Accepted Manuscript

Synthesis and antimicrobial activity of novel Benzoxazine Sulfonamide Deriv-

atives

Saidulu Konda, Srujana Raparthi, K Bhaskar, Rajesh Kumar Munaganti,

Vijayacharan Guguloth, Lingaiah Nagarapu, Dattatray. M. Akkewar

PII: S0960-894X(15)00038-4
DOI: http://dx.doi.org/10.1016/j.bmcl.2015.01.026
Reference: BMCL 22366

To appear in: Bioorganic & Medicinal Chemistry Letters

Received Date: 4 September 2014

Revised Date: 2 December 2014
Accepted Date: 13 January 2015

Please cite this article as: Konda, S., Raparthi, S., Bhaskar, K., Munaganti, R.K., Guguloth, V., Nagarapu, L.,
Akkewar, y.M., Synthesis and antimicrobial activity of novel Benzoxazine Sulfonamide Derivatives, Bioorganic
& Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.01.026

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 Graphical Abstract

Synthesis and antimicrobial activity of novel Benzoxazine Leave this area blank for abstract info.
Sulfonamide Derivatives

Saidulu Konda, Srujana Raparthi, Bhaskar K, Rajesh Kumar Munaganti, Vijayacharan Guguloth, LingaiahNagarapu†,
Dattatray. M. Akkewar*
 Bioorganic & Medicinal Chemistry Letters
j o u r n a l h o m e p a g e : w w w . e ls e v i e r . c o m

Synthesis and antimicrobial activity of novel Benzoxazine Sulfonamide

Derivatives
Saidulu Konda, Srujana Raparthi, Bhaskar K, Rajesh Kumar Munaganti, Vijayacharan Guguloth, Lingaiah
Nagarapu†, Dattatray. M. Akkewar*
Organic Chemistry Division-II (CPC), CSIR- Indian Institute of Chemical Technology, Hyderabad-500007,A.P, India.
*
Tel.: +91-40-27191443; Fax: +91-40-27193382; E-mail:dattatray.akkewar@gmail.com,
†
+91-40-27191510; Fax: +91-40-27193382; E-mail:lnagarapuiict@yahoo.com

ARTICLE INFO ABSTRACT

Article history: A new series of benzoxazine-6-sulfonamide derivatives were synthesized in excellent yields and
Received the resulting compounds were evaluated for their antimicrobial activities. All the synthesized
Revised compounds were assessed for their antibacterial and antifungal activities. Among them 1a, 1b,
Accepted 1c, 1e, 1h, 2c, 2d, 2e, 2g, 2h, 2i, 2j, 2k and 2l showed low inhibitory concentration (MIC of
Available online 31.25 and 62.5 µg/mL) against Gram-positive bacteria, Gram-negative bacteria and fungi, which
are comparable to the inhibitory effect of standard drugs.
Keywords: 2009 Elsevier Ltd. All rights reserved.
Sulfonamide,
Piperazine,
Benzoxazine,
Antibacterial activity,
Antifungal activity.

The present treatments of bacterial and fungal infections Considering the importance of benzoxazine-6-
are a bit unsatisfactory, owing to rapidly developing drug sulfonamide, and in continuation of our research program to
resistance and side effects. This effect has a negative impact on discover and develop novel biologically active compounds,21-24
the usage of most antimicrobial agents.1-4 2,3-Dihydro-1,4- we have planned to synthesize a new series of compounds having
benzoxazines have shown their significance as a part of benzoxazine-6-sulfonamide moiety and screened them for their
biologically active and medicinally important compounds. It is antimicrobial activities. The antibacterial and antifungal activities
evident by the several biological activities, such as anti- of all the newly synthesized compounds were evaluated in vitro
inflammatory,5 antiulcer,6 antibacterial,7 shown by 1,4- against one Gram-positive bacterium, three Gram-negative
benzoxazin-3(4H)-one derivatives. Ofloxacin, (Fig.1) one of the bacteria and one fungus.
antimicrobial agents, possess 1,4-benzoxazine ring system in its O O O O
R O
F O H
structure. OH
N S
N O
O
Sulfonamides forms the basis for a large multiplicity of N N O
drugs and are known for antibacterial,8 antiviral,9 diuretic,10 N O H2N

antimalarial,11 anticonvulsant,12 hypoglycemic,13 anti-carbonic Cl

Sulfadoxine (c)
antibacterial agent(b)
anhydrase14,15 and antithyroid16 activities. A marketable Ofloxacin (a)
O
sulfonamide derivative, KCN1 was shown to display both in vitro O
and in vivo antitumor activity.17,18 Recently Walsh et al. evaluated F
H
N O H
benzoxazine-6-sulfonamides (e) as activators of the tumor cell H O R1 N O O O
N R2 S
specific M2 isoform of pyruvate kinase.19 Newly, certain S O N
O S O
benzoxazine and sulfonamides (Fig. 1), have been reported to R3 N
H O
exhibit interesting antibacterial(b&d)7,19 and anticancer activity.19
anticancer agent (d) anticancer activity (e) KCN1 (f)
The piperazine-based heterocyclic nuclei are a varied
class of chemical compounds, some of which demonstrate Figure1.Structure of 1,4-benzoxazine ring system and sulfonamide
derivatives with antibacterial, anticancer activity.
significant pharmacological properties. A small adjustment in the
additional design in the piperazine core causes obvious
distinction in their biological events. A few related The synthetic pathways for the preparation of the target
arylsulfamides with a spacer to phenyl-piperazine were testified compounds are shown in Scheme 1, 2, 3 and 4. The
as active structure for 5-HT7 antagonist.20 intermediate3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-
sulfonyl chloride 5a-b was attained by the two-step synthetic
route. (Scheme 1)
Treatment of substituted o-amino phenol 3a-b with chloroacetyl
chloride in presence of benzyl triethyl ammonium chloride
(TEBA), afforded 2H-benzo[b][1,4]oxazin-3(4H)-one 4a-b,
which was further subjected to chlorosulfonylation to give
compounds 5a-b (Scheme 1). The synthesisof the intermediates
10a-g was achieved as per the scheme 2. Reaction of pthalimide
(6) with 1,3-dibromo propane (7) in presence of potassium
carbonate, in DMF furnished 2-(3-bromopropyl)isoindoline-1,3-
dione (8). Treatment of 8 with various piperazines and
thiomorpholine in presence of potassium carbonate in DMF,
resulted in the intermediates 9a-g, which were then treated with
hydrazine hydrate in MeOH to give compounds 10a-g. Coupling
of compounds 5a-b with 3-(4-phenylpiperazin-1-yl) propan-1-
amine derivatives 10a-g using diisopropylethylamine (DIPEA) in
DMF furnished benzo[b][1,4]oxazine-6-sulfonamide derivatives
1a-m (Scheme 3). The additional series 2a-n (scheme 4)were
synthesized from 5b. Compound 5b was treated with piperazines
in the presence of DIPEA in DMF to give compounds 11a-b.
Reaction of 11a-b with various phenacyl bromides in the
presence of potassium carbonate in MeOH afforded 2a-n. Benzoxazine-6-sulfonamides 1a-n, 2a-m and 11a-b
were tested in vitro for antibacterial and antifungal activity.
The results obtained showed that the majority of these
compounds show activity against Gram-positive bacteria such
as Bacillus megaterium, Gram-negative bacteria: Xanthomonas
campestris, Pseudomonas aeruginosa, Escherichia coli by broth
micro dilution method.25The anti-fungal activity was performed
against Candida albicans (MTCC 183) in comparison with
Fluconazole by employing Sabouraud’s dextrose broth.26
According to the obtained anti-bacterial data (Table 1),
it is apparent that all the benzoxazine-6-sulfonamides showed
promising activity. Compounds 1b, 1c, 2d, 2g, and 2l showed
low inhibitory concentration (MIC) of 31.25 (µg/mL) and 1a, 1h,
2e, 2h, 2i, and 2k MIC of 62.5 (µg/mL) and were found to be
very active against B.megaterium. Among the tested compounds
for antibacterial activity against Gram-negative bacteria, 1c, 1h,
2i, and 2l exhibited significant activity against X.campestris. In
particular, compounds 1c, 1e, 2c, 2d, 2g and 2l showed excellent
activity against P.aeruginosa. The compounds 2c, 2d, 2j, and 2l
showed low inhibitory concentration (MIC of 62.5 µg/mL)
against E. coli, as compared to Rifampicin (MIC of 64
µg/mL).The compounds with piperazine substituted sulfonamide
moiety 11a and 11b exhibited moderate anti-bacterial activity.
However attachment of the phenacyl group to them significantly
enhanced the anti-bacterial activity. The existence of strong
electron-donating and withdrawing substituent's, in
compounds1a, 1b, 1c, 1e, 1h, 2c, 2d, 2e, 2g, 2h, 2i, 2j, 2k, and 2l
showed favorable antibacterial activity.
Most of the tested compounds were found to be
remarkably active against C. albicans. Compounds 1b, 2d, 2g, 2i,
2j and 2l had comparable activity with the reference drug
fluconazole.

The structure-activity relationship (SAR) study reveals

that the change in substitution on piperazine attached aromatic
ring is important for inducing anti-microbial activity against
particular Gram-positive bacteria, Gram-negative bacteria and
fungi (Table-1). The compounds with fluoro substitution on
aromatic ring had higher anti-microbial activity as compared to
electron donating and strong electron withdrawing groups. For
example, compounds 1a, and 1h with no substitution and 1b and
1c with fluoro substitution showed higher anti-microbial activity.
 Tabale1. Results of anti-bacterial and anti-fungal activities of compounds 1a-m, 2a-n and 11a-b MICs (µg/mL).
Compounds Microorganisms
Gram positive Gram negative Fungi
B.megaterium X.campestris P.aeruginosa E.coli C.albicans
1a 62.5 125 125 500 125
1b 31.25 125 125 250 62.5
1c 31.25 62.5 62.5 125 125
1d 250 500 500 500 500
1e 250 125 62.5 500 250
1f NT NT NT NT NT
1g NT NT NT NT NT
1h 62.5 62.5 250 250 125
1i 250 500 500 500 250
1j 250 250 250 250 250
1k 250 250 250 250 250
1l NT NT NT NT NT
1m 125 250 500 500 250
2a 125 125 125 250 125
2b 250 250 250 250 250
2c 125 125 31.25 62.5 250
2d 31.25 125 31.25 62.5 31.25
2e 62.5 250 125 250 250
2f 250 500 500 500 500
2g 31.25 125 31.25 125 31.25
2h 62.5 125 250 500 500
2i 62.5 62.5 125 125 62.5
2j 125 125 62.5 62.5 62.5
2k 62.5 125 250 250 250
2l 31.25 62.5 31.25 62.5 31.25
2m 250 125 250 250 250
2n 500 250 250 250 250
11a 250 500 250 500 500
11b 250 500 500 500 500
Rifampicin 64 32 32 64 -
Fluconazole - - - - 32

NT-not tested
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Supplementary data
Experimental and copies of the 1H, 13C NMR and ESI-
MS spectra for some of the important compounds.