Novel Antimicrobial Sulfonamides Derived from Nabumetone

Full text of DOI:10.1080/00304948.2020.1850089

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Novel Antimicrobial Sulfonamides Derived from
Nabumetone
Ayad Mohamed Rasheed Raauf , Hala Ayad Mohamed Rasheed & Farah
Abdulhaleem
To cite this article: Ayad Mohamed Rasheed Raauf , Hala Ayad Mohamed Rasheed & Farah
Abdulhaleem (2021) Novel Antimicrobial Sulfonamides Derived from Nabumetone, Organic
Preparations and Procedures International, 53:1, 95-99, DOI: 10.1080/00304948.2020.1850089
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2021, VOL. 53, NO. 1, 95–99
https://doi.org/10.1080/00304948.2020.1850089
OPPI BRIEF
Novel Antimicrobial Sulfonamides Derived from Nabumetone
Ayad Mohamed Rasheed Raaufa , Hala Ayad Mohamed Rasheeda , and
Farah Abdulhaleemb
aDepartment of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad,
b
Iraq; Baghdad College of Medicine, Baghdad, Iraq
ARTICLE HISTORY Received 17 September 2020; Accepted 18 September 2020
Throughout the last decade, novel Mannich bases have served as important sources of
new drug candidates.1–6 These have been evaluated as potential treatments for a multi-
tude of diseases and medical conditions as prodrugs, or as molecules eliciting responses
from specific biological targets.7–9 Nabumetone (Figure 1) is an inexpensive readily-
available non-steroidal anti-inflammatory drug (NSAID) with well-defined activity and
toxicity profiles.5–8 Since it is a methyl ketone, we felt that it would be a useful starting
material for Mannich reactions aimed at preparing a new category of sulfonamide anti-
bacterials. The present work is a pilot study directed toward the building of novel
Mannich bases derived from nabumetone and the well-documented sulfa drug sulfa-
methoxazole (Figure 2).8
In the event, compounds 1-4 were prepared by reaction of nabumetone with aro-
matic aldehydes and sulfamethoxazole in a straightforward procedure (Scheme 1; see
Experimental section), leading to the desired Mannich bases. Sulfonamides in gen-
eral have reduced nucleophilicity due to the electron-withdrawing capability of the
sulfonyl moiety, and sometimes they do not undergo reactions typical of primary
amines. We were thus pleased to note that our procedure led to the desired bases
in moderate to good yields (mean 70%), typical for the Mannich process. The prod-
ucts were obtained in pure form. The novel Mannich bases could be readily identi-
fied on the basis of their characteristic spectra. Thus, the FTIR data of compounds
1-4 showed the appearance of absorption bands near 3400-3344 cmꢀ1 for NH,
3080 cmꢀ1 for C-H (aromatic), 1710 cmꢀ1 for C ¼ O, 1340 and 1160 cmꢀ1 for SO2.
In addition, we observed the disappearance of the two bands near 3300 cmꢀ1
for NH2. The spectrometric data are more extensively listed in Table 1 and
microanalysis data are listed in Table 2.
The compounds showed significant activity against gram-positive and gram-negative
bacteria. These results are gathered in Table 3. We used the well diffusion method to
assess the activities of our new sulfonamides, based on zones of inhibition versus con-
trols. Sulfamethoxazole was used as a positive control, and it showed strong activity;
while DMSO was used as negative control and showed no inhibition. Compound 1
showed strong inhibition against all types of bacteria in all the concentrations used.
CONTACT Ayad Mohamed Rasheed Raauf
halaayad2002@yahoo.com
Department of Pharmaceutical Chemistry,
College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
ß 2020 Taylor & Francis Group, LLC

96
A. M. R. RAAUF ET AL.
Figure 1. Nabumetone.
Figure 2. Sulfamethoxazole.
Scheme 1. Preparation of novel sulfonamides (EtOH/CHCl3 3/1, HCl, 25 h, 25 ꢁC).
Compound 2 showed strong activity against Pseudomonas aeruginosa and moderate
inhibition against Acinetobacter species and Streptococcus pyogenes, while no inhibition
against Staphylococcus aureus was observed. Compound 3 showed strong activity against
S. aureus, moderate activity against Acinetobacter species, S. pyogenes and P. aeruginosa.
Finally, compound 4 showed strong activity against P. aeruginosa and weak activity
against Acinetobacter species, S. pyogenes and no inhibition against S. aureus.
In conclusion, novel Mannich bases were prepared from nabumetone and sulfameth-
oxazole. The compounds were obtained in pure form in a method noteworthy for its
simplicity. Antimicrobial activities were determined against several bacterial strains. It is

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
97
Table 1. Preparation of Mannich derivatives.
Products &
reactants
Time
(h)
Yield
(%)
m.p (ꢁC)
124-126
IR (cmꢀ1
)
1H NMR (d)
1
25
77
3396, 3080, 2899, 2860,
1710, 1346, 1159
2.29 (s, 3H, CH3), 2.52 (m, 2H, CH2),
2.85-3.10 (m, 4H, CH2-CH2), 3.40
(s, 3H, OCH3), 4.94-5.01 (CH), 6.11
(C ¼ C-H), 6.61 (NH), 7.19-7.76
(aromatic ring), 11.01 (s, 1H,
NH-SO2)
2
25
63
96-98
3400, 3097, 2983, 2856,
1712, 1348, 1159
2.29 (s, 3H, CH3), 2.75 (d, 2H, CH2),
2.88-2.97 (m, 4H, CH2-CH2), 3.42
(s, 3H, OCH3), 4.84 (m, 1H, CH),
6.11 (s, 1H, C ¼ C-H), 6.60-6.63 (m,
1H, NH), 7.09-7.77 (aromatic ring),
9.34 (s, 1H, OH), 11.00 (s, 1H,
NH-SO2)
3
4
27
22
85
58
200-202
186-188
3379, 3076, 2931, 2847,
1708, 1344, 1159
2.28 (s, 3H, CH3), 2.52 (d, 2H, CH2),
2.87-3.80 (m, 4H, CH2-CH2), 3.86
(s, 3H, OCH3), 5.00-5.13 (m, 1H,
CH), 6.12 (s, 1H, C ¼ C-H ), 6.64-
6.78 (d, 1H, NH), 7.13-8.26
(aromatic ring), 11.05 (s, 1H,
NH-SO2)
3344, 3087, 2939, 2843,
1703, 1338, 1161
2.52 (s, 3H, CH3 & d, 2H, CH2), 2.85-
3.05 (m, 4H, CH2-CH2), 3.86 (s, 3H,
OCH3), 4.98-6.05 (m, 1H, CH), 6.59-
6.63 (s, 1H, C ¼ C-H & d, 1H, NH),
7.11-8.48 (aromatic ring), 11.37 (s,
1H, NH-SO2)
Nabumetone
–
–
–
–
80-83
167
3053, 3009, 2955, 2901,
2837, 1707
2.12 (s, 3H, CH3), 2.82-2.95 (m, 4H,
CH2-CH2), 3.87 (s, 3H, OCH3), 7.13-
7.76 (aromatic ring)
Sulfamethoxazole
3468, 3375, 3298, 3144,
2931, 1369, 1143
2.30 (s, 3H, CH3), 6.01 (CH isoxazole
ring), 6.5 (NH2), 7.21-7.76
(aromatic ring), 11.55(s, 1H,
NH-SO2).
Table 2. Elemental analyses of new compounds.
Product
Molecular formula
Anal. Calcd.
Found
1
2
3
4
C32H31N3O5S
C32H31N3O6S
C32H30N4O7S
C32H30N3O5SCl
C, 67.47; H, 5.48; N, 7.38
C, 65.62; H, 5.34; N, 7.17
C, 62.53; H, 4.92; N, 9.11
C, 63.62; H, 5.01; N, 6.96
C, 67.40; H, 5.53; N, 7.30
C, 65.68; H, 5.37; N, 7.21
C, 62.58; H, 4.88; N, 9.16
C, 63.54; H, 5.04; N, 7.03
our hope that our convenient method of preparation in moderate to good yields will
foster further exploration of these potentially useful sulfonamide derivatives.
Experimental section
Some related 4-((1-(4-substitutedphenyl)-5-(6-methoxynaphthalen-2-yl)-3-oxopentyl)a-
mino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide derivatives had been synthesized
previously.11 Our anti-bacterial activity tests were conducted in accordance with the
well-diffusion method.12–13 All chemicals were supplied by BDH, Fluka and Sigma
Aldrich chemical companies. Mueller Hinton Agar was supplied from Salucea while

98
A. M. R. RAAUF ET AL.
Table 3. Anti-microbial activity of the prepared compounds.
Zone of inhibition (mm)
Gram negative
Gram positive
Sample code
and standard
Concentration
Acinetobacter
Pseudomonas
aeruginosa
Streptococcus
pyogenes
Staphylococcus
aureus
(mg/ml)
species
1
2
3
500.0
250.0
125.0
62.5
17
15
15
13
15
15
13
11
15
13
11
11
17
15
13
–
500.0
250.0
125.0
62.5
11
9
9
21
17
15
7
10
8
8
–
–
–
–
6
5
500.0
250.0
125.0
62.5
9
5
11
15
13
9
17
13
9
21
17
15
7
5
7
9
4
500.0
250.0
125.0
62.5
500.0
250.0
125.0
62.5
5
7
9
21
15
11
11
10
6
6
4
–
7
6
4
7
–
–
4
5
–
Sulfamethoxazole
DMSO
20
16
16
8
20
18
16
16
–
20
17
14
10
–
–
–
Zone of inhibition: (-) no inhibition; (3-6) weak; (7-10) moderate; (11-21) strong.
blood agar base was supplied from HIMEDIA. Melting points in the experimental work
were recorded through the use of Gallenkamp electro-thermal melting point apparatus
and are uncorrected. Infrared spectra were recorded by using a Shimadzu 8400s instru-
1
ment, as KBr discs. H-NMR (300 MHz) spectra were recorded on a Bruker Avance 300
instrument; DMSO-d6 was used as a solvent. Elemental analyses were recorded on a
Vario MICRO CUBE instrument.
Typical preparation
Sulfamethoxazole (1 mmol) was added to a solution of an aromatic aldehyde (1 mmol)
in a mixed solvent of anhydrous ethanol-chloroform (v/v ¼ 3/1). This mixture was
stirred, nabumetone (1 mmol) was added, followed by a few drops of concentrated
hydrochloric acid as a catalyst. The mixture was stirred continuously for 22 to 27 h at
20–32 ꢁC, then the suspension was chilled in the refrigerator overnight. The suspension
was filtered; then the filter cake was washed with 95% ethanol. The resulting solid was
suspended in water, adjusted to pH 7–8 with 10% K2CO3, and stirring was maintained
for 2 h. The suspension formed was filtered, washed with cold water (2-5 mL) and abso-
lute ethanol (2-3 mL), then dried overnight to yield the product.
Acknowledgments
The authors are very thankful to the management and staff of the Department of Pharmaceutical
Chemistry and Educational Laboratories, College of Pharmacy, Mustansiriyah University, for
their help and support.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
99
ORCID
Ayad Mohamed Rasheed Raauf
Hala Ayad Mohamed Rasheed
http://orcid.org/0000-0002-8957-2093
http://orcid.org/0000-0002-2143-628X
Farah Abdulhaleem
http://orcid.org/0000-0002-4968-8155
References
1. D. Rosenbloom and M. A. Craven, Canadian Family Physician, 29, 2121 (1983).
2. I. Morita, Prostaglandins & Other Lipid Mediators, 68–69, 165 (2002). doi:10.1016/s0090-
6980(02)00029-1
3. P. B. Rathi and K. V. Deshpande, Asian J. of Biomed. and Pharmaceut. Sci., 3, 30 (2013).
ꢀ
4. M. A. Gonzalo-Garijo, C. Cordobes-Dun, A. M. Lamilla-Yerga and I. Moreno-Gaston, J.
Investig. Allergol Clin. Immunol., 17, 274 (2007).
5. N. V. Olsen, N. G. Jensen, J. M. Hansen, N. J. Christensen, N. Fogh-Andersen and I.
Kanstrup, Clin. Sci., 97, 457 (1999).
6. S. Bala, N. Sharma, A. Kajal, S. Kamboj and V. Saini, Int. J. Med. Chem., 1 (2014).
7. G. Bosica and R. Zammit, PeerJ, 1 (2018).
8. M. Mahdi, A. Raauf and S. Rzoqi, Der Pharma Chemica, 8, 424 (2016).
9. R. Bhardwaj, P. Parihar, K. Yadav and N. B. Bardhan, Galore Int. J. Applied Sci. and
Humanities, 2, 19 (2018).
10. T. J. Sindhu, C. Meena and K. Krishnakumar, Hygeia J. D. Med., 10, 27 (2018).
11. W. Hang, Y. Ju-fang, S. Ziao-li, F. Li, X. Jin, Z. Guang-ming, J. Li and Y. Da-cheng, Bioorg.
& Med. Chem., 20, 2119 (2012).
12. V. Kuete, K. O. Eyong, G. N. Folefoc, V. P. Beng, H. Hussain, K. Krohn and A. E.
Nkengfack, Pharmazie, 62, 552 (2007).
13. N. L. Pfoze, Y. Kumar, B. Myrboh, R. K. Bhagobaty and S. R. Joshi, J. of Med. Plants Res., 5,
859 (2011).