H), 8.00–7.96 (m, 1H), 7.73 (126 MHz, DMSO) d 164.2, 161.8, 147.6, 135.6, 130.0, 128.1, 127.4,
d, J ¼ 8.2 Hz, 1H), 7.65 (dd, J ¼ 8.0, 1.3 Hz, 1H), 7.33–7.27 (m, 1H), 126.74 (d, J ¼ 3.7 Hz), 125.3, 118.6, 106.2, and 105.85. HRMS (ESI)
þ
6
.94 (d, J ¼ 8.3 Hz, 1H), 6.80 (s, 2H), 6.73–6.66 (m, 1H), 2.52 (s, 3H). m/z: [M þ H] calculated for
15 3 3
C H10BrF N O 383.9984, found
1
3
C NMR (126 MHz, DMSO) d 165.4, 159.3, 148.4, 146.2, 145.3, 383.9990.
1
2
33.9, 133.4, 132.0, 128.0, 125.3, 117.6, 116.5, 116.1, 103.8, and
þ
1.2. HRMS (ESI) m/z: [M þ H] calculated for C15
13 4 3
H N O 297.0982,
2
-(5-(3,5-Dimethoxyphenyl)-1,3,4-oxadiazol-2-yl)-4-fluoroaniline
found 297.0976.
(3p)
ꢁ
1
Yellow solid, Yield: 139 mg (88%), m.p 152–154 C. H NMR
(500 MHz, DMSO) d 7.78 (dd, J ¼ 9.6, 3.0 Hz, 1H), 7.28 (t, J ¼ 8.4 Hz,
4
-Chloro-2-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)
aniline (3j)
2H), 7.21 (td, J ¼ 8.7, 3.0 Hz, 1H), 6.94 (dd, J ¼ 9.1, 4.8 Hz, 1H), 6.76
ꢁ
1
13
Yellow solid, Yield: 137 mg (81%), m.p 196–198 C. H NMR (t, J ¼ 2.2 Hz, 1H), 6.70 (s, 2H), 3.87 (s, 6H). C NMR (126 MHz,
(
(
1
1
500 MHz, DMSO) d 8.34 (t, J ¼ 44.9 Hz, 2H), 8.17–7.76 (m, 3H), 7.32 DMSO) d 164.1 (d, J ¼ 2.6 Hz), 162.6, 161.4, 154.5, 152.7, 145.2,
13
d, J ¼ 7.2 Hz, 1H), 6.95 (s, 3H). C NMR (126 MHz, DMSO) d 164.2, 125.2, 120.8 (d, J ¼ 22.5 Hz), 117.8 (d, J ¼ 7.4 Hz), 113.4 (d,
61.8, 147.3, 132.9, 128.16, 127.45, 127.19, 126.7 (d, J ¼ 3.7 Hz), J ¼ 24.4 Hz), 105.4, 104.4, 104.01 (d, J ¼ 8.2 Hz), and 56.11 (s). HRMS
þ
25.33, 119.26, 118.3, and 105.1. HRMS (ESI) m/z: (ESI) m/z: [M þ H] calculated for C16
3 3
H15FN O 316.1092, found
þ
[M þ H] calculated for C15
H10ClF
3
N
3
O 340.0459, found 340.0462.
316.1094.

6
18
S. ANGAPELLY ET AL.
2
-(5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethoxy)
aniline (3q)
Yellow solid, Yield: 129 mg (80%), m.p 183–184 C. H NMR (500 MHz, CDCl
2-(5-(Isoquinolin-3-yl)-1,3,4-oxadiazol-2-yl)aniline (6b)
ꢁ
1
Yellow solid, Yield: 126 mg (87%), m.p 256–257 C. H NMR
) d 9.43 (s, 1H), 8.69 (s, 1H), 8.13–7.96 (m, 3H), 7.83
500 MHz, DMSO) d 8.30–8.23 (m, 18H), 7.87 (d, J ¼ 2.6 Hz, 8H), 7.48 (t, J ¼ 7.4 Hz, 1H), 7.76 (t, J ¼ 7.3 Hz, 1H), 7.35–7.27 (m, 1H),
ꢁ
1
3
(
1
3
(
t, J ¼ 8.8 Hz, 18H), 7.32 (dd, J ¼ 9.0, 2.0 Hz, 9H), 7.02 (s, 5H), 7.00 (s, 6.86–6.79 (m, 2H). C NMR (126 MHz, DMSO) d 165.20, 162.55,
13
1
1
1
1
3
7H).
C NMR (126 MHz, DMSO) d 165.6, 163.7 (d, J ¼ 9.4 Hz), 153.88, 148.50, 136.96, 135.62, 133.17, 132.25, 130.01, 129.37,
62.1, 147.5, 138.1 (d, J ¼ 2.0 Hz), 130.1 (d, J ¼ 9.2 Hz), 126.5, 121.8, 128.43, 128.2, 128.1, 121.16, 116.50, 116.11, and 104.40. HRMS (ESI)
þ
20.9, 120.3 (d, J ¼ 3.0 Hz), 119.8, 117.6, 117.1 (d, J ¼ 22.5 Hz), and m/z: [M þ H] calculated for C H N O 289.1084, found 289.1088.
1
7 13 4
þ
04.2. HRMS (ESI) m/z: [M þ H] calculated for C15
10 4 3 2
H F N O
40.0755, found 340.0759.
2
-(5-(1H-indazol-3-yl)-1,3,4-oxadiazol-2-yl)aniline (6c)
ꢁ
1
Yellow solid, Yield: 95 mg (69%) m.p 281–283 C.
500 MHz, DMSO) d 14.05 (s, 1H), 8.27 (d, J ¼ 8.2 Hz, 1H), 7.83 (dd,
J ¼ 8.0, 1.3 Hz, 1H), 7.73 (t, J ¼ 8.5 Hz, 1H), 7.54 (dd, J ¼ 8.2, 7.1 Hz,
H NMR
4
2
-(Trifluoromethoxy)-2-(5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-
-yl)aniline (3r)
(
ꢁ
1
Yellow solid, Yield: 172 mg (87%), m.p 203.5–205 C. H NMR 1H), 7.40 (dd, J ¼ 7.9, 7.2 Hz, 1H), 7.35–7.29 (m, 1H), 6.96 (d,
1
3
(500 MHz, DMSO) d 7.93 (s, 1H), 7.44 (s, 2H), 7.32 (s, 1H), 7.01 (s,
J ¼ 8.0 Hz, 1H), 6.85 (s, 2H), 6.75 (t, J ¼ 7.5 Hz, 1H).
C NMR
1
3
3
1
1
H), 3.93 (s, 6H), 3.77 (s, 3H). C NMR (126 MHz, DMSO) d 163.7,
62.8, 153.9, 147.4, 141.2, 138.1, 126.4, 121.0, 118.7, 117.6, 104.9,
04.2, 60.7, and 56.8. HRMS (ESI) m/z: [M þ H] calculated for
(126 MHz, DMSO) d 164.03, 158.68, 148.42, 141.46, 133.08, 130.12,
1
1
2
28.06, 127.81, 123.35, 121.28, 121.09, 116.48, 116.20, 111.64, and
þ
þ
04.36. HRMS (ESI) m/z: [M þ H] calculated for
15 12 5
C H N O
18 17 3 3 5
C H F N O 411.1166, found 411.1169.
78.1036, found 278.1038.
2
-(5-(3,5-Dimethylphenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethoxy)
aniline (3s)
Yellow solid, Yield: 144 mg (84%), m.p 199–201 C. H NMR
500 MHz, DMSO) d 7.78 (dd, J ¼ 9.6, 3.0 Hz, 1H), 7.28 (t, J ¼ 8.4 Hz,
H), 7.21 (td, J ¼ 8.7, 3.0 Hz, 1H), 6.94 (dd, J ¼ 9.1, 4.8 Hz, 1H), 6.76
4
-Fluoro-2-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)aniline (6d)
ꢁ
1
Yellow solid, Yield: 99 mg (77%), m.p 226–227.5 C. H NMR
ꢁ
1
(
1
3
500 MHz, DMSO) d 8.86 (dd, J ¼ 4.4, 1.6 Hz, 2H), 8.12 (dd, J ¼ 4.4,
(
2
.6 Hz, 2H), 7.75 (dd, J ¼ 9.6, 3.0 Hz, 1H), 7.24 (ddd, J ¼ 8.9, 8.4,
13
.0 Hz, 1H), 6.96 (dd, J ¼ 9.1, 4.8 Hz, 1H), 6.73 (s, 2H). C NMR
1
3
(
t, J ¼ 2.2 Hz, 1H), 6.70 (s, 2H), 3.87 (s, 6H). C NMR (126 MHz,
(126 MHz, DMSO) d 164.8, 161.2, 154.5, 152.6, 151.3, 145.5, 130.7,
DMSO) d 163.6, 163, 147.4, 139.2, 138, 133, 126.4, 124.8, 123.4,
1
21.2 (d, J ¼ 23.7 Hz), 120.8, 118.07 (d, J ¼ 7.5 Hz), 113.3 (d,
þ
1
20.9, 117.6, 104.3, and 21.1. HRMS (ESI) m/z: [M þ H] calculated
þ
J ¼ 22.5 Hz), and 103.6 (d, J ¼ 8.3 Hz). HRMS (ESI) m/z: [M þ H] cal-
for C H F N O 350.1162, found 350.1158.
1
7 15 3 3
4
culated for C13H10FN O 257.0833, found 257.0837.
2
-(5-(5-Methoxy-2-methylphenyl)-1,3,4-oxadiazol-2-yl)-4-nitroani-
line (3t)
Yellow solid, Yield: 139 mg (85%), m.p 240–241 C. H NMR
4
-Chloro-2-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)aniline (6e)
ꢁ
1
Yellow solid, Yield: 115 mg (84%), m.p 208–209 C. H NMR
ꢁ
1
(
500 MHz, DMSO) d 8.86 (dd, J ¼ 7.1, 2.7 Hz, 2H), 8.19–8.07 (m, 2H),
(
500 MHz, DMSO) d 8.63 (t, J ¼ 9.8 Hz, 1H), 8.21–7.92 (m, 4H),
7
7
1
.94 (dd, J ¼ 4.9, 2.5 Hz, 1H), 7.33 (ddd, J ¼ 7.2, 4.0, 2.1 Hz, 1H),
7
.10–6.99 (m, 3H), 3.84 (d, J ¼ 20.0 Hz, 3H), 2.67 (d, J ¼ 25.2 Hz, 3H).
C NMR (126 MHz, DMSO) d 163.3, 162.2, 162.0, 153.0, 140.5,
13
.02–6.89 (m, 3H). C NMR (126 MHz, DMSO) d 164.53, 161.34,
51.34, 147.41, 133.11, 130.77, 127.28, 120.88, 119.29, 118.35, and
1
3
1
36.3, 131.4, 128.0, 125.4, 117.3, 116.2, 114.9, 112.7, 103.9, 55.9,
þ
þ
105.05. HRMS (ESI) m/z: [M þ H] calculated for C13
H10ClN O
4
and 22.3. HRMS (ESI) m/z: [M þ H] calculated for C H N O
1
6 15 4 4
273.0538, found 273.0537.
3
27.1088, found 327.1089.
4
-Chloro-2-(5-(isoquinolin-3-yl)-1,3,4-oxadiazol-2-yl)aniline (6f)
2
-(5-(3,5-Dimethoxyphenyl)-1,3,4-oxadiazol-2-yl)-4-methoxyaniline
ꢁ
1
Yellow solid, Yield: 119 mg (74%), m.p 213–214 C. H NMR
(500 MHz, DMSO) d 9.52 (s, 1H), 8.88 (s, 1H), 8.27 (s, 2H), 7.90 (d,
(
3u)
ꢁ
1
Yellow solid, Yield: 150 mg (92%), m.p 143.5–145 C. H NMR
1
3
J ¼ 37.9 Hz, 3H), 7.34 (s, 1H), 6.99 (s, 3H).
C NMR (126 MHz,
(
500 MHz, DMSO) d 8.30–8.23 (m, 18H), 7.87 (d, J ¼ 2.6 Hz, 8H), 7.48
DMSO) d 164.0, 162.77, 153.9, 147.3, 136.7, 135.6, 132.8, 132.2,
(
t, J ¼ 8.8 Hz, 18H), 7.32 (dd, J ¼ 9.0, 2.0 Hz, 9H), 7.02 (s, 5H), and
1
3
130.0, 129.4, 128.4, 128.1, 126.9, 121.4, 119.2, 118.3, and 105.3.
7
1
1
.00 (s, 17H). C NMR (126 MHz, DMSO) d 164.80, 162.41, 161.47,
50.35, 143.13, 125.36, 121.72, 118.03, 111.04, 105.08, 104.13,
04.12, 56.19, and 56.08. HRMS (ESI) m/z: [M þ H] calculated for
þ
HRMS (ESI) m/z: [M þ H] calculated for C17
4
H12ClN O 323.0694,
þ
found 323.0688.
C H N O 328.1292, found 328.1290.
1
7 18 3 4
2
-(5-(Isoquinolin-3-yl)-1,3,4-oxadiazol-2-yl)-4-methoxyaniline (6g)
ꢁ
1
2
-(5-(Pyridin-4-yl)-1,3,4-oxadiazol-2-yl)aniline (6a)
Yellow solid, Yield: 118 mg (74%), m.p 190–191 C. H NMR
ꢁ
1
Yellow solid, Yield: 108 mg (90%), m.p 174–175 C. H NMR (500 MHz, DMSO) d 9.54 (s, 1H), 8.86 (s, 1H), 8.27 (dd, J ¼ 17.0,
(
1
1
500 MHz, DMSO) d 8.85 (dd, J ¼ 4.5, 1.6 Hz, 2H), 8.07 (dd, J ¼ 4.5, 8.1 Hz, 2H), 7.94 (t, J ¼ 7.5 Hz, 1H), 7.86 (t, J ¼ 7.5 Hz, 1H), 7.36 (d,
.5 Hz, 2H), 7.89 (dd, J ¼ 8.0, 1.4 Hz, 1H), 7.31 (ddd, J ¼ 8.5, 7.2, J ¼ 2.7 Hz, 1H), 7.04 (dd, J ¼ 9.0, 2.8 Hz, 1H), 6.93 (d, J ¼ 9.0 Hz, 1H),
13
.5 Hz, 1H), 6.94 (d, J ¼ 7.9 Hz, 1H), 6.81 (s, 2H), 6.76–6.68 (m, 1H). 6.49 (s, 2H), 3.80 (s, 3H). C NMR (126 MHz, DMSO) d 165.1, 162.5,
C NMR (126 MHz, DMSO) d 165.5, 161.0, 151.3, 148.6, 133.4, 153.8, 150.3, 143.2, 136.9, 135.6, 132.2, 130.1, 129.3, 128.4, 128.1,
1
3
1
[
30.9, 128.4, 120.7, 116.5, 116.0, and 104.0. HRMS (ESI) m/z: 122.0, 121.2, 118.2, 110.5, 104.1, and 56.2. HRMS (ESI) m/z:
M þ H]þ calculated for C13
H
11
N
4
O 239.0927, found 239.0928.
þ
15 4 2
[M þ H] calculated for C18H N O 319.1190, found 319.1191.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
619
þ
4
-(5-(2-Aminophenyl)-1,3,4-oxadiazol-2-yl)benzenesulfonamide (8a) 119.8, 117.7, and 104.0. HRMS (ESI) m/z: [M þ H] calculated for
ꢁ
1
Yellow solid, Yield: 118 mg (75%), m.p 282–283 C. H NMR C H F3N O S 401.0525, found 401.0536.
1
5
12
4 3
(
(
500 MHz, DMSO) d 8.38–8.31 (m, 2H), 8.06 (d, J ¼ 8.5 Hz, 2H), 7.89
dt, J ¼ 12.5, 6.3 Hz, 1H), 7.61 (s, 2H), 7.34–7.27 (m, 1H), 6.93 (t,
1
3
J ¼ 7.0 Hz, 1H), 6.79 (d, J ¼ 13.9 Hz, 2H), 6.76–6.70 (m, 1H). C NMR
4
-(5-(2-Amino-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)benzenesulfona-
mide (8g)
Yellow solid, Yield: 102 mg (61%), m.p 260–261 C. H NMR
500 MHz, DMSO) d 8.38–8.33 (m, 2H), 8.08–8.04 (m, 2H), 7.78 (t,
(126 MHz, DMSO) d 165.2, 161.6, 148.5, 147.0, 133.2, 128.4, 127.7,
þ
1
27.1, 116.4, 116.0, and 104.2. HRMS (ESI) m/z: [M þ H] calculated
ꢁ
1
13 4 3
for C14H N O S 317.0703, found 317.0710.
(
J ¼ 6.3 Hz, 1H), 7.60 (s, 2H), 7.32 (ddd, J ¼ 11.7, 7.9, 1.3 Hz, 1H),
1
3
6
.79–6.72 (m, 3H). C NMR (126 MHz, DMSO) d 164.5 (d, J ¼ 4.1 Hz),
61.9, 152.2, 150.3, 147.2, 137.1 (d, J ¼ 15.6 Hz), 137.1(d,
4
-(5-(2-Amino-5-methylphenyl)-1,3,4-oxadiazol-2-yl)benzenesulfo-
namide (8b)
Yellow solid, Yield: 117 mg (71%), m.p 278–279 C. H NMR
500 MHz, DMSO) d 8.38–8.31 (m, 2H), 8.09–8.02 (m, 2H), 7.71 (d,
J ¼ 0.9 Hz, 1H), 7.59 (s, 2H), 7.14 (dt, J ¼ 14.5, 7.3 Hz, 1H), 6.85 (t,
1
ꢁ
1
J ¼ 15.6 Hz), 127.9, 127.1, 126.4, 124.0 (d, J ¼ 3.4 Hz), 118.0 (d,
J ¼ 17.9 Hz), 115.7 (d, J ¼ 7.3 Hz), and 106.8 (d, J ¼ 5.6 Hz). HRMS
(
þ
(
ESI) m/z: [M þ H] calculated for C H FN O S 335.0609, found
1
4
12
4 3
1
3
335.0611.
J ¼ 8.8 Hz, 1H), 6.59 (d, J ¼ 21.4 Hz, 2H), 2.26 (s, 3H). C NMR
(126 MHz, DMSO) d 165.3, 161.6, 147.1, 146.4, 134.4, 127.7, 127.1,
þ
1
26.6, 124.6, 116.7, 104.0, and 20.3. HRMS (ESI) m/z: [M þ H] cal-
culated for C14
H
13
4
N O
3
S 331.0859, found 331.0866.
4-(5-(2-Amino-3,5-dimethylphenyl)-1,3,4-oxadiazol-2-yl)benzenesul-
fonamide (8h)
ꢁ
1
Yellow solid, Yield: 112 mg (65%), m.p 295–296 C. H NMR
4
-(5-(2-Amino-5-methoxyphenyl)-1,3,4-oxadiazol-2-yl)benzenesulfo-
namide (8c)
Yellow solid, Yield: 130 mg (75%), m.p 253–254 C. H NMR
(
7
500 MHz, DMSO) d 8.34 (d, J ¼ 7.6 Hz, 2H), 8.05 (d, J ¼ 7.7 Hz, 2H),
1
3
.60 (s, 3H), 7.07 (s, 1H), 6.44 (s, 2H), 2.22 (d, J ¼ 35.1 Hz, 6H).
C
ꢁ
1
NMR (126 MHz, DMSO) d 165.6, 161.6, 147.1, 144.6, 135.2, 127.7,
(
(
1
500 MHz, DMSO) d 8.38 (t, J ¼ 10.3 Hz, 2H), 8.09–8.01 (m, 2H), 7.59
1
27.1, 126.6, 125.7, 124.6, 123.7, 104.0, 20.3, and 18.1. HRMS (ESI)
d, J ¼ 7.1 Hz, 2H), 7.40 (d, J ¼ 2.9 Hz, 1H), 7.03 (dd, J ¼ 9.0, 2.9 Hz,
þ
m/z: [M þ H]
16 17 4 3
calculated for C H N O S 345.1016, found
1
3
H), 6.90 (dd, J ¼ 13.1, 8.5 Hz, 1H), 6.44 (s, 2H), 3.78 (s, 3H).
C
3
45.1012.
NMR (126 MHz, DMSO) d 165.1, 161.7, 150.4, 147.1, 143.3, 127.8,
1
[
27.1, 126.6, 122.10, 118.1, 110.8, 103.9, and 56.2. HRMS (ESI) m/z:
M þ H]þ calculated for C15
15 4 4
H N O S 347.0809, found 347.0812.
4-(5-(2-Amino-3,5-dichlorophenyl)-1,3,4-oxadiazol-2-yl)benzenesul-
fonamide (8i)
Yellow solid, Yield: 114 mg (60%), m.p 284–285 C. H NMR
ꢁ
1
4
-(5-(2-Amino-5-fluorophenyl)-1,3,4-oxadiazol-2-yl)benzenesulfona-
(
500 MHz, DMSO) d 8.29–8.24 (m, 2H), 8.08–8.02 (m, 2H), 7.60 (s,
mide (8d)
Yellow solid, Yield: 117 mg (70%), m.p 290–291 C. H NMR
1
3
ꢁ
1
2H), 7.52 (t, J ¼ 9.3 Hz, 1H), 6.85 (d, J ¼ 8.5 Hz, 1H), 6.43 (s, 2H).
C
NMR (126 MHz, DMSO) d 164.1, 161.2, 147.3, 146.5, 133.22 (d,
(
(
500 MHz, DMSO) d 8.42–8.36 (m, 2H), 8.08–8.02 (m, 2H), 7.79–7.71
m, 1H), 7.59 (s, 2H), 7.21 (tdd, J ¼ 11.9, 8.7, 3.0 Hz, 1H), 6.95 (td,
J ¼ 41.0 Hz), 127.9, 127.2, 126.7, 117.5 (d, J ¼ 33.0 Hz), and 106.9.
þ
1
3
13
HRMS (ESI) m/z: [M þ H] calculated for C H Cl N O S 384.9923,
J ¼ 9.4, 4.8 Hz, 1H), 6.71 (s, 2H). C NMR (126 MHz, DMSO) d
C
14 11
2 4 3
found 384.9927.
NMR (126 MHz, DMSO) d 164.49 (s), 161.92 (s), 154.55 (s), 152.71
s), 147.22 (s), 145.39 (s), 127.94 (s), 127.08 (s), 126.50 (s), 121.08 (d,
(
J ¼ 23.2 Hz), 118.02 (d, J ¼ 7.5 Hz), 113.33 (d, J ¼ 24.4 Hz), and
þ
1
C
03.85 (d, J ¼ 8.2 Hz). HRMS (ESI) m/z: [M þ H] calculated for 3-(5-(2-Aminophenyl)-1,3,4-oxadiazol-2-yl)benzenesulfonamide (8j)
ꢁ
1
14
H
12FN
4
O
3
S 335.0609, found 335.0621.
Yellow solid, Yield: 99 mg (63%), m.p 257–258 C.
H NMR
(
500 MHz, DMSO) d 8.56 (s, 1H), 8.36 (d, J ¼ 7.9 Hz, 1H), 8.07 (d,
J ¼ 7.9 Hz, 1H), 7.90–7.82 (m, 2H), 7.62 (s, 2H), 7.34–7.29 (m, 1H),
4
-(5-(2-Amino-5-chlorophenyl)-1,3,4-oxadiazol-2-yl)benzenesulfona-
mide (8e)
Yellow solid, Yield: 117 mg (67%), m.p 306–307 C. H NMR
6
1
1
1
.94 (d, J ¼ 8.3 Hz, 1H), 6.81 (s, 2H), 6.73 (dd, J ¼ 11.1, 4.0 Hz,
13 13
H). C NMR (126 MHz, DMSO) d C NMR (126 MHz, DMSO) d
ꢁ
1
65.1, 161.6, 148.4, 145.7, 133.2, 130.9, 130.1, 129.0, 128.3, 124.6,
(
(
(
1
1
500 MHz, DMSO) d 8.40 (d, J ¼ 8.4 Hz, 2H), 8.08–8.03 (m, 2H), 7.93
þ
24.0, 116.4, 116.0, and 104.2. HRMS (ESI) m/z: [M þ H] calculated
t, J ¼ 4.8 Hz, 1H), 7.60 (s, 2H), 7.33 (dd, J ¼ 8.9, 2.4 Hz, 1H), 6.95
for C H N O S 317.0703, found 317.0711.
1
4 13 4 3
1
3
dd, J ¼ 17.6, 11.7 Hz, 3H). C NMR (126 MHz, DMSO) d 164.2,
61.9, 147.2 (d, J ¼ 11.0 Hz), 132.9, 127.9, 127.1 (d, J ¼ 13.3 Hz),
þ
26.4, 119.2, 118.3, and 105.2. HRMS (ESI) m/z: [M þ H] calculated
3-(5-(2-Amino-5-methylphenyl)-1,3,4-oxadiazol-2-yl)benzenesulfo-
4 3
for C14H12ClN O S 353.0313, found 353.0305.
namide (8k)
ꢁ
1
Yellow solid, Yield: 107 mg (65%), m.p 264–265 C. H NMR
(500 MHz, DMSO) d 8.55 (s, 1H), 8.37 (d, J ¼ 7.7 Hz, 1H), 8.07 (d,
J ¼ 7.7 Hz, 1H), 7.85 (t, J ¼ 7.8 Hz, 1H), 7.65 (d, J ¼ 22.4 Hz, 3H), 7.15
4
-(5-(2-Amino-5-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)
benzenesulfonamide (8f)
ꢁ
1
Yellow solid, Yield: 138 mg (65%), m.p 242–243 C. H NMR (d, J ¼ 8.1 Hz, 1H), 6.86 (d, J ¼ 8.4 Hz, 1H), 6.62 (s, 2H), 2.27 (s,
1
3
(
500 MHz, DMSO) d 8.42–8.37 (m, 2H), 8.08–8.03 (m, 2H), 7.90 (d, 3H). C NMR (126 MHz, DMSO) d 165.2, 161.5, 146.4, 145.7, 134.4,
J ¼ 2.8 Hz, 1H), 7.60 (s, 2H), 7.34 (dt, J ¼ 11.2, 5.6 Hz, 1H), 7.04–7.00 130.8, 130.2, 129.0, 127.6, 124.6 (d, J ¼ 2.3 Hz),124.0, 116.7, 104.0,
1
3
þ
(
m, 3H). C NMR (126 MHz, DMSO) d 164.1, 162.0, 147.6, 147.4 (d, and 20.3. HRMS (ESI) m/z: [M þ H] calculated for C15
15 4 3
H N O S
J ¼ 51.9 Hz), 147.2, 138.1, 128.0, 127.0, 126.8,126.4, 121.8, 121.1, 331.0859, found 331.0855.

6
20
S. ANGAPELLY ET AL.
3
-(5-(2-Amino-5-methoxyphenyl)-1,3,4-oxadiazol-2-yl)benzenesulfo- assay buffer mentioned above. At least seven different inhibitor
namide (8l)
concentrations have been used for measuring the inhibition con-
Yellow solid, Yield: 119 mg (69%), m.p 240–242 C. H NMR stant. Inhibitor and enzyme solutions were preincubated together
500 MHz, DMSO) d 8.57 (t, J ¼ 1.5 Hz, 1H), 8.42–8.37 (m, 1H), for 10 min at room temperature prior to assay, in order to allow
.09–8.04 (m, 1H), 7.85 (t, J ¼ 7.8 Hz, 1H), 7.64 (s, 2H), 7.38 (d, for the formation of the E-I complex. Triplicate experiments were
ꢁ
1
(
8
J ¼ 2.9 Hz, 1H), 7.04 (dd, J ¼ 9.0, 2.9 Hz, 1H), 6.92 (d, J ¼ 9.0 Hz, 1H), done for each inhibitor concentration, and the values reported
1
3
6
1
1
.45 (s, 2H), 3.78 (s, 3H). C NMR (126 MHz, DMSO) d 165.0, 161.6, throughout the paper are the mean of such results. The inhibition
50.36, 145.7, 143.2, 130.8, 130.3, 129.0, 124.5, 124.0, 121.9, 118.1, constants were obtained by non-linear least-squares methods
þ
10.9, 103.9, and 56.2. HRMS (ESI) m/z: [M þ H] calculated for using the Cheng–Prusoff equation, as reported earlier, and repre-
C H N O S347.0809, found 347.0818.
sent the mean from at least three different determinations. All CA
isozymes used here were recombinant proteins obtained as
1
5 15 4 4
2
5,26
reported earlier by our group
.
3
-(5-(2-Amino-5-fluorophenyl)-1,3,4-oxadiazol-2-yl)benzenesulfona-
mide (8m)
Yellow solid, Yield: 100 mg (60%), m.p225–226 C.
ꢁ
1
H
NMR Results and discussion
(
8
7
500 MHz, DMSO) d 8.59 (t, J ¼ 1.6 Hz, 1H), 8.41 (d, J ¼ 7.8 Hz, 1H),
Chemistry
.06 (ddd, J ¼ 11.1, 6.1, 4.8 Hz, 1H), 7.85 (t, J ¼ 7.8 Hz, 1H),
.74–7.67 (m, 1H), 7.63 (s, 2H), 7.23 (td, J ¼ 8.6, 3.0 Hz, 1H), 6.96
We commenced our investigation with a reaction using an equi-
molar ratio of isatin and 4-methyl benzohydrazide as model sub-
strates using molecular iodine (100 mol%) and Cs
1
3
(
dd, J ¼ 9.1, 4.8 Hz, 1H), 6.71 (s, 2H). C NMR (126 MHz, DMSO) d
2
CO
3
(1.0 equiv.)
1
1
1
64.38, 161.8, 154.5, 152.7, 145.7, 145.3, 130.8, 130.3, 129.1, 124.4,
ꢁ
24.1, 121.1, 121.0 (d, J ¼ 23.1 Hz), 120.9, 118.0 (d, J ¼ 7.4 Hz), in DMSO at 100 C (Table 1). The desired product was obtained in
13.3, 113.2 (d, J ¼ 24.3 Hz), 113.1, and 103.8 (d, J ¼ 8.2 Hz). HRMS 71% yield (Table 1, entry 1). No product was obtained in the
þ
(
3
ESI) m/z: [M þ H] calculated for C H FN O S335.0609, found absence of either catalyst or base which suggests that an iodine/
1
4
12
4 3
35.0617.
base combination is required for the reaction to occur (Table 1,
entries 2–4). Exploring the possibility for improving the reaction
efficiency, the effect of other alkali metal carbonates/other bases
on the reaction efficiency was then examined. The transformation
3
-(5-(2-Amino-5-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)
benzenesulfonamide (8n)
underwent smoothly in the presence of K CO3 to afford the
2
ꢁ
1
Yellow solid, Yield: 120 mg (60%), m.p 253–255 C. H NMR desired product 3a in 80% yield after 12 h (Table 1, entry
500 MHz, DMSO) d 8.56 (s, 1H), 8.37 (d, J ¼ 8.0 Hz, 1H), 8.07 (d, 5),whereas other bases, such as Na CO , K PO , and NaHCO were
(
2
3
3
4
3
J ¼ 8.3 Hz, 1H), 7.85 (t, J ¼ 7.8 Hz, 1H), 7.75 (d, J ¼ 8.0 Hz, 1H), 7.62 found to be less effective (Table 1, entries 6–8). With an attempt
1
3
(
(
s, 2H), 7.32 (dd, J ¼ 10.7, 8.0 Hz, 1H), 6.80–6.72 (m, 3H). C NMR to further optimise the yield of the product, we investigated the
126 MHz, DMSO) d 164.4, 161.9, 152.2, 150.3, 145.8, 137.1 (d,
influence of various iodine reagents. TBAI, N-iodosuccinimide (NIS)
and KI gave poor to moderate yields, i.e. of 18, 45, and 35%,
respectively (Table 1, entries 9–11). However, phenyliodine(III)
J ¼ 15.6 Hz), 130.9, 130.3, 129.2, 124.4, 124.1, 123.9 (d, J ¼ 3.2 Hz),
1
18.0 (d, J ¼ 17.9 Hz), 115.7 (d, J ¼ 7.2 Hz), and 106.8 (d, J ¼ 5.4 Hz).
þ
HRMS (ESI) m/z: [M þ H] calculated for C15
H
12
3
F N
4
O
4
S401.0526,
found 401.0533.
Table 1. Optimisation of the reaction conditions for the synthesis of compound
a
3
a .
b
Entry
Iodine (mol%)
Base
Solvent
DMSO
Yield (3a) (%)
3
-(5-(2-Amino-3-fluorophenyl)-1,3,4-ovxadiazol-2-yl)benzenesulfo-
1
2
3
4
5
6
7
8
I
I
2
2
(100)
Cs
2
CO
3
71
namide (8o)
d
ꢃ
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
n.r
n.r
n.r
ꢁ
1
d
Yellow solid, Yield: 101 mg (61%), m.p 231–233 C. H NMR
ꢃ
Cs
2
CO
3
d
ꢃ
ꢃ
(
8
500 MHz, DMSO) d 8.58 (t, J ¼ 1.6 Hz, 1H), 8.45–8.40 (m, 1H),
I
I
I
I
2
2
2
2
(100)
K
K
2
CO
3
80
52
59
56
18
42
35
.10–8.06 (m, 1H), 7.85 (dd, J ¼ 9.0, 6.6 Hz, 2H), 7.63 (s, 2H), 7.35
(100)
(100)
(100)
3
PO
4
1
3
(
dd, J ¼ 9.1, 2.0 Hz, 1H), 7.05–7.00 (m, 3H). C NMR (126 MHz,
Na CO
2 3
DMSO) d 164.0, 161.9, 147.6, 145.7, 138.0 (d, J ¼ 1.9 Hz), 130.8,
NaHCO
3
9
10
TBAI (100)
NIS (100)
KI (100)
PIDA (100)
HTIB (100)
K
K
K
K
K
K
K
K
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
3
3
3
1
30.5, 129.2, 126.7, 124.4, 124.2 (d, J ¼ 33.0 Hz), 124.1, 120.9, 117.7,
þ
and 104.09. HRMS (ESI) m/z: [M þ H]
calculated for
1
1
1
1
1
2
3
4
C
14
H
12FN
4
O
3
S335.0609, found 335.0615.
d
n.r
n.r
d
c
c
I
I
I
2
2
2
(100)
(100)
(100)
86
80
31
15
45
39
27
Carbonic anhydrase inhibition assay
15
1
6
MeCN
THF
1,4-dioxane
EtOH
An SX.18 MV-R Applied Photophysics (Oxford, UK) stopped-flow 17
I2 (100)
(100)
I2 (100)
K2CO3
CO
K2CO3
1
8
I
2
K
2
3
instrument has been used to assay the catalytic/inhibition of vari-
2
4
19
ous CA isozymes . Phenol Red (at a concentration of 0.2 mM) has
been used as indicator, working at the absorbance maximum of
2
0
I
2
(100)
K
K
2
CO
3
MeOH
d
2
1
I
2
(100)
2
CO
3
H
2
O
n.r
5
57 nm, with 10 mM Hepes (pH 7.4) as buffer, 0.1 M Na
2
SO
4
or 22
I2 (20)
K2CO3
DMSO
DMSO
DMSO
DMSO
33
52
59
NaClO (for maintaining constant the ionic strength; these anions 23
are not inhibitory in the used concentration), following the CA-cat-
alysed CO2 hydration reaction for a period of 5–10 s. Saturated
CO
tions of inhibitors were prepared at a concentration of 10 mM (in
DMSO-water 1:1, v/v) and dilutions up to 0.01 nM done with the microwave irradiation at 160 C.
I
I
I
2
2
2
(50)
(75)
(100)
2
K CO
2
K CO
2
K CO
3
3
3
4
2
2
a
4
5
e
91
ꢁ
Standard reaction conditions: 1a (1.0 equiv.), 2a (1.0 equiv.), reagents (equiv.)
b c
2
solutions in water at 25 C were used as substrate. Stock solu-
were heated in 3 ml solvent in a sealed tube for 12 h; Isolated yields; Reaction
ꢁ
d
e
was carried out at 120 C; n.r.: no reaction; Reaction was carried out under
ꢁ

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
621
R2
R4
R1
R1
O
N N
R2
O
R
I , K CO
3
R
R3
2
2
O
O
R3
HN NH2
N
µW, DMSO, 160 °C
H
NH2
R4
1
a-g
2a-k
3a-t
Me
N
N
N
OMe
OMe
OMe
N
N
N
O
Me
O
O
OMe
NH2
NH2
NH2
3c, 30 min, 91%
3
a, 30 min, 91%
3b, 30 min, 90%
N
N
N
N
N
N
O
O
CF3
F
O
Br
NH2
NH2
NH2
3d, 30 min, 84%
3e, 30 min, 83%
3f, 30 min, 85%
Me
Cl
N
N
N
N
N
N
Cl
O
O
O
CF3
NH2
g, 30 min, 83%, (80%) c
NH2
NO2
3h, 40 min, 81%
NH2
Cl
3
3i, 30 min, 81%
Cl
N
N
N
N
N
N
Cl
Cl
Cl
O
O
O
F
Br
NH2
NH2
3k, 30 min, 83%
NH2
3l, 30 min, 81%
Cl
3
j, 30 min, 81%
Me
N
N
N
N
N
N
OMe
Cl
Br
F
O
O
CF3
O
NH2
OMe
NH2
NH2
OMe
3m, 30 min, 89%
3n, 30 min, 82%
3o, 40 min, 88%
OMe
Me
N
N
N
N
N
N
F3C
F3C
F3C
OMe
O
O
O
F
NH2
NH2
OMe
NH2
3r, 30 min, 84%
Me
3p, 40 min, 80%
3q, 30 min, 87%
Me
OMe
N
N
N
N
O
MeO
O N
2
O
NH2
OMe
NH2
s, 40 min, 85%
OMe
3
3t, 30 min, 92%
Scheme 2. One pot synthesis of the 2-(1,3,4-oxadiazo-2-yl)aniline derivatives. (a) Reaction conditions: 1 (1 equiv.), 2 (1.05 equiv.), I
DMSO (3 ml) under mW irradiation at 160 C for 30–40 min, (b) isolated yields, and (c) The reaction was performed on gram scale.
2
(1.0 equiv.), K CO
2 3
(1.5 equiv.) in
ꢁ
diacetate (PIDA), and hydroxy(tosyloxy)iodobenzene (HITB) did not identical result, albeit with a lower yield in the latter case (Table 1,
at all lead to the formation of the desired product 3a (Table 1, entries 14–15), whereas, MeCN, THF, 1,4-dioxane, EtOH, MeOH, and
entries 12–13). Furthermore, a series of experiments were also car-
2
H O at reflux temperatures proved to be less effective (Table 1,
ried out in various other solvents, such as, DMF, MeCN, THF, 1,4- entries 16–21). Furthermore, the iodine loading was also investi-
dioxane, EtOH, MeOH, and H
2
O. From the obtained results, it can gated in this reaction, and the yields were dropped to 59 and 52
ꢁ
be seen that the use of DMSO and DMF at 120 C gave an almost at 0.75 and 0.5 equiv., respectively (Table 1, entries 22–23) of I
2
,

6
22
S. ANGAPELLY ET AL.
and to a significantly lower value of 33% at 0.2 mol equiv. of I
Table 1, entry 24). We also conducted a control experiment under zoles in good to excellent yields of 80–92% (3j–3u). Considering
nitrogen atmosphere, but the yield under these conditions was the significance of the heterocyclic scaffolds in organic synthesis
diminished to 25%. This indicated that atmospheric O
played an and medicinal chemistry, we further investigated as substrate of
important role in the above transformation. Surprisingly, when the this protocol a variety of heteroaryl hydrazides, such as isonicoti-
2
underwent smoothly to render the corresponding 1,3,4-oxadia-
(
2
noylhydrazide, isoquinoline-3-carbohydrazide, and indazole-3-car-
bohydrazide (Scheme 3). Under the optimal conditions mentioned
above, these heteroaryl derivatives smoothly reacted with isatin
and provided the corresponding 1,3,4-oxadiazoles in moderate to
good yields, i.e. 69–90% (6a–c), whereas, the reactions with 5-
chloro, 5-fluoro, and 5-methoxy-isatin required longer reaction
times (40 min) to furnish the desired product in satisfying yields
same reaction was performed under microwave irradiation gave
better yield of 3a (91%) within a short span of time (40 min).
Indeed, the use of microwave technology has never been men-
tioned in the literature for the synthesis of 2–(1,3,4-oxadiazol-2-
yl)aniline derivatives up until now. Thus the foregoing experiments
led to the conclusion that the conditions used under entry 25 of
Table 1 are the optimal ones for the reaction and, therefore, the
microwave conditions were employed subsequently for all further
reactions to generate compounds 3a–3u/6a–6g/8a–o.
(
6d–g, 74–84%). The structure of 3g was confirmed by X-ray crys-
tallographic analysis, as depicted in Figure 2.
With the optimised conditions in hand, we started our explor-
ation towards finding the potential applicability of this intramo-
lecular decarboxylating domino reaction by attempting to prepare
a variety of 1,3,4-oxadiazoles, using a varied set number of substi-
tuted isatins and benzohydrazides. The results are summarised in
Scheme 2. In this way, a diversified set of 1,3,4-oxadiazoles 3a–3u
were obtained in moderate to excellent yields. It was found that
the reactions were equally successful with both electron withdraw-
ing (4-CF
3
, 4-F, 4-Br, and 3,5-dichloro) as well as electron donating
] on the hydra-
substituents [4-Me, 2-Me-4-OMe, and 3,4,5-(OMe)
3
zide component. However, it may be emphasised that in contrast
to other electron-withdrawing substituents, the 4-nitro group-bear-
ing substrates required longer time to complete the reaction satis-
factorily (3h).
We also studied the effect of electron-donating (–OMe) and
electron-withdrawing groups (5-Cl, 5-Br, 5-F, 5-OCF , and 5-NO )
3
2
on the isatin component on the reaction efficiency, in terms of
Figure 2. ORTEP diagram of the single crystal structure of compound 3g as
both the yield and the reaction time. Notably, these reactions also determined by X-ray crystallography.
O
N
N
R
O
R
R
5
I , K CO
3
2
2
R5
O
O
N
HN NH
2
µW, DMSO, 160 °C
H
NH2
4
a-d
5a-c
6a-g
N
N
N
N
N
N
N
O
N
N
O
O
NH
N
NH2
NH
2
NH2
6c, 30 min,
6
a, 30 min, 90%
6b, 30 min, 87%
6
9%
N
N
N
O
Cl
N
F
O
N
NH2
d, 40 min, 77%
NH2
6
6e, 40 min, 84%
N
N
N
N
N
N
Cl
MeO
O
O
NH2
f, 40 min, 74%
NH
2
6
6g, 40 min, 78%
Scheme 3. One-pot synthesis of 2-(1,3,4-oxadiazo-2-yl)aniline derivatives from various isatins and heteroaryl hydrazides. Reaction conditions: 4 (1.0 equiv.), 5 (1.05
ꢁ
equiv.), I
2
(1.0 equiv.), K CO
2 3
(1.5 equiv.) in DMSO (3 ml) under mW irradiation at 160 C for 30–40 min, isolated yields.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
623
O
N
N
O
SO NH2
2
R
R
NHNH2
I , K CO
3
2
2
O
O
N
µW, DMSO, 160 °C
NH2
H NO S
H
2
2
R6
R6
1
a-i
7a-b
8a-o
N
N
O
N
N
N
N
SO NH2
SO2NH2
H CO
3
SO2NH2
2
O
O
NH2
NH2
NH2
8
a, 40 min, 75%
8b, 40 min, 71%
8c, 40 min, 75%
N
N
N
N
N
N
Cl
SO NH2
2
F
SO NH2
F3CO
SO NH2
2
2
O
O
O
NH2
NH2
NH2
8
d, 40 min, 70%
8e
, 40 min, 67%
8f, 40 min, 69%
N
N
N
N
N
O
N
Cl
SO NH2
SO NH2
SO NH2
O
2
2
2
O
NH2
NH2
NH2
Cl
F
8
g, 40 min, 61%
8h, 40 min, 65%
8i, 40 min, 60%
N
N
N
N
N N
O
H CO
3
O
O
SO NH2
SO2NH2
SO2NH2
2
NH2
NH2
NH2
8
j, 40 min, 63%
8k, 40 min, 65%
8l, 40 min, 69%
N
N
N
N
N
N
F
F3CO
O
O
O
SO NH2
2
SO NH2
SO NH2
NH2
2
2
NH2
NH2
F
8
m, 40 min, 60%
8n, 40 min, 60%
8o, 40 min, 61%
Scheme 4. One pot synthesis of 2-(1,3,4-oxadiazolo-2-yl)aniline-benzene sulfonamide derivatives. Reaction conditions: 1 (1.0 equiv.), 7 (1.05 equiv.), I
2
(1.0 equiv.),
ꢁ
K CO
2 3
(1.5 equiv.) in DMSO (3 ml) under mW irradiation at 160 C for 40 min, isolated yields.
N
O
N
O
I , K CO
2 2 3
TEMPO
CH3
H C
CONHNH2
O
3
µW, DMSO, 160 °C
N
NH2
a (0%)
H
40 min
3
Scheme 5. Control experiment using TEMPO.
In addition to various substituted aryl and heteroaryl hydra- when the reaction was performed in the presence of TEMPO, sug-
zides, we applied this protocol on hydrazides incorporating a sul- gesting clearly that the reaction took place through a radical path-
fonamide moiety. Under the optimised conditions mentioned way (Scheme 5).
earlier, 3 or 4-sulfamoyl benzhydrazides 7a,b reacted smoothly
with a variety of substituted isatins to afford different 2-(1,3,4-oxa- the literature , a plausible reaction mechanism is proposed,
diazolo-2-yl)aniline-benzene sulfonamides 8a–o (Scheme 4).
which is shown in Figure 3, using 1a and 2a as the starting mate-
In the light of the obtained results and the work reported in
8
,17
In order to obtain some mechanistic insights into the nature of rials for the iodine-mediated domino reaction. Isatin (1a) con-
the reaction, radical trapping experiments were performed by denses with the hydrazide (2a) to give the intermediate
employing TEMPO (0.5 equiv.) under the set of optimised condi- hydrazone A, which subsequently undergoes a hydrolytic ring
tions mentioned above. Indeed, no desired product was obtained cleavage to form the carboxylate B. Iodine in the presence of

6
24
S. ANGAPELLY ET AL.
O
O
N
O
O
NH
N
NH
Condensaion
NHNH2
H2O, K2CO3
O
O
COOK
N
H
N
2
H O
H
NH2
1
a
2a
A
B
I2/O2
O
N
O
N
H
N
N
N
N
H
Base
OOC
O
COO
COO
NH2
NH2
Protonation
NH2
E
C
D
I
CO + HI
2
N
N
O
NH2
3
a
Figure 3. Possible reaction mechanism for the domino reaction investigated here.
Figure 4. Fluorescence emission spectra of compounds 3g, 3q, and 3s in DMSO.
Carbonic anhydrase inhibition
oxygen, oxidises
B
to form the radical intermediate C.
Subsequently, abstraction of a proton by the base, followed by a
cyclisation gave the intermediate E, which by elimination of
one molecule of CO and HI, led to the formation of the final
2
product 3a.
Carbonic anhydrases (CAs, EC 4.2.1.1) are a superfamily of metal-
loenzymes, present in most living organisms, in which they cataly-
ses a simple physiological reaction, i.e. the reversible hydration of
CO2 to bicarbonate and protons via a ping–pong mechanism.
These enzymes are involved in many physiological and patho-
1
,3,4-Oxadiazoles are well known for exhibiting a specific fluor-
2
1
escence . In this regard, we investigated the excitation and emis-
2
logical processes, such as pH and CO homeostasis, respiration
sion spectra of some representative molecules described here in and transport of carbon dioxide and bicarbonate between metab-
diluted DMSO as solvent. The excitation and emission spectra of olising tissues and lungs, electrolyte secretion in various tissues
compounds 3e and 3o showed prominent shifts to longer wave- and organs, biosynthetic reactions (gluconeogenesis, lipogenesis,
lengths, in contrast to the other cases in which the shifts were and ureagenesis); calcification, bone resorption, and tumourigenic-
typically only marginal. Figure 4 shows the fluorescence emission ity (in mammals)2 . Dysregulated activities of these carbonic
spectra of compounds 3g, 3q, and 3s. Fluorescence properties of anhydrases were proven to be connected with different human
these compounds suggest that they may hold a potential for diseases, and inhibition of these enzymes by small molecules rep-
2,23
applications as chemical probes.
resents an efficient strategy in chemotherapeutic intervention.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
625
Table 2. Inhibition of hCA isoforms I, II, IV, and IX with sulphonamides 8a–o by iii. hCA IV, which is a membrane-associated isoform majorly
24
a stopped-flow CO
(nM)ꢄ
2
hydrase assay .
expressed in the eye, lungs, and kidneys, being involved
among others in glaucoma and retinitis pigmentosa diseases,
was not particularly prone to inhibition by the sulphona-
mides investigated here In fact, all screened molecules (8a–o)
displayed micromolar inhibitory activity, except 8j–m and 8o,
K
I
Compound
hCA I
hCA II
hCA IV
hCA IX
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
222.2
270.1
320.7
735.5
3497.2
709.6
81.4
34.1
51.5
16.4
43.7
221.5
93.2
6.4
17.6
46.4
46.9
64.6
515.7
307.0
480.4
86.3
12.1
7339.5
5608.9
5924.3
6326.7
8239.1
2173.5
2022.7
7592.0
6777.9
526.0
437.3
588.2
548.3
9428.0
521.5
1892.5
1599.6
282.1
I
which showed high nanomolar CA inhibitory activity, with K s
of 437.3–548.3 nM (Table 2).
1604.2
2366.0
2453.5
2267.5
2030.7
2738.5
2915.5
2964.0
2715.2
2566.0
254.7
iv. hCA IX, the tumour-associated isoform, was moderately inhib-
ited by all tested compounds with K s in the range of
I
89.1
140.3–2964.0 nM. Substitution on both phenyl rings did not
significantly influence the inhibition profile of these com-
pounds for this isoform. Of the screened compounds, 8c, 8n,
and 8o exhibited better CA IX inhibitory profile against this
812.6
3311.9
5828.3
3514.0
746.6
344.1
731.0
250
I
isozyme, with K s of 140.3–282.1 nM (Table 2).
140.3
25.8
AAZ
74
Conclusions
ꢄ
Mean from three different assays, by a stopped-flow technique (errors were in
the range of ±5–10% of the reported values).
We have developed a more efficient and environmentally friendly
protocol for the construction of 2-(1,3,4-oxadiazol-2-yl)aniline
derivatives through one-pot domino decarboxylation by employ-
ing molecular iodine under microwave irradiation. This strategy
works well with various substituted isatins and hydrazides belong-
ing to both aryl and heteroaryl series, also showing good func-
tional group tolerance. Furthermore, this protocol provided
various oxadiazoles, which can be used for further functionalisa-
tion protocols. The reaction mechanism of this domino reaction
was also delineated and presented in this article. Many of the syn-
thesised molecules exhibited fluorescence properties that indicate
their potential usefulness in the field of material chemistry. The
synthesised 2-(1,3,4-oxadiazolo-2-yl)aniline-benzene sulfonamides
Sulphonamides and their bioisosteres (sulfamates and sulfamides),
represents the main class of pharmacologically relevant CA inhibi-
tors. Hence, it was of interest to evaluate the CA inhibitory activity
of 2-(1,3,4-oxadiazolo-2-yl)aniline-benzene sulfonamides (8a–o)
reported here. Thus, compounds 8a–o were investigated as inhibi-
tors of four catalytically active human (h) CA isoforms, i. e. wide-
spread, cytosolic, hCA I, and hCA II, the membrane-anchored hCA
IV, as well as the transmembrane hCA IX, using the clinically used
compound acetazolamide as a standard inhibitor.
The inhibition data are shown in Table 2. The following struc-
ture-activity relationship (SAR) can be delineated from the data of
Table 2:
(
8a–o) were tested for their CA inhibitory activity and it was
noticed that compounds 8c, 8g, and 8h displayed promising and
selective activity against isoform hCA II with K s of 16.4, 6.4, and
7.6 nM, respectively. Such compounds may be useful for various
I
1
i. The slow cytosolic isoform hCA I was inhibited by all the
applications in which the CA activity must be inhibited, such as
for the design of anti-glaucoma, antiobesity, or antitumor
examined sulphonamide derivatives 8a–o with inhibition con-
stants (K s) spanning between 81.4 and 5828.3 nM.
I
Sulphonamides incorporating fluoro (8g) and dimethylaniline
2
7,28
agents
.
moieties (8h) showed medium nanomolar activity (K of 81.4
I
and 89.1 nM, respectively). The other analogues were less
potent and exhibited high nanomolar to low micromolar
Acknowledgements
inhibitory potency against this isoform (K
I
s ranging between Authors are thankful to DoP, Ministry of Chemicals and Fertilisers,
2
5,26
222.2 and 5828.3, respectively)
.
Govt. of India, New Delhi, for the award of a Research Fellowship
ii. hCA II, the dominant physiological isozyme, which is an anti- and to Prof. K. P. R. Kartha, Department of Medicinal Chemistry,
glaucoma drug target, was inhibited by all the tested com- National Institute of Pharmaceutical Education and Research
pounds, with efficacy spanning from the low to the high (NIPER), Sector 67, S. A. S. Nagar, Punjab 160062, India, for his
nanomolar range (K s of 6.4–515.7 nM, Table 2). Among these, valuable suggestions.
I
compound 8g displayed the highest inhibitory activity with a
KI of 6.4 nM. Compounds 8a–d, 8f, 8h–k, and 8o also showed
nanomolar inhibitory activity against this isoform, with K
I
s in Disclosure statement
the range of 16.4–86.3 nM, whereas remaining analogues
exhibited high nanomolar inhibitory action. Among all these
compounds, the 4-sulfamoyl derivatives showed a better CA
II inhibitory activity compared to the 3-sulfamoyl derivatives.
For example compounds, 8c and 8g were 31 and 13 times
more potent than 8l and 8o, respectively. On the other hand,
substitution on the aniline fragment also had a significant
role on activity, i.e. o-fluoro substituted aniline bearing ana-
logues 8g and 8o were more active in comparison to the p-
substituted analogues 8d and 8m. From these observations,
it can be clearly demonstrated that the substitution pattern
on both phenyl rings had significant effect on the inhibitory
activity against hCA II.
No potential conflict of interest was reported by the authors.
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