Synthesis and antimicrobial evaluation of novel pyrazolopyrimidines incorporated with mono- And diphenylsulfonyl groups

Article abstract of DOI:10.3390/molecules24214009

A novel series of pyrazolo[1,5-a]pyrimidine ring systems containing phenylsulfonyl moiety have been synthesized via the reaction of 2-(phenylsulfonyl)-1-(4-(phenylsulfonyl) phenyl)ethan-1-one, 2-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-3-dimethylamino-propenone and 3-(dimethylamino)-1-(4-(phenylsulfonyl)phenyl)prop-2-en-1-one each with various substituted aminoazopyrazole derivatives in one pot reaction strategy. The proposed structure as well as the mechanism of their reactions were discussed and proved with all possible spectral data. The results of antimicrobial activities of the new sulfone derivatives revealed that several derivatives showed activity exceeding the activity of reference drug. Contrary to expectations, we found that derivatives containing one sulfone group are more effective against all bacteria and fungi used than those contain two sulfone groups.

Full text of DOI:10.3390/molecules24214009

molecules
Article
Synthesis and Antimicrobial Evaluation of Novel
Pyrazolopyrimidines Incorporated with Mono- and
Diphenylsulfonyl Groups
Amani M. R. Alsaedi , Thoraya. A. Farghaly * and Mohamed R. Shaaban 1,2,
1
2,
*
1
Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University,
Makkah Almukaramah 21514, Saudi Arabia; ams_ksa85@hotmail.com
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
2
*
Correspondence: thoraya-f@hotmail.com (T.A.F.); mrgenidi@uqu.edu.sa (M.R.S.);
Tel.: +966-545917568 (M.R.S.)
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 30 September 2019; Accepted: 31 October 2019; Published: 5 November 2019
Abstract: A novel series of pyrazolo[1,5-a]pyrimidine ring systems containing phenylsulfonyl
moiety have been synthesized via the reaction of 2-(phenylsulfonyl)-1-(4-(phenylsulfonyl)
phenyl)ethan-1-one, 2-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-3-dimethylamino-propenone
and 3-(dimethylamino)-1-(4-(phenylsulfonyl)phenyl)prop-2-en-1-one each with various substituted
aminoazopyrazole derivatives in one pot reaction strategy. The proposed structure as well as the
mechanism of their reactions were discussed and proved with all possible spectral data. The results
of antimicrobial activities of the new sulfone derivatives revealed that several derivatives showed
activity exceeding the activity of reference drug. Contrary to expectations, we found that derivatives
containing one sulfone group are more effective against all bacteria and fungi used than those contain
two sulfone groups.
Keywords: antimicrobial activity; pyrazolopyrimidine; aminopyrazoles; microwaves; structure-activity
relationship (SAR)
1
. Introduction
Pyrazolo[1,5-a]pyrimidine is known to be purine analog that has protruded a vital
building block for pharmaceutical drugs. It has several potent biological implementations as
antischistosomal, antimetabolites in purine bio-chemical interactions, sedative and antitrypanosomal [ ],
AMP phosphodiesterase inhibitors [ ], anxiolytic [ ], benzodiazepine receptor ligands [ ], KDR (kinase
insert domain receptor) kinase inhibitors [ ], HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A
reductase) reductase inhibitors [ ], COX-1 (cyclooxygenase-1), COX-2 (cyclooxygenase-2) selective
inhibitors [ ], HCV (hepatitis C virus) inhibitors [ ], serotonin 5-HT6 (5-hydroxytryptamine) receptor
antagonists [ ], PET (positron emission tomography) tumor imaging agents [10], kinase inhibitors [11],
1
2
3
4
5
6
7
8
9
CCR1 (C-C chemokine receptor type 1) antagonists [12], HIV (human immunodeficiency viruses) reverse
transcriptase inhibitors [13], and antifungal and antimalarial activities [14]. Many marketed drugs have
pyrazolo[1,5-a]pyrimidine nucleus such as indiplon, zaleplon, dorsomorphin, dinaciclib, anagliptin,
pyrazophos, lorediplon, and ocinaplon [15] are showed in Figure 1. Another important scaffold
is benzene-sulfone moiety which present in several important pharmaceutical and agrochemical
molecules due to their distinctive structural and electronic features. As for instance, molecules
used as gamma-secretase inhibitors (I) [16], in migraine and prostate cancer, or as the herbicides
mesotrione and cafenstrole, all feature aryl sulfone units [17] (Figure 1). Due to the specific physical
and chemical properties as well as the biological activities of azobenzene dyes, they have found wide
Molecules 2019, 24, 4009; doi:10.3390/molecules24214009
www.mdpi.com/journal/molecules

Molecules 2019, 24, 4009
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applications in the cosmetic, pharmaceutical, dyeing/textile industry, food, and analytical chemistry [18].
Many of these compounds exhibit biomedical activity because they exhibit various properties such
as anti-inflammatory activity, antibacterial activity, cell protection, protease inhibitors (enzymes
that play functions in many pathological disorders), or have anti-HIV activity [19
proved recently that azo-benzene based compounds showed a killing effect on bacteria or fungi
through the interaction with their protein receptors, rather than an interaction with membrane [22 23].
–21]. Also, it was
,
On the other hand, the molecular hybridization is specialized with synthesis new compounds from
combination of biologically active substances for the production of a new hybrid compound. In several
cases, it generates derivatives having effective biological activities more potent than their starting
moieties [24].
N
O
N
N
S
N
OC H
2
5
C H OOC
2
5
N
P
N
N
N
N
O
OC H
2
5
N
O
N
CN
N
Pyrazophos
Zaleplon
Ocinaplon
(Fungicide and insecticide)
(Insonmma)
(Anxiolytic, sedative
and anmestic)
NEt3
Me
O
O
S
N
N
O
N
N
S
O
Me
Me
O
N
Me
H
Cafenstrole
Eletriptan
treatment of migraine)
(herbicide)
(
O
S
O
F
HO Me
O
O
S
H
F3C
NC
N
F
O
F
Blcalutamide
treatment of prostate cancer)
(I)
(
(
gamma-secretase inhibitors)
Figure 1. Biological activity of some pyrazolopyrimidines and drugs having benzenesulfone moiety.
Inspired by these observations and in resumption of our recent research aiming at the design
and synthesis of new bioactive heterocyclic systems [25
synthesize of two new series of pyrazolo[1,5-a]pyrimidine derivatives,
–
31], we are interested herein to design and
and 15 (Figure 2), which have
8
one or two arylsulfonyl and an arylazo groups to investigate their antimicrobial activities. The aim of
such synthesis is to study the effect of the combination of such scaffold on the activity of these new
series, as we expect to generate a potent active drug as an antimicrobial agent.

Molecules 2019, 24, 4009
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Sulfone group
O S O
O S O
O
S
N
N
Pyrazolopyrimidine
Azobenzene-group
N
N
N
O
NH2
NH2
N
N
N
N
N
X
X
8
13
Figure 2. The structure of the new pyrazolopyrimidines 8 and 13.
. Results and Discussion
2
Chemistry
Initially, three consecutive steps were enough to access of the hitherto unreported
-(dimethylamino)-2-(phenylsulfonyl)-1-(4-(phenylsulfonyl)phenyl)prop-2-en-1-one as a versatile
multifunctional building block for construction of the targeted pyrazolo[1,5-a]pyrimidine derivatives.
We started with modified method for -bromination of 1-(4-(phenylsulfonyl)phenyl)ethan-1-one
using N-bromosuccinimide (NBS) in the presence of p-toluene sulfonic acid (p-TsOH) and acetonitrile
as a solvent either under thermal or microwaves irradiation conditions (Scheme 1). The -bromoketone
was obtained in excellent yield (94%) under pressurized microwave irradiation (MW) for 15 min
3
6
α
1
α
3
using 400 W microwaves operating power. Then, treatment of compound
3 with sodium benzene
sulfinate in ethanol under thermal as well as microwave conditions afforded the corresponding
-(phenylsulfonyl)-1-(4-(phenylsulfonyl)phenyl)ethan-1-one in high yield (Scheme 1). The suggested
structure of compound as illustrated in Scheme 1 was confirmed from its spectral data. The IR spectrum
of compound showed the carbonyl absorption signal vibrating at 1700 cm . The H NMR spectrum
of compound displayed the characteristic signal of the CH group which clearly appeared at
.39 ppm in addition to the other protons that are resonating at their expected values (see experimental
part). Further evidence that confirm the structure of compound
was supported from its 13C NMR
which revealed fourteen carbon signals resonating at values as follows: 62.6 (CH ), 127.6, 127.7, 128.1,
2
4
4
−1
1
4
4
δ
2
5
4
δ
2
1
29.2, 130.0, 130.2, 134.1, 134.3, 139.1, 139.2, 140.2, 145.3 (12 Ar-C), and 188.6 (C=O) ppm.
Thermal or microwaves heating of the 2-(phenylsulfonyl)-1-(4-(phenylsulfonyl)phenyl)ethan-1-one
with N,N-dimethylformamide-dimethylacetal (DMF-DMA) using dry xylene as a solvent,
4
5
afforded a single product identified as the corresponding 3-(dimethylamino)-2-(phenylsulfonyl)-
-(4-(phenylsulfonyl)phenyl)prop-2-en-1-one , in high yields (Scheme 2). All spectral data of the
formed enaminosulfone were in agreement with the proposed structure. The presence of low
frequency of the C=O at 1624 cm in the IR spectrum of enaminosulfone
1
6
6
−1
6
confirm its structure
which attributed to the conjugation with the aromatic-C=C and the C=C of the enamine moiety.
1
Also, the H NMR spectrum of enaminosulfone
6
clearly displayed two characteristic singlet signals
for the two CH and =CH protons at 3.29 and 8.11 ppm in addition to an aromatic multiplets in the
3
region
enaminone moiety (
δ
7.36–7.99 ppm. It is important to notice that the large value of chemical shift of =CH of
= 8.11 ppm) indicated that enaminone was assigned the E-configuration [32].
δ
6

Molecules 2019, 24, 4009
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This large value of the trans-H can be attributed to the high deshielding effect of the direct interaction
with SO group. While, Z-isomer analogous structure was reported to appear at δ 6.9 ppm [33].
2
Scheme 1. Synthesis of compound 4.
O
S
O
O
S
O
Me
N
Xylene/ Δ, 8h
O
S
O
S
OMe
OMe
O
Me
or Xylene/MW,
O
O
3
5 min
Me
2
N
O
4
5
6
Δ Yield = 83 %
MW Yield = 91%
Scheme 2. Synthesis of enaminosulfone 6.
The reaction of the enaminosulfone
investigated using two different pathways under thermal and microwaves irradiation conditions.
Thus, when enaminosulfone was treated with arylazodiaminopyrazoles 7a in glacial acetic
under thermal as well as
6 with arylazodiaminopyrazole derivatives 7a–h was
6
–h
acid, it furnished the corresponding pyrazolopyrimidines derivatives 8a–h
microwaves conditions (Scheme 3, Table 1).
Table 1. A comparison between the conventional and microwave heating for the synthesis of
compounds 8a–h.
Conventional Heating
Yield%
Microwave Heating
Yield%
Compound No.
Ar
4-ClC H -
8
a
77
85
77
78
80
75
90
95
95
95
91
90
90
90
91
95
6
4
8
b
3-CH C H -
3 6 4
8
c
3-ClC H -
6 4
8
d
2-ClC H -
6 4
8
e
3-CH OC H -
3 6 4
8
f
C H -
6 5
8
g
2-NO C H -
2 6 4
8
h
4-CH OC H -
3 6 4
1
H NMR of the isolated pyrazolopyrimidine derivatives gave a strong evidence for the structure
8
1
rather than
singlet signal at
Figure 3. The presence of the pyrimidine-CH-2 at
group via X-ray crystallography of the same ring system [34].
9
. The H NMR spectra of all derivatives 8a
–
h
were characterized with the existence of
as shown in
9.13–9.23 ppm was confirmed previously by our
δ
9.13–9.23 ppm for the pyrimidine-CH-2 and not CH-4 in structure 9
δ

Molecules 2019, 24, 4009
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Ar
O
S
N
N
NH2
O
O
S
N
O
+
H N
H
2
N
O
6
7a-h
NMe2
AcOH
Δ/7h or MW/15 min
Ar
N
N
O
S
N
Ar
N
H N
2
O
S
N
N
O
N
N
O
H N
2
O
S
N
N
O
O S O 8a-h
9
Ar: a, 4-ClC H ; b, 3-CH C H ; c, 3-ClC H ; d, 2-ClC H ;
6
4
3
6
4
6
4
6 4
DMF DMA/ EtOH
e, 3-CH OC H ; f, C H ; g, 2-NO C H ; h, 4-CH OC H
3
6
4
6
5
2
6
4
3
6
4
Δ/7h or MW/15 min
Ar
+
O
S
O
N
N
NH2
O
S
O
N
H
H N
2
N
O
4
7a-h
Scheme 3. Synthesis of pyrazolopyrimidines 8a–h.
1
Figure 3. H NMR of compound 8a.

Molecules 2019, 24, 4009
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Also, the structure
8
was firmly established for the reaction products by an alternate
synthesis. Thus, 2-(phenylsulfonyl)-1-(4-(phenylsulfonyl)phenyl)ethan-1-one
triethylorthoformate 10 and subsequent condensation of the formed ethoxymethylene derivative 11 with
arylazodiaminopyrazole derivatives 7a gave products identical in all respects (m.p., mixed m.p., and
spectra) with those formed from the reaction enaminosulfone with pyrazoles . It should be noted that,
multi-components condensation of 2-(phenylsulfonyl)-1-(4-(phenylsulfonyl)-phenyl)ethan-1-one 4,
DMF-DMA, and arylazodiaminopyrazole derivatives 7a have failed to afford the
products 8a as shown in Scheme 3. On the other hand, one pot multi-components
condensation of 2-(phenylsulfonyl)-1-(4-(phenylsulfonyl)phenyl)ethan-1-one 4, triethylortho-formate
4 was condensed with
–h
6
7
–
h
–
h
1
0, and arylazodiamino-pyrazoles 7a–h afforded the products 8a–h as shown in Scheme 4.
Ar
N
N
N
Ar
O
S
NH2
O
S
O
CH(OEt)
3
N
N
NH
2
N
N
O
S
10
+
O
O
N
H
H
2
N
Δ, 7h or MW,15 min
N
O
4
7
O
S
O
CH(OEt)
3
10
8a-h
Ar
O
S
O
N
N
NH
2
O
S
O
+
N
AcOH
Δ, 7h or MW,15 min
H N
H
2
N
EtO
O
7
1
1
Scheme 4. Alternative synthesis of pyrazolopyrimidines 8a–h.
In order to examine the influence of phenyl sulfonyl group pendent to pyrimidine ring on the
antimicrobial activity, we have decided to synthesize a series of novel pyrazolo[1,5-a]pyrimidines
derivatives 13a which have an analogue structure to pyrazolo[1,5-a]pyrimidines derivatives 8a
–h
–h
by exclusion of the phenyl sulfonyl moiety in the pyrimidine ring in the pyrazolo[1,5-a]pyrimidine
ring system. The latter can be achieved via reaction of another enaminosulfone derivative 12 with
arylazodiaminopyrazoles 7a–h without catalyst in glacial acetic acid under thermal as well as microwave
conditions (Scheme 5). The reaction products were identified as the pyrazolo [1,5-a]pyrimidines
derivatives 13a–h and not the isomeric products 14 (Table 2).
Table 2. A comparison between the conventional and microwave heating for the synthesis of compounds
1
3a–h.
Conventional Heating
Yield%
Microwave Heating
Yield%
Compound No.
Ar
4-ClC H -
1
3a
3b
3c
3d
3e
3f
3g
3h
92
90
90
85
90
80
92
94
98
97
94
97
93
90
96
98
6
4
1
3-CH C H -
3 6 4
1
3-ClC H -
6 4
1
2-ClC H -
6 4
1
3-CH O C H -
3 6 4
1
C H -
6 5
1
2-NO C H -
2 6 4
1
4-CH O C H -
3 6 4

Molecules 2019, 24, 4009
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DMFDMA
O
S
O
O
S
O
5
CH3 Δ, 7 h or MW,40 min
O
O
N(CH3)2
1
2
1
Ar
N
N
NH
2
AcOH
Δ/7h or MW/15min
N
H N
2
H
N
7
a-h
Ar
O
N
N
1
N
S
2
3
O
H N
2
N
Ar
1
N
N
N
N
3
N
H N
2
N
4
O S O
14
Ar: a, 4-ClC H ; b, 3-CH C H ; c, 3-ClC H ; d, 2-ClC H ;
6
4
3
6
4
6
4
6 4
e, 3-CH OC H ; f, C H ; g, 2-NO C H ; h, 4-CH OC H
3
6
4
6
5
2
6
4
3
6
4
13a-h
Ar
+
CH(OEt)3
O
S
O
N
N
NH
2
10
CH3
N
O
H N
H
2
N
1
7a-h
Scheme 5. Synthesis of compounds 13a–h.
The structure of the products 13 have been confirmed based on spectral data (Figure 4).
The structures of the products 13a
their elemental analyses. For example, all H NMR spectra of derivatives 13a
–
h
were established on investigation their spectral data and
1
–h
revealed two doublet
signals (J
≈
4.5 Hz) near
δ
7.3 and 8.8 due to pyrimidine CH-3 and CH-2 protons, respectively. The other
1
expected products 14 were ruled out on the basis of spectral data such as H NMR where the CH-4
protons was expected to resonate at low value of chemical shift
1
δ
in their H NMR spectrum [35] as well
as the literature reports which proved the regioselectivity of such reaction by X-ray crystallographic
analysis of the product [32,36].
Attempts to achieve the pyrazolo[1,5-a]pyrimidines derivatives 13a
–h via alternative pathway
through multicomponent condensation of the acetyl derivative , triethylorthoformate 10, and
1
arylazodiaminopyrazoles 7a–h were not useful in this case (Scheme 5).
From the mechanistic point of view, the multi component synthesis of 8a
to proceed via Michael-type addition in acidic medium of arylazodiaminopyrazoles 7a–h
–
h
was expected
to
the activated double bond of the ethoxymethylene derivative 11 of 2-(phenylsulfonyl)-1-(4-
phenylsulfonyl)phenyl)ethan-1-one followed by loss of ethanol and subsequent intramolecular
cyclization via elimination of water to afford the corresponding pyrazolo[1,5-a] pyrimidines derivatives
h, all intermediates were illustrated in Scheme 6. In the same manner and under the same acidic
medium, the mechanism of the formation of pyrazolo[1,5-a]pyrimidines derivatives 13a is shown in
Scheme 6 which involves Michael type addition followed by cyclocondensation of the non-isolable
Michael adduct 18 by loss of dimethylamine to form another three non-isolable intermediates 19 21
(
4
8a–
–h
–
then followed by elimination of water molecule to afford the corresponding pyrazolo[1,5-a]pyrimidines
derivatives 13a–h.

Molecules 2019, 24, 4009
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1
Figure 4. H NMR of compound 13e.
O
S
O
O
S
O H
R
H+
O
S
O H
R
O
R
O
O
X
X
16
X
1
1
1, X = OEt, R = SO Ph
15
2
2, X = NMe2 R = H
Ar
H N
2
N N
NH2
N
H
N
NH2
N
NH2
N
HN
N
HN
N
-
H+
O
S
O
N
H
Ar
N
X
O
S
O
R
N
Ar
-HX
H
O
NH
R H
O
1
7
18
H+
NH2
Ar
NH2
N
HN
N
H
N
N
H
N
N
O
S
N
O
S
O
R
Ar
N H
NH
O
HO
O
R
20
1
9
-
H+
NH2
Ar
N
H
N
N
-
H O
2
O
N
8
1
a-h, X = OEt, R = SO Ph
3a-h, X = NMe2 R = H
2
S
N
O
HO
R
21
Scheme 6. The general mechanism of formation of compounds 8a
derivative 11 and enaminone 12.
–h
and 13a
–h
from ethoxymethylene

Molecules 2019, 24, 4009
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3
. Antimicrobial Activity
The antimicrobial activity of twelve new synthesized derivatives 8a
–d
,
8h
,
13a, and 13c
–h
were
tested against two fungi species (Aspergillus niger and Geotrichum candidum) (Table 3), four Gram-positive
bacteria as well as four Gram-negative which listed in Tables 4 and 5. The reference drugs were commonly
applied antibiotics such as Amphotericin B (For Fungi), Ampicillin, and Gentamicin (For Gram-positive
and Gram-negative bacteria). The first thing that can be seen from the listed results of antimicrobial
activity is that all the studied derivatives did not have any effect on P. aeruginosa and S. pyogenes.
For the activity of the tested derivatives against two fungi: There are three pyrazolopyrimidine sulfone
derivatives 13c, 13d, and 13g were found more potent than Amphotericin B.
Table 3. The antifungal activity of the tested derivatives 8a–d, 8h, 13a, and 13c–h.
Compound No.
Aspergillus Niger *
Geotrichum Candidum *
8
a
15.5 ± 1.2
15.2 ± 0.60
17.6 ± 1.2
18.3 ± 0.63
22.4 ± 2.1
23.1 ± 0.72
25.1 ± 1.2
21.4 ± 1.2
22.3 ± 1.2
22.6 ± 0.72
26.3 ± 0.63
19.2 ± 0.72
23.3 ± 0.58
17.4 ± 0.72
17.2 ± 0.63
18.5 ± 0.63
19.3 ± 0.58
24.3 ± 2.1
22.6 ± 0.72
22.6 ± 1.2
25.2 ± 1.2
20.4 ± 0.58
23.6 ± 1.20
23.2 ± 0.63
17.3 ± 0.72
25.2 ± 0.72
8
b
8
c
8
8
d
h
1
3a
3c
3d
3e
3f
3g
3h
Amphotericin B
1
1
1
1
1
1
*
The zone of inhibition (IZD) is measured in millimeter.
Table 4. The antimicrobial activity of the tested derivatives (µg/mL) against Gram-positive bacteria.
Compound No.
S. aureus
S. epidermidis
B. subtilis
S. pyogenes
8
a
16.3 ± 0.63
18.4 ± 0.85
17.6 ± 0.63
19.7 ± 0.58
21.1 ± 1.2
20.8 ± 0.43
23.4 ± 0.63
22.7 ± 0.63
19.8 ± 0.63
21.4 ± 0.58
22.7 ± 1.2
13.5 ± 1.2
23.7 ± 0.63
15.8 ± 0.58
15.7 ± 1.2
16.9 ± 0.53
18.6 ± 0.63
21.3 ± 0.53
20.7 ± 1.2
NA
NA
NA
NA
NA
NA
NA
NA
NA
8
b
8
c
16.4 ± 0.72
18.3 ± 0.58
20.8 ± 0.67
20.6 ± 0.58
21.8 ± 0.72
22.6 ± 0.72
16.7 ± 0.58
17.7 ± 0.72
22.3 ± 0.58
15.3 ± 0.44
22.4 ± 1.2
8
8
d
h
24.3 ± 0.58
25.4 ± 0.53
23.6 ± 0.63
25.5 ± 0.63
23.6 ± 0.53
26.5 ± 0.58
23.7 ± 0.72
18.2 ± 0.58
32.4 ± 0.72
1
3a
3c
3d
3e
3f
3g
3h
Ampicillin
1
1
1
1
NA
NA
NA
1
1
24.5 ± 0.63
*
The zone of inhibition (IZD) is measured in millimeter.
In case of the activity against the Gram-positive bacteria only one derivative 13d exceeds the activity
of the reference drug Ampicillin against S. epidermidis (Table 4). While, two derivatives 13d and 13g
revealed activity more than the reference drug used against E. coli. Otherwise, three pyrazolopyrimidine
derivatives 13c, 13d, and 13g were found more reactive than Gentamicin against S. typhimurium (Table 5).
All the other tested pyrazolopyrimidines revealed activity good to moderate against all tested
microbes except P. aeruginosa and S. pyogenes.
Minimum inhibitor concentration of the three most potent pyrazolopyrimidine derivatives 13c
3d, and 13g listed in Table 6 indicated that derivative 13d is the most effective compound.
,
1

Molecules 2019, 24, 4009
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Table 5. The antimicrobial activity of the tested derivatives (µg/mL) against Gram-negative bacteria.
Compound No.
P. aeruginosa
E. coli
K. pneumoniae
S. typhimurium
8
a
NA
NA
NA
NA
NA
NA
NA
NA
NA
15.6 ± 1.2
17.5 ± 0.58
18.7± 1.2
11.8 ± 0.44
14.8 ± 1.2
15.9 ± 1.2
17.6 ± 0.58
21.3 ± 0.58
20.4 ± 0.53
22.5 ± 1.2
26.6 ± 1.2
18.4 ± 0.53
19.5 ± 0.63
23.3 ± 1.2
16.3 ± 0.63
2.6 ± 0.63
18.5 ± 0.72
16.7 ± 0.63
17.4 ± 0.58
20.2 ± 0.72
19.8 ± 1.2
8
b
8
c
8
8
d
h
18.6 ± 0.63
23.2 ± 0.58
22.4 ± 0.53
24.3 ± 1.2
25.7 ± 1.2
19.8 ± 1.2
23.2 ± 0.72
25.5 ± 1.2
19.3 ± 0.63
25.4 ± 1.2
1
3a
3c
3d
3e
3f
3g
3h
Gentamicin
21.6 ± 0.63
26.3 ± 0.58
26.2 ± 0.58
21.1 ± 0.63
22.5 ± 0.63
26.6 ± 0.72
19.3 ± 0.58
23.3 ± 0.58
1
1
1
1
NA
NA
NA
1
1
22.3 ± 0.58
*
The zone of inhibition (IZD) is measured in millimeter.
Table 6. Minimum inhibitory concentration (µg/mL) for compounds 15c, 15d, and 15g.
Compound No.
Fungi
13c
13d
13g
Reference
Amphotericin B
Aspergillus niger
Geotrichum candidum
3.9
7.81
0.98
1.95
1.95
3.9
0.98
0.49
G+ Bacteria
Ampicillin
St. aureus
St. epidermidis
B. subtilis
3.9
15.63
0.98
NA
3.9
15.63
31.25
1.95
0.98
1.95
0.49
0.49
7.81
0.49
NA
St. pyogenes
NA
-
G Bacteria
Gentamicin
P. aeruginosa
E. coli
K. pneumoniae
S. typhimurium
NA
3.9
7.81
3.9
NA
0.49
3.9
NA
3.9
15.63
3.9
1.95
0.49
0.98
0.98
1.95
It is clear that the presence of one sulfone group in the pyrazolopyrimidine system enhances the
antimicrobial activity of the synthesized drugs, and increasing the number of sulfone groups in our case
does not increase the biological activity of the compounds. Therefore, we recommend the preparation
of pyrazolopyrimidine system with one sulfone group and complete the study by determining the
antibacterial activity of most promising compounds on mice models 3. Materials and Methods
3
.1. General
Melting points of synthesized compounds were measured on a Gallenkamp melting point
apparatus. The infrared spectra were recorded in potassium bromide discs Shimadzu a FT-IR-4100
infrared spectrophotometer (400–4000 cm 1, JASCO, Easton, MD, USA). Nuclear magnetic resonance
−
spectra were recorded in DMSO-d or CDCl Using a Varian Mercury VXR-300 NMR spectrometer
6
3
(JEOL, Tokyo, Japan). Chemical shifts
δ
were related to that of the used solvents. MS spectra were
recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer at 70 eV (Tokyo, Japan). The Microwave
irradiation was carried out on a CEM mars machine (CEM Corporation, Matthews, NC, USA). CEM has
several vessel types that are designed for their ovens: Closed-system vessels including the HP-500
◦
(
CEM Corporation, Matthews, NC, USA) (500 psig material design pressure and 260 C), liners are
composed of PFA, and are ideal for many types of samples. HP-500 Plus vessels are ideal for routine
◦
digestion applications. Process up to 14 high-pressure vessels per run with temperatures up to 260 C

Molecules 2019, 24, 4009
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or pressures up to 500 psi. Elemental analyses were carried out at the microanalytical center of Cairo
University, Giza, Egypt.
3
.2. Synthesis of 1-(4-benzenesulfonyl-phenyl)-2-bromo-ethanone (3)
3
.2.1. Method A: Thermal Method
To a stirred solution of 1-(4-benzenesulfonyl-phenyl)-ethanone (1) (2.6 g, 0.01 mol) and
p-toluenesulfonic acid (2) (2 g, 0.01 mol) in acetonitrile (12 mL) was added N-bromosuccinimide
(1.78 g, 0.01 mol) portion wise then the reaction mixture was heated for 3 h. After the reaction
mixture was cooled, the solvent was evaporated and H O was added and the product was extracted
2
using chloroform to give 1-(4-benzenesulfonyl-phenyl)-2-bromo-ethanone (3) as pale yellow solid,
yield (80%).
3
.2.2. Method B: Microwaves Method
In a HP-500 process vial a mixture of 1-(4-benzenesulfonyl-phenyl)-ethanone (1) (2.6 g, 0.01 mol)
and p-toluenesulfonic acid (2 g, 0.01 mol) in acetonitile (12 mL) was added N-bromosuccinimide (1.78 g,
0
.01 mol) portion wise then the vial was capped properly and was irradiated by microwaves irradiation
◦
(400 W power) using pressurized conditions at 90 C for a period of 15 min. After the reaction mixture
was cooled, the solvent was evaporated and H O was added and the product was extracted using
2
chloroform to give 1-(4-benzenesulfonyl-phenyl)-2-bromo-ethanone (3) as pale yellow solid, yield
◦
2
3
−1
1
(
94%), mp.: 115–117 C (EtOH), IR υ´ : 3091, 3011 (sp C-H), 2951 (sp C-H), 1705 (C=O) cm ; H
NMR (DMSO-d6) 4.99 (s, 2H, CH ), 7.64 (t, J = 7.65 Hz, 2H, Ar-H), 7.72 (t, J = 6.8 Hz, 1H, Ar-H), 8.01
δ
2
13
(
(
d, J = 7.65 Hz, 2H, Ar-H), 8.13 (d, J = 8.5 Hz, 2H, Ar-H), 8.18 (d, J = 7.65 Hz, 2H, Ar-H). C NMR
DMSO-d6) : 34.5 (CH ), 127.7, 127.9, 129.9, 130.0, 134.2, 137.8, 140.2, 145.1 (8 Ar-C), 191.0 (C=O).
δ
2
+
+
Ms m/z (%) 340 (M + 1, 12), 339 (M , 20), 299 (73), 267 (68), 253 (37), 246 (48), 220 (65), 168 (32), 120 (15),
9
3 (100), 77 (42), and 64 (37). Anal. Calcd. For: C H BrO S (339.20) C, 49.57; H, 3.27. Found: C, 49.46;
14 11 3
H, 3.19%
3
.3. Synthesis of 2-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-ethanone (4)
3
.3.1. Method A: Thermal Method
A mixture of compound (3.4 g, 0.01 mol) and sodium benzene sulfinate (1.64 g, 0.01 mol) in
3
ethanol (12 mL) in suitable round flask was refluxed for 5 h with constant stirring. After the reaction
was completed which evidenced using TLC technique, the reaction mixture was poured into ice cold
water, the white precipitate was filtered off, dried, and crystallized from ethanol/n-hexane to give the
disulfone derivative 4 as white crystals, yield (95%),
3
.3.2. Method B: Microwaves Method
A mixture of compound (3.4 g, 0.01 mol) and sodium benzene sulfinate (1.64 g, 0.01 mol) in
3
ethanol (12 mL) were mixed in a HP-500 process vial. The vail was capped properly and was irradiated
◦
by microwaves irradiation (800 W power) using pressurized conditions at 70 C for a period of 25 min.
The reaction mixture was the reaction mixture was poured into ice cold water, the white precipitate was
filtered off, dried, and crystallized from ethanol/n-hexane to give the disulfone derivative
4
as white
◦
2
3
crystals, yield (96%), mp.: 180–182 C (EtOH), IR υ´ : 3100 (sp C-H), 2951, 2911 (sp C-H), 1700 (C=O)
−
1
1
13
cm ; H NMR (DMSO-d ) δ: 5.39 (s, 2H, CH ), and 7.53–8.13(m, 14H, Ar–H). C NMR (DMSO-d6)
2
6
δ
: 62.6 (CH ), 127.6, 127.7, 128.1, 129.2, 130.0, 130.2, 134.1, 134.3, 139.1, 139.2, 140.2, 145.3 (12 Ar-C),
2
+
1
88.6 (C=O). Ms m/z (%) 400 (M , 48), 362 (55), 330 (100), 324 (23), 287 (63), 243 (41), 219 (41), 183 (16),
1
40 (40), 118 (19), 106 (9), and 41 (68). Anal. Calcd. For: C H O S (400.47) C, 59.98; H, 4.03. Found:
20
16
5 2
C, 59.84; H, 3.98%.

Molecules 2019, 24, 4009
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3
.4. Synthesis of 2-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-3-dimethylamino-propenone (6) and
1
-(4-benzenesulfonyl-phenyl)-3-dimethylamino-propenone (12)
3
.4.1. Method A: Thermal Method
A mixture of 2-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-ethanone (4) or 1-(4-(phenylsulfonyl)-
phenyl)ethan-1-one (1) (0.005 mol) and DMF-DMF (0.7 g, 0.005 mol) in xylene (20 mL) was heated
under reflux for the sufficient time of reaction (checked by TLC). After the reaction was completed,
the solvent was evaporated and the residue was triturated with hexane to give a solid product that
was collected by filtration and crystallized from the proper solvent to give enaminodi-sulfone
6 or
enaminosulfone 12, with isolated yields 83% and 94%, respectively.
3
.4.2. Method B: Microwaves Method
A mixture of 2-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-ethanone (4) or 1-(4-(phenylsulfonyl)-
phenyl)ethan-1-one (1) (0.005 mol), DMF-DMF (0.7 g, 0.005 mol), and xylene (20 mL) were mixed in
a HP-500 process vial. The vail was capped properly and was irradiated by microwaves irradiation
◦
(
400 W power) using pressurized conditions at 110 C for a period of 30–40 min. the excess xylene was
evaporated and the residue was triturated with hexane to give a solid product that was collected by
filtration and crystallized from ethanol to give enaminosulfone or enaminone 12, with isolated yields
1% and 96%, respectively.
The physical and spectral data of the synthesized compounds 6 and 12 are listed below.
6
9
◦
2
-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-3-dimethylamino-propenone (6), mp.: 212–214 C,
2
3
−1
1
IR υ´ : 3059 (sp C-H), 2933 (sp CH), 1624 (C=O) cm ; H NMR (DMSO-d )
δ
: 3.29 (s, 6H, 2CH3),
6
13
7
.36–7.99 (m, 14H, Ar-H), 8.11 (s, 1H, =CH). C NMR (DMSO-d6) δ: 34.3 (CH ), 106.2, 120.6, 126.1,
3
1
27.4, 127.9, 128.5, 129.7, 130.5, 133.5, 140.5, 143.4, 143.9, 144.3, 156.1, and 187.2 (C=O). Ms m/z (%) 455
+
(M , 39), 440 (13), 431 (100), 429 (100), 412 (25), 378 (31), 314 (13), 237 (24), 218 (35), 144 (82), 141 (26),
7
7 (34), and 43 (26). Anal. Calcd. For: C H NO S (455.55) C, 60.64; H, 4.65; N, 3.07. Found: C, 60.54;
23 21 5 2
H, 4.49; N, 3.12%.
◦
1
-(4-benzenesulfonyl-phenyl)-3-dimethylamino-propenone (12), mp.: 225–227 C, IR υ´
:
2
3
−1
1
3
5
100 (sp -CH), 2921 (sp -CH), 1644 (C=O) cm ; H NMR (DMSO-d )
δ
: 2.91, 3.15 (2s, 6H, 2CH3),
6
.77 (d, J = 12 Hz, 1H, =CH), 7.59–7.73 and 7.89–8.11 (m, 9H, Ar-H), and 7.74 (d, J = 12 Hz, 1H, =CH).
13
C NMR (DMSO-d6)
C=O). Ms m/z (%) 315 (M+, 8), 302 (71), 272 (14), 258 (6), 245 (16), 218 (9), 140 (7), 99 (15), 77 (24), 56
100), and 44 (88). Anal. Calcd. For: C H NO S (315.39) C, 64.74; H, 5.43; N, 4.44. Found: C, 64.59;
δ: 44.6 (2CH ), 91.0, 127.3, 128.2, 129.7, 133.8, 140.8, 142.4, 144.7, 154.9, and 184.0
3
(
(
17
17
3
H, 5.21; N, 4.36%.
3
.5. Synthesis of 2-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-3-ethoxy-propenone (11)
Fusion of disulfone derivative (0.4 g, 0.001 mol) and triethylorthoformate (1 mL) in round flask
4
was achieved on hotplate for 15 min to form clear solution. After the solution was left to cool, the solid
formed was collected by filtration and crystallized from ethanol to give white crystals, yield (80%),
◦
2
3
−1
+
mp.: 165–167 C, IR υ´ : 3101 (sp -CH), 2911 (sp -CH), 1700 (C=O) cm .; Ms m/z (%) 456 (M , 100),
2
3
3
74 (99), 103 (54), Anal. Calcd.For: C H O S (456.53) C, 60.51; H, 4.42. Found: C, 60.38; H, 4.25%.
23 20 6 2
.6. Synthesis of pyrazolo[1,5-a]pyrimidine derivatives 8a–h and 13a–h
.6.1. Thermal Methods
Method A: Enaminodisulfone
6 or enaminosulfone 12 (0.001 mol) was reacted with the appropriate
arylazodiaminopyrazoles 7a (0.001 mol) in 20 mL glacial acetic acid under reflux for 7 h. The reaction
–
h
mixture was left to cool and the precipitated solid product was collected by filtration, washed with EtOH,
dried and finally recrystallized from DMF/EtOH to afford the corresponding pyrazolo[1,5-a]pyrimidines

Molecules 2019, 24, 4009
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8
a
–
h
or 13a
listed below.
Method B (for compounds 8a
an equivalent molar ratio of the appropriate arylazodiaminopyrazoles 7a
20 mL), was heated under reflux for 7 h. The excess solvent was removed by distillation under reduced
–h. The physical and spectral data of the synthesized compounds 8a–h and 13a–h are
–h
only): A solution of disulfone derivative
4 (0.4 g, 0.001 mol) and
–h
in triethylorthoformate
(
pressure and the residue was left to cool. The precipitated solid product was collected by filtration,
washed with EtOH, dried, and finally recrystallized from DMF/EtOH to afford the corresponding
pyrazolo[1,5-a]pyrimidines 8a–h.
Method C (for compounds 8a
–
h
only): Compound 11 (0.001 mol) was reacted with the
appropriate arylazodiaminopyrazoles 7a
–
h
(0.001 mol) in 20 mL glacial acetic acid under reflux
for 7 h. The reaction mixture was left to cool and the precipitated solid product was collected
by filtration, washed with EtOH, dried, and finally recrystallized from DMF/EtOH to afford the
corresponding pyrazolo[1,5-a]pyrimidines 8a–h.
3
.6.2. Microwaves Methods
Method A: A mixture of Enaminone
6 or enaminone 12 (0.001 mol) and the appropriate
arylazodiaminopyrazoles 7a–h (0.001 mol) in in 20 mL glacial acetic acid were mixed in a HP-500 process
vial. The vail was capped properly and was irradiated by microwaves irradiation (800 W power) using
◦
pressurized conditions at 110 C for 15 min. The reaction mixture was left to cool and the precipitated
solid product was collected by filtration, washed with EtOH, dried, and finally recrystallized from
DMF/EtOH to afford the corresponding pyrazolo[1,5-a]pyrimidines 8a
spectral data of the synthesized compounds 8a–h and 13a–h are listed below.
Method B (for compounds 8a only): A mixture of disulfone derivative
equivalent molar ratio of the appropriate arylazodiaminopyrazoles 7a in triethylorthoformate (20 mL),
–h or 13a–h. The physical and
–
h
4 (0.4 g, 0.001 mol) and an
–
h
was mixed in a HP-500 process vial. The vail was capped properly and was irradiated by microwaves
◦
irradiation (800 W power) using pressurized conditions at 110 C for 15 min. The reaction mixture was
left to cool and the precipitated solid product was collected by filtration, washed with EtOH, dried,
and finally recrystallized from DMF/EtOH to afford the corresponding pyrazolo[1,5-a]pyrimidines
8
a–h. The physical and spectral data of the synthesized compounds 8a–h and 13a–h are listed below.
Method C (for compounds 8a only): A mixture of compound 11 (0.001 mol) and the appropriate
arylazodiaminopyrazoles 7a (0.001 mol) in in 20 mL glacial acetic acid were mixed in a HP-500
–h
–
h
process vial. The vail was capped properly and was irradiated by microwaves irradiation (800 W
◦
power) using pressurized conditions at 110 C for 15 min. The reaction mixture was left to cool
and the precipitated solid product was collected by filtration, washed with EtOH, dried, and finally
recrystallized from DMF/EtOH to afford the corresponding pyrazolo[1,5-a]pyrimidines 8a–h.
6
-Benzenesulfonyl-7-(4-benzenesulfonyl-phenyl)-3-(4-chloro-phenylazo)-
pyrazolo[1,5-a]pyrimidin-2-ylamine (8a)
◦
2
3
Yellow solid, mp.: 235–237 C, IR υ´ : 3464, 3362 (NH ), 3100 (sp -CH), 2900 (sp -CH),
2
−
616 (C=N) cm ; H NMR (DMSO-d ) δ: 7.17–7.89 (m, 12H, Ar-H and NH ), 7.56 (d, J = 8 Hz,
6 2
1 1
1
2
(
1
H, Ar-H), 7.86 (d, J = 8 Hz, 2H, Ar-H), 7.92 (d, J = 8 Hz, 2H, Ar-H), 8.09 (d, J = 8 Hz, 2H, Ar-H), 9.17
s, 1H, pyrimidine-H). 13C NMR (DMSO-d6)
: 115.6, 120.6, 122.1, 123.0, 126.7, 127.0, 127.7, 128.9, 129.1,
29.9, 130.9, 132.3, 133.6, 134.1, 140.1, 140.5, 142.8, 144.9, 147.9, 148.7, 151.4, 153.9. Ms m/z (%) 628
δ
+
(
(
M , 16), 557 (14), 521(28), 508 (93), 483 (15), 410 (38), 381 (98), 346 (16), 335 (100), 274 (17), 236 (27), 217
13). Anal. Calcd. For: C H ClN O S (629.11) C, 57.27; H, 3.36; N, 13.36. Found: C, 57.09; H, 3.16;
30
21
6
4 2
N, 13.27%.
6
-Benzenesulfonyl-7-(4-benzenesulfonyl-phenyl)-3-(3-methyl-phenylazo)-
pyrazolo[1,5-a]pyrimidin-2-ylamine (8b)

Molecules 2019, 24, 4009
14 of 19
◦
2
3
Pale brown solid, mp.: 233–235 C, IR υ´ : 3459, 3337 (NH ), 3096 (sp -CH), 2980 (sp -CH),
2
−
609 (C=N) cm ; H NMR (DMSO-d ) δ: 2.39 (s, 3H, CH ), 7.15–7.80 (m, 16H, Ar-H and NH ), 7.99
6 3 2
1 1
1
(
13
d, J = 9 Hz, 2H, Ar-H), 8.09 (d, J = 9 Hz, 2H, Ar-H), and 9.16 (s, 1H, pyrimidine-H). C NMR (DMSO-d )
6
δ
: 20.9 (CH ), 115.4, 119.2, 121.5, 121.8, 126.8, 127.0, 127.8, 128.9, 129.1, 130.0, 130.2, 131.0, 132.4, 133.7,
3
+
134.2, 138.5, 140.2, 140.6, 142.7, 144.9, 147.8, 148.5, 152.7, and 154.0. Ms m/z (%) 610 (M + 2, 13), 608
+
(
(
M , 23), 593 (14), 541 (100), 532 (23), 517 (32), 489 (16), 391 (34), 326 (9), 235 (16), 217 (9), 140 (15), 129
90), 95 (43), and 76 (10). Anal. Calcd. For: C H N O S (608.69) C, 61.17; H, 3.97; N, 13.81. Found:
31
24
6
4 2
C, 61.03; H, 3.82; N, 13.69%.
6
-Benzenesulfonyl-7-(4-benzenesulfonyl-phenyl)-3-(3-chloro-phenylazo)-
pyrazolo[1,5-a]pyrimidin-2-ylamine (8c)
◦
2
1
Yellow crystals, mp.: 260–262 C, IR υ´ : 3408, 3280 (NH ), 3068 (sp -CH) 1616 (C=N); H NMR
2
(
(
8
1
1
DMSO-d6)
d, J = 7.65 Hz, 2H, Ar-H), 7.53–7.86 (m, 7H, Ar-H), 7.95 (s, 1H, Ar-H), 7.99 (d, J = 7.65 Hz, 2H, Ar-H),
.10 (d, J = 7.65 Hz, 2H, Ar-H), and 9.19 (s, 1H, N=CH). 13C NMR (DMSO-d6)
: 115.8, 120.4, 120.9,
22.4, 126.9, 127.1, 127.9, 128.8, 129.0, 130.0, 130.1, 131.0, 132.4, 133.8, 134.0, 134.3, 140.1, 140.6, 142.8,
45.1, 148.1, 148.8, 153.9, and 154.0. Ms m/z (%) 628 (M+
1, 18), 552 (27), 520 (11), 483 (17), 409 (26), 345
δ: 3.57 (s, 2H, NH ), 7.16 (t, J = 7.65 Hz, 2H, Ar-H), 7.30 (d, J = 8.5 Hz, 2H, Ar-H), 7.46
2
δ
−
(15), 274 (10), 236 (15), 216 (17), 111 (8), and 72 (100). Anal. Calcd. For: C H ClN O S (629.11) C,
30 21 6 4 2
5
7.27; H, 3.36; N, 13.36. Found: C, 57.08; H, 3.21 N, 13.29%.
6
-Benzenesulfonyl-7-(4-benzenesulfonyl-phenyl)-3-(2-chloro-phenylazo)-
pyrazolo[1,5-a]pyrimidin-2-ylamine (8d)
◦
1
Yellow solid, mp.: 250–252 C, IR υ´ :br. 3458 (NH ), 1612 (C=N); H NMR (DMSO-d ) 5.40
2
6
(
9
s, 2H, NH ), 7.17–7.82 (m, 14H, Ar-H), 7.98 (d, J = 8Hz, 2H, Ar-H), 8.09 (d, J = 8Hz, 2H, Ar-H), and
.22 (s, 1H, pyrimidine-H). C NMR (DMSO-d6) δ: 111.9, 116.4, 116.7, 122.7, 126.8, 127.8, 127.1, 127.6,
2
13
1
28.1, 128.9, 130.3, 130.7, 132.2, 132.3, 134.2, 138.0, 139.9, 140.5, 142.8, 145.2, 147.8, 149.0, 153.7, and 156.7.
+
Ms m/z (%) 629 (M , 32), 579 (100), 552 (49), 519 (17), 504 (35), 489 (15), 412 (7), 346 (34), 275 (8), 141 (6),
and 111 (19). Anal. Calcd. For: C H ClN O S (629.11) C, 57.27; H, 3.36; N, 13.36. Found: C, 57.07;
30
21
6
4 2
H, 3.30; N, 13.15%.
-Benzenesulfonyl-7-(4-benzenesulfonyl-phenyl)-3-(3-methoxy-phenylazo)-
pyrazolo[1,5-a]pyrimidin-2-ylamine (8e)
6
◦
1
Dark yellow solid, mp.: 200–202 C, IR υ´ br. 3450 (NH ), 1618 (C=N); H NMR (DMSO-d )
δ: 3.57
2
6
(
6
5
s, 3H, OCH ), 5.40 (s, 2H, NH ), 7.56–8.12 (m, 18H, Ar-H), and 9.17 (s, 1H, pyrimidine-H). Ms m/z (%)
24 (M , 50), 453 (87), 439 (99), 318 (94), and 274 (100). Anal. Calcd.For: C H N O S (624.69) C,
31 24 6 5 2
9.60; H, 3.87; N, 13.45. Found: C, 59.46; H, 3.73; N, 13.21%.
3
2
+
6-Benzenesulfonyl-7-(4-benzenesulfonyl-phenyl)-3-phenylazo-pyrazolo[1,5-a]pyrimidin-2-ylamine (8f)
◦
1
Dark yellow solid, mp.: 270–272 C, IR υ´ : br, 3456 (NH ), 1614 (C=N); H NMR (DMSO-d ) δ:
2
6
7
.15–7.89 (m, 15H, Ar–H), 7.98 (d, J = 8 Hz, 2H, Ar-H), 8.09 (d, J = 8 Hz, 2H, Ar-H), and 9.18 (s, 1H,
13
pyrimidine-H). C NMR (DMSO-d6)
δ
: 115.4, 121.6, 121.9, 126.9, 127.1, 127.9, 129.0, 129.2, 129.6, 130.1,
+
1
31.0, 132.5, 133.8, 134.3, 140.2, 140.6, 142.8, 145.0, 147.9, 148.6, 152.7, and 154.0. Ms m/z (%) 594 (M , 20),
5
80 (18), 523 (22), 490 (32), 457 (49), 375 (100), 273 (28), 218 (28), 142 (24), and 77 (27). Anal. Calcd. For:
C H N O S (594.66) C, 60.59; H, 3.73; N, 14.13. Found: C, 60.46; H, 3.61; N, 14.02%.
30
22
6
4 2
6
-Benzenesulfonyl-7-(4-benzenesulfonyl-phenyl)-3-(2-nitro-phenylazo)-
pyrazolo[1,5-a]pyrimidin-2-ylamine (8g)
◦
1
Dark red solid, mp.: 285–287 C, IR υ´ : 3446, 3340 (NH ), 1620, 1585 (C=N).; H NMR (DMSO-d ) δ:
2
6
13
7
.16–8.12 (m, 20H, Ar–H), 9.23 (s, 1H, pyrimidine-H). C NMR (DMSO-d6) δ:117.3, 117.4, 120.5, 123.3,
1
1
24.4, 126.8, 127.1, 127.8, 128.9, 129.5, 129.9, 130.9, 132.2, 133.6, 133.8, 134.2, 139.9, 140.6, 142.9, 144.6,
45.3, 146.0, 149.4, and 153.6. Ms m/z (%) 639 (M , 23), 620 (19), 563 (15), 516 (13), 494 (14), 438 (99),
+

Molecules 2019, 24, 4009
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4
5
23 (32), 148 (21), 137 (17), 123 (12), 77 (8), and 60 (100). Anal. Calcd. For: C H N O S (639.66) C,
30 21 7 6 2
6.33; H, 3.31; N, 15.33. Found: C, 56.18; H, 3.29; N, 15.08%.
6
-Benzenesulfonyl-7-(4-benzenesulfonyl-phenyl)-3-(4-methoxy-phenylazo)-
pyrazolo[1,5-a]pyrimidin-2-ylamine (8h)
◦
1
Pale brown solid, mp.: 220–222 C (EtOH), IR υ´ : br. 3450 (NH ), 1616 (C=N); H NMR (DMSO-d )
2
6
δ
: 3.83 (s, 3H, OCH ), 7.05 (d, J = 8 Hz, 2H, Ar-H), 7.14–7.47 (m, 10H, Ar-H), 7.53 (s, 2H, NH ), 7.85
3 2
(
d, J = 8 Hz, 2H, Ar-H), 7.97 (d, J = 8 Hz, 2H, Ar-H), 8.09 (d, J = 8 Hz, 2H, Ar-H), and 9.13 (s, 1H,
pyrimidine-H). 13C NMR (DMSO-d6)
: 55.5, 114.4, 115.0, 121.4, 123.1, 126.8, 127.0, 127.8, 128.9, 129.9,
30.9, 132.5, 133.6, 134.1, 140.3, 140.6, 142.8, 144.8, 146.8, 147.2, 148.2, 154.2, and 160.6. Ms m/z (%) 624
δ
1
+
(M , 24), 550 (16), 488 (18), 407 (47), 273 (38), 217 (44), 159 (100), 133 (6), and 80 (28). Anal. Calcd.
For: C H N O S (624.69) C, 59.60; H, 3.87; N, 13.45. Found: C, 59.42; H, 3.70; N, 13.31%.
31
24
6
5 2
7
-(4-Benzenesulfonyl-phenyl)-3-(4-chloro-phenylazo)- pyrazolo[1,5-a]pyrimidin-2-ylamine (13a)
◦
2
3
Orange crystals, mp.: 280–282 C (EtOH), IR υ´ : 3421, 3298 (NH ), 3099 (sp -CH), 2900 (sp -CH),
2
−
1 1
1
616 (C=N) cm ; H NMR (DMSO-d )
δ
: 7.30 (d, J = 3.9 Hz, 1H, Pyrimidine-H), 7.52 (d, J = 9 Hz,
6
2
8
H, Ar-H), 7.68–7.70 (m, 7H, Ar-H and NH ), 7.83 (d, J = 9 Hz, 2H, Ar-H), 8.04–8.25 (m, 4H, Ar-H),
.63 (d, J = 3.9 Hz, and 1H, Pyrimidine-H). C NMR (DMSO-d6) δ: 110.0, 114.9, 122.8, 127.4, 127.7,
2
1
3
1
29.18, 130.0, 131.0, 132.7, 134.2, 135.2, 140.6, 142.9, 143.5, 147.6, 150.9, 151.7, and 151.9. Ms m/z (%) 488
+
(M , 14), 414 (14), 363 (24), 270 (17), 255 (29), 218 (13), 140 (9), 131 (100), 121 (74), 110 (24), and 102 (29).
Anal. Calcd. For: C H ClN O S (488.95) C, 58.95; H, 3.50; N, 17.19. Found: C, 58.76; H, 3.41;
24
17
6
2
N, 17.06%.
7
-(4-Benzenesulfonyl-phenyl)-3-m-tolylazo- pyrazolo[1,5-a]pyrimidin-2-ylamine (13b)
◦
2
3
Red solid, mp.: 235–237 C (AcOH), IR υ´ : 3421, 3274 (NH ), 3165 (sp -CH), 2919 (sp -CH), 1616
2
−
C=N) cm ; H NMR (DMSO-d ) δ: 2.39 (s, 3H, CH ), 7.18 (d, J = 7.65 Hz, 2H, Ar-H), 7.25 (s, 2H, NH ),
6 3 2
1 1
(
7
7
.27 (d, J = 5.1 Hz, 1H, Pyrimidine-H), 7.37 (t, J = 7.65 Hz, 2H, Ar-H), 7.62 (d, J = 7.65 Hz, 1H, Ar-H),
.64 (s, 1H, Ar-H), 7.69 (t, J = 7.65 Hz, 1H, Ar-H), 7.75 (t, J = 7.65 Hz, 1H, Ar-H), 8.06 (d, J = 7.65 Hz,
H, Ar-H), 8.18 (d, J = 7.65 Hz, 2H, Ar-H), 8.23 (d, J = 7.65 Hz, 2H, Ar-H), 8.63 (d, J = 5.1 Hz, 1H,
1
Pyrimidine-H). 13C NMR (DMSO-d6)
δ
: 20.9 (CH ), 109.5, 114.6, 118.9, 120.5, 121.2, 127.3, 127.6, 128.8,
3
+
129.3, 129.9, 134.0, 135.2, 138.4, 140.6, 142.9, 143.3, 147.5, 150.6, 151.8, 152.9. Ms m/z (%) 468 (M , 8),
454 (14), 395 (11), 377 (15), 311 (12), 250 (7), 215 (7), 171 (74), 142 (2), 91 (14), 81 (100). Anal. Calcd.
For: C H N O S (468.53) C, 64.09; H, 4.30; N, 17.94. Found: C, 63.89; H, 4.21; N, 17.85%.
25
20
6
2
7
-(4-Benzenesulfonyl-phenyl)-3-(3-chloro-phenylazo)- pyrazolo[1,5-a]pyrimidin-2-ylamine (13c)
◦
2
−1
Red crystals, mp.: 245–247 C (AcOH), IR υ´ : 3421, 3274 (NH ), 3067 (sp -CH), 1616 (C=N) cm ;
2
1
H NMR (DMSO-d6) δ: 7.26–8.23 (m, 16H, Ar-H and NH ), 8.61 (d, J = 4.5 Hz, 1H, pyrimidine-H).
2
13
C NMR (DMSO-d6)
35.1, 140.6, 142.9, 143.4, 147.7, 150.9, 151.9, and 154.2. Ms m/z (%) 488 (M , 8), 458 (19), 412 (19), 377 (11),
73 (44), 249 (100), 218(7), 161 (14), 143 (37), 111 (59), and 108 (74). Anal. Calcd. For: C H ClN O S
δ: 110.0, 115.1, 120.2, 120.3, 127.3, 127.6, 127.8, 129.9, 130.5, 130.9, 133.8, 134.0,
+
1
2
24
17
6
2
(488.95) C, 58.95; H, 3.50; N, 17.19. Found: C, 58.88; H, 3.41; N, 17.01%.
7
-(4-Benzenesulfonyl-phenyl)-3-(2-chloro-phenylazo)- pyrazolo[1,5-a]pyrimidin-2-ylamine (13d)
◦
2
3
Orange crystals, mp.: 280–282 C (AcOH), IR υ´ : 3398, 3298 (NH ), 3164 (sp -CH), 2997 (sp -CH),
2
−
615 (C=N) cm ; H NMR (DMSO-d ) δ: 7.32 (d, J = 4 Hz, 1H, pyrimidine-H), 7.46 (s, 2H, NH ),
6 2
1 1
1
7
.67–8.24 (m, 13H, Ar-H), and 8.66 (d, J = 4 Hz, 1H, pyrimidine-H). 13C NMR (DMSO-d6)
δ: 110.6,
1
1
16.4, 116.43, 127.4, 127.7, 128.0, 129.8, 130.0, 130.3, 131.1, 131.5, 134.2, 135.1, 140.6, 143.0, 143.8, 147.8,
48.2, 151.3, and 151.9. Ms m/z (%) 488 (M , 8), 452 (13), 411 (100), 378 (28), 364 (20), 272 (30), 254 (17),
+
2
13 (25), 111 (26), and 90 (27). Anal. Calcd. For: C H ClN O S (488.95) C, 58.95; H, 3.50; N, 17.19.
24 17 6 2
Found: C, 58.82; H, 3.34; N, 17.06%.

Molecules 2019, 24, 4009
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7
-(4-Benzenesulfonyl-phenyl)-3-(3-methoxy-phenylazo)- pyrazolo[1,5-a]pyrimidin-2-ylamine (13e)
◦
2
3
Red solid, mp.: 258–260 C (AcOH), IR υ´ : 3437, 3298 (NH ), 3155 (sp -CH), 2909 (sp -CH), 1612
2
−
C=N) cm ; H NMR (DMSO-d ) δ: 3.83 (s, 3H, OCH ), 6.94–6.95 (m, 1H, Ar-H), 7.27 (s, 2H, NH ),
6 3 2
1 1
(
7
(
.29 (d, J = 4.5 Hz, 1H, pyrimidine-H), 7.39–7.44 (m, 3H, Ar-H), 7.68 (t, J = 7.65 Hz, 2H, Ar-H), 7.74
t, J = 6.8 Hz, 1H, Ar-H), 8.06 (d, J = 7.65 Hz, 2H, Ar-H), 8.18 (d, J = 8.5 Hz, 2H, Ar-H), 8.23 (d, J = 8.5
Hz, 2H, Ar-H), and 8.64 (d, J = 4.5 Hz, 1H, pyrimidine-H). 13C NMR (DMSO-d6)
: 55.2, 105.5, 109.6,
14.1, 114.6, 114.9, 127.3, 127.6, 129.7, 129.9, 130.9, 134.0, 135.2, 140.6, 142.9, 143.3, 147.5, 150.7, 151.9,
δ
1
1
+
54.2, and 160.0. Ms m/z (%) 484 (M , 15), 454 (24), 407 (11), 379 (17), 360 (100), 349 (12), 327 (10), 267
(
7), 218 (15), 160 (7), 136 (41), and 78(17). Anal. Calcd. For: C H N O S (484.53) C, 61.97; H, 4.16; N,
25 20 6 3
1
7.34. Found: C, 61.76; H, 4.00; N, 17.15%.
7
-(4-Benzenesulfonyl-phenyl)-3-phenylazo- pyrazolo[1,5-a]pyrimidin-2-ylamine (13f)
◦
2
3
Red solid, mp.: 215–217 C (AcOH), IR υ´ : 3420, 3270 (NH ), 3162 (sp -CH), 2998 (sp -CH), 1616
2
−
C=N) cm ; H NMR (DMSO-d ) δ: 7.22–8.24 (m, 17H, Ar-H and NH ), 8.60 (d, J = 4.5 Hz, 1H,
6 2
1 1
(
pyrimidine-H). 13C NMR (DMSO-d6)
35.1, 140.6, 142.9, 143.3, 147.5, 150.6, 151.8, and 152.9. Ms m/z (%) 454 (M , 19), 438 (27), 364 (7), 361
δ
: 114.7, 121.1, 127.3, 127. 6, 129.0, 129.2, 129.9, 130.9, 131.1, 134.0,
+
1
(
(
27), 349 (16), 313 (14), 237 (10), 217 (14), 208 (27), and 106 (100). Anal. Calcd. For: C H N O S
24 18 6 2
454.50) C, 63.42; H, 3.99; N, 18.49. Found: C, 63.32; H, 3.88; N, 18.32%.
7-(4-Benzenesulfonyl-phenyl)-3-(2-nitro-phenylazo)-pyrazolo[1,5-a]pyrimidin-2-ylamineylamine (13g)
◦
2
3
Red solid, mp.: 265–267 C (AcOH), IR υ´ : 3410, 3294 (NH ), 3165 (sp -CH), 2900 (sp -CH), 1617
2
−
C=N) cm ; H NMR (DMSO-d ) δ: 7.46 (d, J = 4.5 Hz, 1H, pyrimidine-H), 7.60 (t, J = 7 Hz, 1H, Ar-H),
6
1 1
(
7
8
.73–7.83 (m, 6H, Ar-H and NH ), 7.95 (dd, J = 8, 1.7Hz, 1H, Ar-H), 8.05 (dd, J = 8, 1.7Hz, 1H, Ar-H),
2
.11 (dd, J = 8, 1.7Hz, 2H, Ar-H), 8.24 (d, J = 8.5 Hz, 2H, Ar-H), 8.27 (d, J = 8.5 Hz, 2H, Ar-H), and 8.76
+
(d, J = 4.5 Hz, 1H, pyrimidine-H). Ms m/z (%) 499 (M , 58), 453 (11), 422 (28), 378 (27), 362 (5), 218 (6),
2
3
08 (100), 151(11), 142 (5), 122 (10), and 77 (30). Anal. Calcd. For: C H N O S (499.50) C, 57.71; H,
24 17 7 4
.43; N, 19.63. Found: C, 57.56; H, 3.40; N, 19.52%.
7
-(4-Benzenesulfonyl-phenyl)-3-(4-methoxy-phenylazo)- pyrazolo[1,5-a]pyrimidin-2-ylamine (13h)
◦
2
3
Red, yield (94%), mp.: 255–257 C (AcOH), IR υ´ : 3447, 3337 (NH ), 3066 (sp -CH), 2900 (sp -CH),
2
−
611 (C=N) cm ; H NMR (DMSO-d ) δ: 3.83 (s, 3H, OCH ), 7.06 (d, J = 8.5 Hz, 2H, Ar-H), 7.17 (s, 2H,
6 3
1 1
1
NH ), 7.24 (d, J = 5.1 Hz, 1H, pyrimidine-H), 7.68 (t, J = 7.65 Hz, 2H, Ar-H), 7.74 (t, J = 7.65 Hz, 1H,
2
Ar-H), 7.81 (d, J = 8.5 Hz, 2H, Ar-H), 8.06 (d, J = 8.5 Hz, 2H, Ar-H), 8.18 (d, J = 8.5 Hz, 2H, Ar-H), 8.23
13
(
d, J = 8.5 Hz, 2H, Ar-H), and 8.61(d, J = 4.5 Hz, 1H, pyrimidine-H). C NMR (DMSO-d6)
δ
: 55.4, 109.1,
1
1
1
6
14.1, 114.3, 122.6, 127.3, 127.6, 129.9, 130.8, 134.0, 135.3, 140.6, 142.9, 143.2, 147.1, 147.2, 150.4, 151.9,
+
59.9. Ms m/z (%) 484 (M , 22), 454 (16), 406 (23), 377 (24), 351 (90), 327 (22), 251 (50), 134(5), 124 (43),
05 (19), and 58 (100). Anal. Calcd. For: C H N O S (484.53) C, 61.97; H, 4.16; N, 17.34. Found: C,
25
20
6
3
1.78; H, 4.03; N, 17.25%.
3
.7. Biological Methods
Antimicrobial Activity Test
The antimicrobial activity of the synthesized compounds have been determined using the agar
diffusion well method which is a suitable for such biological activity measurement. Culture collection
of the Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University, Cairo, Egypt
provided all strains in this study. For fungi, the microbes’ inoculums were spread using sterile cotton
swab with uniform manner on a sterile petri dish malt extract agar. In case of bacteria, the microbes’
inoculums were spread on the nutrient agar. 100 µL of a given sample was added to each well which is
ten mm diameter holes cut in the agar gel, twenty mm apart from each other). All systems prepared
◦
were incubated for 1–2 days at 37 C for antibacterial activity measurements and at a temperature

Molecules 2019, 24, 4009
17 of 19
◦
of 28 C for antifungal measurements. The microorganism’s growth was observed after the latter
incubation. The inhibition zone of the bacterial and fungal growth have been measured as IZD in
millimeter. Finally, all the mentioned tests were performed in triplicate for all compounds.
In case of estimation the MIC of the examined samples, micro-dilution test was performed in
96-well plates. Two-fold dilutions of each sample were prepared in the test wells, the final drug
concentrations being (125–0.004)
µ
g/mL, control wells were prepared with culture medium only and
◦
microbial suspension only. The plates were sealed and incubated for 24 h at 37 C for bacteria and for
◦
4
8 h at 28 C for fungi, after each incubation time, MIC was detected as the lowest sample concentration
that prevented microbial growth. Each MIC was determined three times.
4
. Conclusions
In conclusion, we have synthesized new series of pyrazolo[1,5-a]pyrimidine derivatives
incorporated phenylsulfonyl and arylazo moieties using a simple methodology. The synthetic
methodology included the use of conventional heating and microwaves irradiation under pressurized
conditions in a safe manner. The antimicrobial activities of novel compounds are evaluated and three
compounds 13c, 13d, and 13g demonstrated the highest antibacterial activity against all Gram-positive
and -negative bacteria. Other sulfone derivatives showed fair to low antibacterial and antifungal
activities. In general, derivatives containing one phenylsulfonyl group are more effective against all
most antibacterial and antifungal species used than that contain two phenylsulfonyl groups.
Author Contributions: M.R.S. Conceived and designed the experiments, analyzed and interpreted the data,
contributed reagents and materials, and wrote the paper. T.A.F. Conceived and designed the experiments, analyzed
and interpreted the data, and wrote the paper. A.M.R.A. Performed the experiments, analyzed, and interpreted
the data.
Funding: All authors would like to thank Deanship of Scientific Research at Umm Al-Qura University for
supporting this work (Project code: 18-SCI-5-06-0005).
Conflicts of Interest: The authors declare no conflict of interest.
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