Synthesis and biological evaluation of substituted phenyl azetidine-2-one sulphonyl derivatives as potential antimicrobial and antiviral agents

Article abstract of DOI:10.1016/j.bioorg.2020.104320

In the present study, we intend to synthesize a series of novel substituted phenyl azetidine-2-one sulphonyl derivatives. The entire set of derivatives 5 (a-t) were screened for in-vitro antibacterial, and antifungal activity, and among them eleven compou

Full text of DOI:10.1016/j.bioorg.2020.104320

Journal Pre-proofs
Synthesis and biological evaluation of substituted phenyl azetidine-2-one sul-
phonyl derivatives as potential antimicrobial and antiviral agents
Milan Kumar Mandal, Swagatika Ghosh, Hans Raj Bhat, Lieve Naesens,
Udaya Pratap Singh
PII:
S0045-2068(20)31618-7
DOI:
https://doi.org/10.1016/j.bioorg.2020.104320
YBIOO 104320
Reference:
To appear in:
Bioorganic Chemistry
Received Date:
Revised Date:
Accepted Date:
11 August 2020
22 September 2020
24 September 2020
Please cite this article as: M. Kumar Mandal, S. Ghosh, H. Raj Bhat, L. Naesens, U. Pratap Singh, Synthesis and
biological evaluation of substituted phenyl azetidine-2-one sulphonyl derivatives as potential antimicrobial and
antiviral agents, Bioorganic Chemistry (2020), doi: https://doi.org/10.1016/j.bioorg.2020.104320
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Synthesis and biological evaluation of substituted phenyl azetidine-2-one
sulphonyl derivatives as potential antimicrobial and antiviral agents
Milan Kumar Mandala, Swagatika Ghoshb, Hans Raj Bhatc, Lieve Naesensd, Udaya Pratap
Singha*
aDrug Design & Discovery Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of
Agriculture, Technology & Sciences, Allahabad, Uttar Pradesh 211007, India
b Food Saftey and Drug Administration, Government of Uttar Pradesh, Lucknow, Uttar Pradesh 226018, India
c Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004, India
d Rega Institute Medical Research, KU Leuven, B-3000 Leuven, Belgium
1

Abstract:
In the present study, we intend to synthesize a series of novel substituted phenyl
azetidine-2-one sulphonyl derivatives. The entire set of derivatives 5 (a-t) were screened for in-
vitro antibacterial, and antifungal activity, and among them eleven compounds were further
screened for the antiviral activity to predict their efficacy against pathogenic viruses.
Interestingly, compound 5d, 5e, 5f, 5h, 5i, and 5j showed similar or better antibacterial activity
as compared to ampicillin (standard). Moreover, compounds 5h, 5i, 5j, and 5q showed good
inhibitory activity against fungal strains whereas other derivatives had mild or diminished
activity in comparison with standard drug clotrimazole. The antimicrobial study indicated that
compounds having electron-withdrawing groups showed the highest activity. Interestingly, these
tested compounds showed weak antiviral activity against Vaccinia virus, Human Coronavirus
(229E), Reovirus-1, Sindbis virus, Coxsackievirus B4, Yellow Fever virus, and Influenza B virus
in HEL cell, Vero cell, and MDCK cell cultures. The findings of the present study might open
new avenues to target human disease-causing deadly microbes and viruses.
Keywords: β-lactams; sulphonamides; schiff base; antimicrobial; antiviral.
2

1.
Introduction
The current therapeutics to treat pathogenic microorganisms has lost their effectiveness due to
resistant strain. Moreover, the rise of multidrug resistance strains (MDR) further aggravates the
situation which limits the options for clinicians.1-4 The major cause for the development of
antimicrobial resistance is the irrational use of antibiotics which triggered unwanted mutation
and developed resistant strains.5 According to the Center for Disease Control and Prevention
(CDC) USA, more than 2.8 million antibiotic-resistant infections occurred in 2019, and as a
result, more than 35,000 people lost their life. Many therapies like, cancer chemotherapy, anti-
tubercular therapy, organ transplantation, surgery, and antiretroviral therapy (ART) directly rely
on the effectiveness of antimicrobial drugs and resistance to those antibacterial could undermine
our fight against these deadly diseases. Antimicrobial resistance has become a global concern
because it consumes more health care resources and increases the financial burden of treatment.6-
8
In the present scenario, antimicrobial chemotherapy needs to understand the pathophysiology
of resistance, identify the mechanism of resistance and discover its effective treatment.9, 10
Research advancements have precisely proved that azetidine-2-ones (β-lactams) are present in
effective antimicrobials and possessed prominent antimicrobial property.11,12 It is a well-
documented fact they interfere with the biosynthetic pathway, like penicillin-binding proteins13
(PBPs) needed for the synthesis of peptidoglycans, which is a vital raw material for bacterial cell
wall synthesis. The azetidine-2-ones ring system is the central core of many clinically relevant
antibiotics, such as, penicillins, cephalosporins, cephamycin, carbapenems, and monobactams.
Azetidine-2-ones also reported having antitubercular, anticancer, anticonvulsants, antiviral,
enzyme inhibition and hypoglycemic actions.14-17
Many researchers have reported using a hybrid molecule for multi-drug target as a rational drug
design approach, single molecules with multi-functionality.18 Molecular hybridization approach
(covalently combining two or more pharmacophores) proved to be an effective tool for the
development of novel chemical entities.19-21 The hybrid molecules believed to exert improved
affinity and efficacy when compared to the parent drugs. This technique focuses on the
modulation of the pharmacophores giving rise to innovative hybrids that are believed to act by
one or more than one mechanism to target pathogenic micro-organisms or diseases. Such an
approach has been found more fruitful against devastating diseases, such as cancer, bacterial
infections, malaria, and HIV.22-25 A thorough study of various archives and literature proved that
azetidine-2-ones(β-lactams) and sulfur-derived functional groups containing drugs showed
diverse array of biological activities (Fig. 1).26, 27 Thus, prompted by the above, in the present
manuscript, we intended to synthesize a hybrid molecule composed of a substituted azetidine-2-
one (β-lactam) and sulphonyl benzene pharmacophore into a single skeleton in search of novel
inhibitor.28 These molecules were subsequently evaluated their antibacterial, antifungal, and
antiviral activities.
3

2.
Experimental
2.1.
Materials & Method
All the reagents and solvents were obtained from SD Fine and Sigma-Aldrich and were used
without purification unless otherwise stated. Melting points of the synthesized compounds were
determined in open capillaries using a Temp Star Pvt. apparatus and are expressed in °C and are
uncorrected. The completion of the reaction was monitored by thin-layer chromatography and
visualized by ultraviolet light or Iodine vapors. Infra-red spectra of synthesized compounds were
recorded using FTIR-8400S, Shimadzu, Japan using KBr pellets in the range of 4000-500 cm-1
1
on a Fourier Transform IR and frequencies described in wave numbers cm-1. H-NMR spectra
were recorded by Bruker Avance 400/AvIII HD-300 (FT NMR) with low and high-temperature
facility (-150°C - +180°C) in the solvents CDCl3 & DMF. Chemical shifts are reported in parts
per million (δ) and NMR data are given as multiplicity(s, singlet; d, doublet; t, triplet, q, quartet;
m, multiplet). The Mass spectra were obtained by Agilent 6520 Q-TOF (ESI-MS). The
Elemental analysis was performed using the Elemental Analyzer: Vario EL-III.
2.2.
Synthetic procedure
2.2.1. General procedure for the synthesis of N-[(E)-(R-phenyl)methylidene]-4-
methylbenzenesulfonamide 3 (a-t)29
An equimolar quantity of substituted aromatic aldehyde 2 (a-t) (0.01mol) and 4-methylbenzene
sulfonamide (1) (1.12 g, 0.01mol) were refluxed for 5-6 h. in 20ml of dehydrated ethanol, and
completion of the reaction was detected by TLC (carbon tetrachloride/methanol, 2:1) plates.
After completion of the reaction as ascertained by TLC, the product was transferred in boiling
condition to a beaker having crushed ice. The resulting mixture was filtered after attaining the
room temperature, kept overnight, dried, and recrystallized from ethanol to afford the
corresponding pure product.
2.2.2. General procedure for the synthesis of 4-(R-phenyl)-3-chloro-1-[(4-methylphenyl)
sulfonyl]azetidin-2-one 5 (a-t) 30
The corresponding compounds 3 (a-t) (0.01 mol) were stirred with triethylamine in equal
proportion in anhydrous ethanol, then chloroacetyl chloride (4) (1.12 g, 0.01 mol) was added
dropwise to the reaction mixture. After this whole reaction mixture was refluxed for 9-10 h and
reaction completion was checked by TLC (n-Hexane/Ethyl acetate 3:1). The resulting reaction
mixture was then treated with ice-cold water and the precipitate obtained was washed
thoroughly, filtered and recrystallized from ethanol to obtain final derivatives (4-(R-phenyl)-3-
chloro-1-[(4-methylphenyl)sulfonyl] azetidin-2-one).
2.2.2.1. 3-Chloro-1-[(4-methylphenyl)sulfonyl]-4-phenylazetidin-2-one (5a)
Yield 72 %; m.p. 179 ºC; IR (KBr, cm-1): 3120 (Ar C-H str), 2924 (C-CH3 str), 1840 (C=O str),
1
1569 (C=C str), 1725 (CH=N str), 1151(S=O str), 668(C-Cl str); H-NMR (CDCl3, 400 MHz):
2.40 (s, 3H, CH3), 5.02-5.32 (d, 2H, C-H, J=5.07 Hz), 4.32 (s, 1H, CH-Cl), 7.29-7.34 (m, 4H,
Ar-H), 7.80 (d, 3H, Ar-H, J=7.5 Hz), 8.24 (s, 1H, CH=N). ESI-MS (m/z) calcd. is 335.80, found
4

336.81: [M + H]+; anal. calcd. for C16H14ClNO3S: C 57.23, H 4.20, N 4.22; found C 57.28, H
4.22, N 4.14.
2.2.2.2. 4-(2-Bromophenyl)-3-chloro-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5b)
Yield 65 %; m.p. 109 ºC; IR (KBr, cm-1): 3051 (Ar C-H str), 2598 (C-CH3 str), 1840 (C=O str),
1
1598 (C=C str), 1780(CH=N str), 1160 (S=O str), 708(C-Cl str), 560 (C-Br str); H-NMR
(CDCl3, 400 MHz): 2.41(s, 3H, CH3), 5.27(d, 1H, C-H, J=5.07 Hz), 4.33(s, 1H, CH-Cl), 7.36(m,
4H, Ar-H), 7.82 (d, 3H, Ar-H, J=7.5 Hz), 8.40 (s, 1H, CH=N). ESI-MS (m/z) calcd. is 414.70,
found 415.70: [M + H]+; anal. calcd. for C16H13BrClNO3S: C 46.34, H 3.16, N 3.38; found C
46.29, H 3.14, N 3.40.
2.2.2.3. 4-(3-Bromophenyl)-3-chloro-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5c)
Yield 58 %; m.p. 166 ºC; IR (KBr, cm-1): 3049 (Ar C-H str), 2598 (C-CH3 str), 1870 (C=O str),
1
1598 (C=C str), 1789 (CH=N str), 1172 (S=O str), 704 (C-Cl str), 668 (C-Br str); H-NMR
(CDCl3, 400 MHz): 2.41(s, 3H, CH3), 5.11-5.28(d, 1H, C-H, J=5.07 Hz), 4.28(s, 1H, CH-Cl)
7.31-7.32(t, 1H, Ar-H, J=7.50 Hz), 7.45-7.58(m, 3H, Ar-H), 7.80(d, 3H, Ar-H, J=7.5 Hz),
8.24(s, 1H, CH=N). ESI-MS (m/z) calcd. is 414.70, found 415.68: [M + H]+; anal. calcd. for
C16H13BrClNO3S: C 46.34, H 3.16, N 3.38; found C 46.34, H 3.09, N 3.39.
2.2.2.4. 4-(4-Bromophenyl)-3-chloro-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5d)
Yield 61 %; m.p. 201 ºC; IR (KBr, cm-1): 3048 (Ar C-H str), 2596 (C-CH3 str), 1819 (C=O str),
1
1598 (C=C str), 1758 (CH=N str), 1160 (S=O str), 704 (C-Cl str), 533 (C-Br str); H-NMR
(CDCl3, 400 MHz): 2.40(s, 3H, CH3), 5.35(d, 1H, C-H, J=5.07 Hz), 4.33(s, 1H, CH-Cl) 7.34(m,
3H, Ar-H), 7.80(t, 4H, Ar-H, J=7.5 Hz), 8.40(s, 1H, CH=N). ESI-MS (m/z) calcd. is 414.70,
found 415.71: [M + H]+; anal. calcd. for C16H13BrClNO3S: C 46.34, H 3.16, N 3.38; found C
46.31, H 3.12, N 3.32.
2.2.2.5. 3-Chloro-4-(2-chlorophenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5e)
Yield 63 %; m.p. 164 ºC; IR (KBr, cm-1): 3125 (Ar C-H str), 2924 (C-CH3 str), 1818 (C=O str),
1596 (C=C str), 1725 (CH=N str), 1150 (S=O str), 670 (C-Cl str); 1H-NMR (CDCl3, 400 MHz):
2.40(s, 3H, CH3), 5.07(d, 1H, C-H, J=5.07 Hz), 4.34(s, 1H, CH-Cl) 7.29-7.36(m, 3H, Ar-H),
7.82(d, 4H, Ar-H, J=7.50 Hz), 8.42(s, 1H, CH=N). ESI-MS (m/z) calcd. is 370.25, found 371.20:
[M + H]+; anal. calcd. for C16H13Cl2NO3S: C 51.90, H 3.54, N 3.78; found C 51.88, H 3.51, N
3.79.
2.2.2.6. 3-Chloro-4-(3-chlorophenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5f)
Yield 65 %; m.p. 157 ºC; IR (KBr, cm-1): 3128 (Ar C-H str), 2894 (C-CH3 str), 1821 (C=O str),
1598 (C=C str), 1728 (CH=N str), 1152 (S=O str), 675 (C-Cl str); 1H-NMR (CDCl3, 400 MHz):
2.41(s, 3H, CH3), 5.11(d, 1H, C-H, J=5.07 Hz), 4.33(s, 1H, CH-Cl) 7.31(t, 1H, Ar-H, J=7.50
Hz), 7.58(m, 4H, Ar-H), 7.80 (d, 2H, Ar-H, J=7.50 Hz), 8.48(s, 1H, CH=N). ESI-MS (m/z)
calcd. is 370.25, found 371.23: [M + H]+; anal. calcd. for C16H13Cl2NO3S: C 51.90, H 3.54, N
3.78; found C 51.89, H 3.51, N 3.79.
5

2.2.2.7. 3-Chloro-4-(4-chlorophenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5g)
Yield 71 %; m.p. 195 ºC; IR (KBr, cm-1): 3129 (Ar C-H str), 2896 (C-CH3 str), 1820 (C=O str),
1598 (C=C str), 1729 (CH=N str), 1160 (S=O str), 678 (C-Cl str); 1H-NMR (CDCl3, 400 MHz):
2.40(s, 3H, CH3), 5.05-5.36(d, 1H, CH, J=5.07 Hz), 4.29(s, 1H, CH-Cl), 7.32-7.34(m, 5H, Ar-
H), 7.80(d, 2H, Ar-H, J=7.5 Hz), 8.43(s, 1H, CH=N). ESI-MS (m/z) calcd. is 370.25, found
371.28: [M + H]+; anal. calcd. for C16H13Cl2NO3S: C 51.90, H 3.54, N 3.78; found C 51.84, H
3.72, N 3.71.
2.2.2.8. 3-Chloro-4-(2-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5h)
Yield 52 %; m.p. 169 ºC; IR (KBr, cm-1): 3125 (Ar C-H str), 2924 (C-CH3 str), 1804 (C=O str),
1
1577 (C=C str), 1751 (CH=N str), 1303 (S=O str), 668 (C-Cl str), 531 (C-F str); H-NMR
(CDCl3, 400 MHz): 2.43(s, 3H, CH3), 5.05-5.47(d, 1H, CH, J=5.07 Hz), 4.33(s, 1H, CH-Cl),
7.32-7.36(m, 4H, Ar-H), 7.42-7.45(m, 2H, Ar-H), 7.80(d, 1H, Ar-H, J=5.07 Hz), 8.40(s, 1H,
CH=N). ESI-MS (m/z) calcd. is 353.79, found 354.79: [M + H]+; anal. calcd. for
C16H13ClFNO3S: C 54.32, H 3.70, N 3.96; found C 54.28, H 3.68, N 3.99.
2.2.2.9. 3-Chloro-4-(3-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5i)
Yield 59 %; m.p. 162 ºC; IR (KBr, cm-1): 3126 (Ar C-H str), 2924 (C-CH3 str), 1808 (C=O str),
1
1579 (C=C str), 1749 (CH=N str), 1308 (S=O str), 669 (C-Cl str), 538 (C-F str); H-NMR
(CDCl3, 400 MHz): 2.40(s, 3H, CH3), 5.11(d, 1H, C-H, J=5.07 Hz), 4.34(s, 1H, CH-Cl), 7.32(t,
1H, Ar-H, J=5.07 Hz), 7.59(m, 4H, Ar-H), 7.81(d, 2H, Ar-H, J=5.07 Hz), 8.40(s, 1H, CH=N).
ESI-MS (m/z) calcd. is 353.79, found 354.80: [M + H]+; anal. calcd. for C16H13ClFNO3S: C
54.32, H 3.70, N 3.96; found C 54.30, H 3.75, N 3.85.
2.2.2.10. 3-Chloro-4-(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5j)
Yield 71 %; m.p. 183 ºC; IR (KBr, cm-1): 3129 (Ar C-H str), 2897 (C-CH3 str), 1828 (C=O str),
1
1598 (C=C str), 1729 (CH=N str), 1159 (S=O str), 690 (C-Cl str), 580 (C-F str); H-NMR
(CDCl3, 400 MHz): 2.40(s, 3H, CH3), 5.11(d, 1H, C-H, J=5.07 Hz), 4.33(s, 1H, CH-Cl) 7.32(t,
1H, Ar-H, J=5.07 Hz), 7.59(m, 3H, Ar-H), 7.81(d, 3H, Ar-H, J=5.07 Hz), 8.42(s, 1H, CH=N).
ESI-MS (m/z) calcd. is 353.79, found 354.74: [M + H]+; anal. calcd. for C16H13ClFNO3S: C
54.32, H 3.70, N 3.96; found C 54.34, H 3.80, N 3.82.
2.2.2.11. 3-Chloro-4-(2-hydroxyphenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5k)
Yield 70 %; m.p. 142 ºC; IR (KBr, cm-1): 3495 (Ar-OH str) 3059 (Ar C-H str), 2928 (C-CH3 str),
1
1809 (C=O str), 1579 (C=C str), 1728 (CH=N str), 1165 (S=O str), 678 (C-Cl str); H-NMR
(CDCl3, 400 MHz): 2.40(s, 3H, CH3), 5.06(d, 2H, CH, J=5.07 Hz), 4.38(s, 1H, CH-Cl), 6.97-
7.19(m, 4H, Ar-H, J=2.5 Hz), 7.80(d, 2H, Ar-H, J=7.50 Hz), 8.42(s, 1H, CH=N) 10.5(s, 1H,
OH). ESI-MS (m/z) calcd. is 351.80, found 352.82: [M + H]+; anal. calcd. for C16H14ClNO4S: C
54.62, H 4.01, N 3.98; found C 54.60, H 4.08, N 3.89.
2.2.2.12. 3-Chloro-4-(3-hydroxyphenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5l)
6

Yield 72 %; m.p. 149 ºC; IR (KBr, cm-1): 3525 (Ar-OH str) 3056 (Ar C-H str), 2928 (C-CH3 str),
1
1895 (C=O str), 1598 (C=C str), 1728 (CH=N str), 1154 (S=O str), 669 (C-Cl str); H-NMR
(CDCl3, 400 MHz): 2.41(s, 3H, CH3), 5.42(d, 2H, CH, J=5.07 Hz), 4.33(s, 1H, CH-Cl), 7.36(t,
1H, Ar-H, J=5.07 Hz), 7.58(m, 3H, Ar-H), 7.81(d, 2H, Ar-H, J=7.50 Hz), 8.44(s, 1H, CH=N),
9.21(s, 1H, OH). ESI-MS (m/z) calcd. is 351.80, found 352.81: [M + H]+; anal. calcd. for
C16H14ClNO4S: C 54.62, H 4.01, N 3.98; found C 54.60, H 4.02, N 3.95.
2.2.2.13. 3-Chloro-4-(4-hydroxyphenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5m)
Yield 85 %; m.p. 166 ºC; IR (KBr, cm-1): 3555 (Ar-OH str) 3090 (Ar C-H str), 2989 (C-CH3 str),
1
1890 (C=O str), 1596 (C=C str), 1782 (CH=N str), 1160 (S=O str), 678 (C-Cl str); H-NMR
(CDCl3, 400 MHz): 2.40(s, 3H, CH3), 5.03-5.32(d, 2H, CH, J=5.07 Hz), 4.28(s, 1H, CH-Cl),
6.74-7.05(t, 1H, Ar-H, J=7.50 Hz), 7.32(m, 3H, Ar-H), 7.80(d, 2H, Ar-H, J=7.50 Hz), 8.19(s,
1H, OH), 8.44(s, 1H, CH=N). ESI-MS (m/z) calcd. is 351.80, found 352.80: [M + H]+; anal.
calcd. for C16H14ClNO4S: C 54.62, H 4.01, N 3.98; found C 54.61, H 4.08, N 3.89.
2.2.2.14. 3-Chloro-1-[(4-methylphenyl)sulfonyl]-4-[4-(propan-2-yl)phenyl]azetidin-2-one (5n)
Yield 79 %; m.p. 195 ºC; IR (KBr, cm-1): 3190 (Ar C-H str), 2928 (C-CH3 str), 1821 (C=O str),
1696 (C=C str), 1720 (CH=N str), 1152 (S=O str), 690 (C-Cl str); 1H-NMR (CDCl3, 400 MHz):
1.32(s, 6H, 2xCH3), 2.40(s, 3H, CH3), 4.28(s, 1H, CH-Cl), 5.06(d, 2H, CH, J=6.40 Hz), 7.14(m,
3H, Ar-H), 7.80(d, 4H, Ar-H, J=6.40 Hz), 8.44(s, 1H, CH=N). ESI-MS (m/z) calcd. is 377.85,
found 378.85: [M + H]+; anal. calcd. for C19H20ClNO3S: C 60.39, H 5.33, N 3.71; found C 60.38,
H 5.35, N 3.70.
2.2.2.15. 3-Chloro-1-[(4-methylphenyl)sulfonyl]-4-(2-nitrophenyl)azetidin-2-one (5o)
Yield 74 %; m.p. 198 ºC; IR (KBr, cm-1): 3100 (Ar-CH str), 2926 (C-CH3 str), 1809 (C=O str),
1
1520 (C=C str), 1450 (C-NO2 str), 1740 (CH=N str), 1120 (S=O str), 710 (C-Cl str); H-NMR
(CDCl3, 400 MHz): 2.42(s, 3H, CH3), 5.40(d, 1H, C-H, J=5.07 Hz), 4.38(s, 1H, CH-Cl) 7.19(m,
4H, Ar-H), 7.32(d, 3H, Ar-H, J=5.07 Hz), 8.44(s, 1H, CH=N). ESI-MS (m/z) calcd. is 380.80,
found 381.82: [M + H]+; anal. calcd. for C16H13ClN2O5S: C 50.46, H 3.44, N 7.36; found C
50.42, H 3.38, N 7.39.
2.2.2.16. 3-Chloro-1-[(4-methylphenyl)sulfonyl]-4-(3-nitrophenyl)azetidin-2-one (5p)
Yield 78 %; m.p. 201 ºC; IR (KBr, cm-1): 3129 (Ar-CH str), 2920 (C-CH3 str), 1819 (C=O str),
1
1580 (C=C str), 1410 (C-NO2 str), 1765 (CH=N str), 1128 (S=O str), 698 (C-Cl str); H-NMR
(CDCl3, 400 MHz): 2.40(s, 3H, CH3), 5.30(d, 2H, CH, J=5.07 Hz), 4.33(s, 1H, CH-Cl) 7.09(m,
2H, Ar-H), 7.23(t, 1H, Ar-H, J=5.07 Hz), 7.80(d, 3H, Ar-H, J=7.5 Hz), 8.42(s, 1H, CH=N). ESI-
MS (m/z) calcd. is 380.80, found 381.81: [M + H]+; anal. calcd. for C16H13ClN2O5S: C 50.46, H
3.44, N 7.36; found C 50.44, H 3.47, N 7.26.
2.2.2.17. 3-Chloro-1-[(4-methylphenyl)sulfonyl]-4-(4-nitrophenyl)azetidin-2-one (5q)
Yield 81 %; m.p. 206 ºC; IR (KBr, cm-1): 3180 (Ar-CH str), 2950 (C-CH3 str), 1825 (C=O str),
1
1550 (C=C str), 1470 (C-NO2 str), 1725 (CH=N str), 1150 (S=O str), 718 (C-Cl str); H-NMR
7

(CDCl3, 400 MHz): 2.41(s, 3H, CH3), 5.34(d, 2H, CH, J=5.07 Hz), 4.38(s, 1H, CH-Cl), 7.19-
7.32(m, 3H, Ar-H), 7.60-7.80(d, 3H, Ar-H, J=7.5 Hz), 8.42(s, 1H, CH=N). ESI-MS (m/z) calcd.
is 380.80, found 381.83: [M + H]+; anal. calcd. for C16H13ClN2O5S: C 50.46, H 3.44, N 7.36;
found C 50.49, H 3.39, N 7.38.
2.2.2.18. 3-Chloro-4-(2-methylphenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5r)
Yield 69 %; m.p. 171 ºC; IR (KBr, cm-1): 3110 (Ar C-H str), 2892 (C-CH3 str), 1816 (C=O str),
1696 (C=C str), 1750 (CH=N str), 1105 (S=O str), 685 (C-Cl str); 1H-NMR (CDCl3, 400 MHz):
2.40(s, 3H, CH3), 2.42(s, 3H, CH3), 5.40(q, 2H, CH, J=7.5 Hz), 4.33(s, 1H, CH-Cl), 7.19(m, 4H,
Ar-H), 7.80(d, 2H, Ar-H, J=7.80 Hz), 8.40(s, 1H, CH=N). ESI-MS (m/z) calcd. is 349.83, found
350.81: [M + H]+; anal. calcd. for C17H16ClNO3S: C 58.37, H 4.61, N 4.00; found C 58.31, H
4.65, N 4.04.
2.2.2.19. 3-Chloro-4-(3-methylphenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5s)
Yield 74 %; m.p. 172 ºC; IR (KBr, cm-1): 3099 (Ar C-H str), 2845 (C-CH3 str), 1896 (C=O str),
1678 (C=C str), 1746 (CH=N str), 1109 (S=O str), 681 (C-Cl str); 1H-NMR (CDCl3, 400 MHz):
2.41(s, 3H, CH3), 2.44(s, 3H, CH3), 5.38(q, 2H, CH, J=7.5 Hz), 4.28(s, 1H, CH-Cl), 7.23(m, 4H,
Ar-H), 7.80(d, 2H, Ar-H, J=5.07 Hz), 8.44(s, 1H, CH=N). ESI-MS (m/z) calcd. is 349.83, found
350.81: [M + H]+; anal. calcd. for C17H16ClNO3S: C 58.37, H 4.61, N 4.00; found C 58.29, H
4.60, N 4.08.
2.2.2.20. 3-Chloro-4-(4-methylphenyl)-1-[(4-methylphenyl)sulfonyl]azetidin-2-one (5t)
Yield 78 %; m.p. 182 ºC; IR (KBr, cm-1): 3106 (Ar C-H str), 2816 (C-CH3 str), 1843 (C=O str),
1685 (C=C str), 1744 (CH=N str), 1116 (S=O str), 673 (C-Cl str); 1H-NMR (CDCl3, 400 MHz):
2.40(s, 3H, CH3), 2.42(s, 3H, CH3), 5.40(q, 2H, CH, J=7.5 Hz), 4.30(s, 1H, CH-Cl), 7.20(m, 4H,
Ar-H,), 7.79(d, 2H, Ar-H, J=7.80 Hz) 8.42(s, 1H, CH=N). ESI-MS (m/z) calcd. is 349.83, found
350.81: [M + H]+; anal. calcd. for C17H16ClNO3S: C 58.37, H 4.61, N 4.00; found C 58.35, H
4.66, N 4.05.
2.3.
In-vitro antimicrobial assay/studies
2.3.1. Minimal Inhibitory Concentrations
All the synthesized compounds were screened for minimal inhibitory concentrations
(MICs, µg/mL) using the broth micro dilution procedure as per the guidelines of the Clinical
Laboratory Standard Institute (CLSI).31,32 Microbial Strains of gram-negative bacteria
Pseudomonas aeruginosa (MCCB 0035), Escherichia coli (ATCC 8739) and gram +ve bacteria
Staphylococcus aureus (ATCC 29213) and fungal strains Aspergillus fumigatus (NCIM 2081),
Aspergillus niger (NCIM 2191) and Candida albicans (NCIM 2087) were used for antimicrobial
screening. Mueller–Hinton Broth for bacterial strains and Sabouraud liquid medium was used for
fungal strains growth. Various concentrations of target compounds and standard drugs were
prepared using two-fold serial dilution in a suitable medium ranging from 512-0.25 µg/mL. The
bacterial broth culture was incubated at 35 °C (2-6 h) and the fungal broth culture was incubated
8

for 24 h until it achieves the turbidity of a 0.5 McFarland standard. The final concentration of 5 x
105 CFU/mL for bacteria suspension and 0.5-2.5 x 103 CFU/mL for the fungal suspension was
prepared by diluting with a sterile solution.
2.3.2. Agar Disk Diffusion method
Measurement of the zone of inhibition was performed using the agar disc diffusion
method as per CLSI guidelines with slight modifications. Mueller–Hinton agar (MHA) Petri
plates were prepared and then standardized microbial suspensions were inoculated. Stock
solutions of test compounds and standards were prepared in DMSO and then diluted with
distilled water to get a final concentration of 100 µg/mL. Sterilized 8 mm diameter disks were
prepared from Whatman filter paper, then the standard and test solutions were added to each disk
(100 µg/8mm disk). The disks were added to each Petri plates in a triplicate manner ensuring
complete contact of a disk with agar plates. The agar Petri plates were incubated at 35°C for 24 h
for bacterial strains and 48 h for fungal strains. The zone of inhibition of standard and test
solutions against microbial growth was recorded in mm.
2.3.3. Antiviral activity assays
Some of the synthesized compounds were evaluated for their antiviral activity in relevant
mammalian cell cultures by using Cytopathic effect (CPE) reduction assay with a broad panel of
RNA and DNA viruses. Human embryonic lung (HEL) cells were used to study Human
Coronavirus (229E), Adeno virus-2, and Vaccina virus African green monkey kidney Vero cells
were used to evaluate Parainfluenza-3virus, Reovirus-1, Sindbis virus, Coxsackievirus B4, Punta
Toro virus, and Yellow fever virus. Finally Influenza A/H1N1A/Ned/378/05, Influenza
A/H3N2A/HK/7/87, and Influenza B B/Ned/537/05 viruses evaluated on Madin-Darby Canine
Kidney (MDCK) cells.
To study the antiviral assays the viruses were inoculated into the subconfluent cultures of
the cells in 96 well plates. Then the serial dilutions of test compounds were added to the well
plates. Various reference compounds were included i.e. dextran sulfate (DS) (viral entry
inhibitor), broad-spectrum acting mycophenolic acid (an inhibitor of cellular IMP
dehydrogenase), antiviral agent Ribavirin, Acyclovir, Amantadine, Rimantadine, antiherpetic
agents Ganciclovir and Brivudin. After 3-6 days of incubation at 37 °C the test compounds
antiviral effect and their cytotoxic effect was monitored by light microscopy or by performing
the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-
tetrazolium) cell viability assay. Antiviral activity was expressed as EC50 (50% effective
concentration) by examining microscopic scoring of CPE or virus plaque formation, whereas
cytotoxicity of compounds was expressed as MCC (Minimal Cytotoxic Concentration) measured
by MTS assay.
3.
3.1.
Result & Discussion
Chemistry
9

The synthesis of final derivatives (4-(R-phenyl)-3-chloro-1-[(4-methylphenyl)
sulfonyl]azetidin-2-one) 5 (a-t) was accomplished as displayed scheme 1. The approach involves
the preparation of 3 (a-t) derivatives by condensation reaction between equimolar quantities of
4-methylbenzene sulfonamide (1) with different aromatic aldehydes 2 (a-t) in the presence of
ethanol at room temperature. These reactive imine derivatives (Schiff’s base) further underwent
ketene-imine cyclo-condensation with chloroacetyl chloride in presence of triethylamine to
afford target compounds phenyl azetidine -2-one benzyl sulfonyl derivatives 5 (a-t) in good
yield. Typically ketenes are generated in-situ by reacting acid chlorides with a mild base.
Initally, a nucleophilic addition of imine nitrogen across the electrophilic carbon of the ketene at
a less hindered site results in zwitterion intermediate which undergoes conrotatory electrocyclic
ring closure to form azetidine-2-ones or β-lactams.
Scheme 1 Scheme for the synthesis of 4-(R-phenyl)-3-chloro-1-[(4-methylphenyl)sulfonyl] azetidin-2-one
derivatives 5 (a-t). Reagents and Condition: (a) C2H5OH, reflux, 80 ºC, 5-6 h.; (b) N(CH2CH3)3, C2H5OH, reflux
100ºC, 9-10 h.
The structures of these phenyl azetidine-2-one sulphones derivatives 5 (a-t) were
1
established by their IR, H NMR, and Mass spectra which were found in line with their
molecular structures. The IR spectra bands observed at 1730 – 1780 cm-1 confirmed the
formation of β-lactams. Stretching absorptions in the region of 1800 – 1890 correspond to the
presence of carbonyl group in the azetidinone ring. In 1H NMR broad singlets at 3.83 - 4.33 ppm
and 8.2 - 8.56 ppm attributes to CH=N protons and CH-Cl of β-lactams or azetidine moieties
respectively. Whereas multiplets at 7.20 - 7.65 correspond to other aromatic protons. Mass
spectra (ES-MS) of synthesized showed a molecular ion peak in agreement with their molecular
structure.
3.2.
In-vitro antimicrobial activity
All the novel derivatives (4-(R-phenyl)-3-chloro-1-[(4-methylphenyl)sulfonyl]azetidin-2-one) 5
(a-t) were assayed in-vitro for their growth inhibitory activity against pathogenic microorganism
10

and the results are presented in Table 1 & 2. The results for antimicrobial potency for all the
newly synthesized compounds showed variable in-vitro antibacterial and antifungal activity in
comparison to standard drug ampicillin and clotrimazole respectively. Compounds 5j, 5f, 5h, 5i,
and 5d showed significant activity against the entire set of tested pathogenic bacterial strains as
compared to ampicillin. Moreover against Gram-negative bacteria E. coli, 5f and 5j exhibited
higher activity with MIC, of 0.5µg/ml and 1 µg/ml respectively. The compounds 5j, 5f, 5i, and
5e showed a continuous increase in inhibitory activity against P. aeruginosa. Similarly against
bacterial strain S. aureus, compound 5j and 5f showed remarkable activities followed by
compounds 5i, 5e, 5c, 5p and 5q. Against fungal micro-organisms, compounds 5j, 5i, and 5q
showed considerable activity against the entire set of tested fungal strains. Compounds 5i, 5j, 5q,
and 5h showed the highest activity against C. albicans. Whereas against A. niger, 5j, 5i, and 5q
selectively showed moderate activity. Compounds 5j, 5q and 5i found equipotent to
cotrimoxazole against A. fumigatus. Some of the synthesized compounds 4a, 5r, 5s, 5t displayed
the least activity against the tested fungal strains.
3.3.
Structure-activity relationship
As shown in Fig. 2, the structure-activity relationship studies of target compounds suggested that
minor structural variations on the compound have a profound effect on the microbial activity.
The study suggested that the inhibitory activity was greatly influenced by the presence of an
electron-withdrawing group (5j, 5i, 5h, 5f, and 5d) while their donating counterparts (5n, 5r, 5s,
and 5t) showed mild to moderate activity. Moreover, the absence of phenyl substitution on
azetidine-2-one arm (5a) was detrimental in determining the biological activity. The microbial
assay revealed that activity improved by the replacement of hydrogen with electron-withdrawing
groups. Whereas substitution by electron-donating groups with bulkier (5n, 5o) size had the
lowest range of activity.
3.4.
Antiviral activity and cytotoxicity
The antiviral activities and cytotoxicity of some selected compounds (5a, 5c, 5e, 5g, 5h, 5k, 5m,
5n, 5o, 5p, 5q) were determined in HEL cell, Vero cell, and MDCK cell with a broad pool of
DNA and RNA viruses. Almost all the tested compounds demonstrated marginal activity (Table-
3) in HEL cell cultures against the Vaccina virus and Human Coronavirus (229E) strain. A lower
level of activity was also noted against Herpes simplex virus-1 (KOS) strain but diminished
activity was noted in the case of Herpes simplex virus-2 (G) and Herpes simplex virus-1 TK-
KOS ACVr. In Vero cell culture (Table- 4) against the Sindbis virus, Coxsackievirus B4, and
Yellow Fever Virus same set of synthesized compounds displayed weak activity. Tested
compounds had much lower activity against strains of Para- influenza-3 virus and Punta Toro
virus. The data obtained from Anti-influenza virus activity against different strains of Influenza
virus using standard assay protocols in Madin Darby canine kidney (MDCK) cells (Table- 5)
cultures exhibited some activity against the Influenza B strain in contrast against both the strains
of Influenza A viruses. From this antiviral study, the structure-activity relationship profile cannot
be predicted as all the compounds exhibited similar intensity of activity. This antiviral testing
provided cytotoxicity data against HEL cell, Vero cell, and MDCK cell lines which can guide us
11

in further studies. In combination, these antiviral data suggest that neither of the screened
compounds showed any promising activity, so further structural optimization is required for
getting an effective antiviral scaffold.
4.
Conclusion
Collectively, we have synthesized series of novel (4-(R-phenyl)-3-chloro-1-[(4-
methylphenyl)sulfonyl]azetidin-2-one) 5 (a-t) derivatives and tested for their antimicrobial and
antiviral activity. Compounds 5h, 5i, 5j, and 5q showed significant activity against fungal strains
as compared to Clotrimazole. On the other hand compounds 5j, 5f, 5i, and 5d found equipotent
to ampicillin against comparable activity against the entire set of tested pathogenic bacterial
strains. In a comparative antimicrobial study, compounds containing electron-withdrawing
groups were found more active than their electron-donating counterparts. Antiviral study of
selected derivatives showed a low level of inhibitory activity against various DNA and RNA
viruses, so the structures of the compounds can be considered for further modification in a search
of potent antiviral agents.
Acknowledgment
The authors (MKM) would like to sincerely thank the University Grant Commission, New Delhi,
Government of India for doctoral fellowship (RGNF/2013-14-SC-ORI-36328) and SHUATS for
providing necessary infrastructural facilities.
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13

Fig. 1. Chemical structures of commercially available drugs containing azetidine-2-ones
(β-lactams) and phenylsulphone moieties.
14

Fig. 2. Structure-activity relationship study of compound 5 (a-t) against bacterial and fungal
microorganisms.
Table1. Minimum inhibitory concentration (MIC) in µg/ml of 5 (a-t)a against pathogenic
bacterial and fungal strainsb.
Comp.
Code
Bacterial Strains
Fungal Strains
R
EC
128
64
32
32
16
1
8
4
2
0.5
32
32
64
>512
64
32
32
64
64
>256
1
PA
>256
64
32
64
32
16
64
32
16
4
SA
>256
32
AN
128
128
32
64
128
32
16
16
16
8
32
64
64
>512
16
32
32
64
CA
256
64
32
32
128
32
16
16
8
AF
128
128
64
8
16
64
64
4
16
2
32
64
128
>512
32
32
16
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
H
2-Br
3-Br
4-Br
2-Cl
3-Cl
4-Cl
2-F
3-F
64
32
32
16
64
4
8
1
4-F
2
2-OH
3-OH
4-OH
4-CH(CH3)2
2-NO2
3-NO2
4-NO2
2-CH3
3-CH3
4-CH3
Std. AA
Std. CL
32
32
64
>512
128
32
64
64
64
128
4
32
64
64
32
64
>512
16
8
>256
>512
32
16
64
8
128
128
>256
2
64
64
128
-
>256
>256
128
-
>256
128
-
5t
AA
CL
-
-
-
16
4
1
aMinimum inhibitory concentration was determined by the micro-broth dilution method.
bEscherichia coli (EC), Pseudomonas aeruginosa (PA), Staphylococcus aureus (SA), Aspergillus
fumigatus (AF), Aspergillus niger (AN), Candida albicans (CA).
Where AA is Ampicillin and CL is Clotrimazole.
15

Table 2. Zone of inhibition of compounds 5 (a-t) in the concentration of 100 µg/8 mm disc
compared with broad-spectrum antibacterial drug Ampicillin (AA) and antifungal drug
Clotrimazole (CL) against pathogenic bacterial and fungal strainb.
Com.
*Diameter of growth inhibition zone (mm)
Codea
R
Bacterial Strainb
Fungal Strainb
EC
PA
SA
9.8±0.9
11±0.93
16±0.23
AN
CA
AF
10.2±1.2
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
H
12±1.2
15±3.2
17±0.9
10±1.5
14±2.3
15±0.6
10.1±0.93 10.8±2.3
2-Br
3-Br
4-Br
2-Cl
3-Cl
4-Cl
2-F
3-F
4-F
2-OH
3-OH
4-OH
10.8±0.53 11.6±0.65 10±0.9
12±0.6 12.1±0.9
11.8±0.66 12.5±0.5
11±1.5
9.8±0.3
9.6±1.2
11.8±1.5
13±0.6
15±0.9
16±1.1
19±0.63
13±1.5
12±2.3
10±1.2
08±1.2
14±1.2
14±0.6
16±1.2
9.6±0.9
9.2±1.5
09±1.5
-
19±0.32 14±0.56 12±1.5
20±0.56 18±1.5
23±0.35 21±0.6
16±1.1
19±0.69
10.2±0.9
11.2±0.6
14.9±1.1
17.8±1.5
18.8±0.9
20±0.46
15±0.93
14±1.5
13±0.6
09±1.5
12±0.66
16±0.9
18±0.6
9.8±0.9
9.6±0.63
9.5±0.9
-
10.8±1.5
12±0.32
15±1.5
18±0.36
21±1.5
22±1.2
16±1.1
17±1.9
15±0.35
12±0.5
13±0.56
15±0.32
18±1.6
10±1.1
10±0.23
9.8±1.6
-
18±0.6
16±0.36 14±0.56
19±0.23 18±1.5
20±0.32 19±0.6
24±0.31 23±1.2
12±1.1
11±1.5
12±3.2
16±1.1
17±0.9
21±0.6
12±1.2
14±1.5
16±1.9
12±1.5
15±0.56
16±1.9
16±1.2
14±0.3
11.8±0.69
12±1.5
21
11±1.5
11±1.2
14±1.5
11±1.2
12±1.2
14±1.5
15±0.9
16±0.9
15±1.1
12±0.3
17
4-CH(CH3)2 10±1.2
2-NO2
3-NO2
4-NO2
2-CH3
3-CH3
4-CH3
12±1.1
15±1.9
16±0.8
14±0.6
13±1.5
10±1.2
5t
AA
CL
Stand. drug 18
Stand. drug
-
-
-
23
24
22
aAgar Disk diffusion assay with standard and test solutions of (100µg/8mm disk).
bEscherichia coli (EC), Pseudomonas aeruginosa (PA), Staphylococcus aureus (SA), Aspergillus
fumigatus (AF), Aspergillus niger (AN), Candida albicans (CA).
* (Average of Triplicate)
(±) standard deviation
16

Table 3. Antiviral activity and cytotoxicity of selected compounds in HEL cell cultures.
Antiviral EC50b (µM)
Minimum
cytotoxic
conc.a
Herpes
simplex simplex
virus-1
(KOS)
Herpes
Herpes
simplex
virus-1
TK- KOS
ACVr
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.9
Adeno
Human
Com.
Code
Vaccinia virus- Coronavirus
virus-2
(G)
virus
2
(229E)
(µM)
5a
5c
5e
5g
5h
5k
5m
5n
5o
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>250
>250
>250
>100
>250
>250
>250
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.04
2.8
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>250
1.0
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
3.5
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
-
7.2
-
-
50
1.4
-
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
-
5p
5q
Brivudin
Cidofovir
Acyclovir
Ganciclovir
Zalcitabine
Alovudine
Ribavirin
3.4
22
0.4
-
-
-
10
-
-
-
-
0.1
0.05
-
-
-
0.2
0.05
-
-
-
>250
>100
-
-
-
-
>250
aRequired to cause a microscopically detectable alteration of normal cell morphology.
bRequired to reduce virus-induced cytopathogenicity by 50 %.
17

Table 4. Antiviral activity and cytotoxicity of selected compounds in Vero cell cultures.
Antiviral EC50 (µM)
Minimum
cytotoxic
conc.a
Para-
influenza
-3
Reovirus Sindbis Coxsackie
Punta Yellow
Com. Code
-1
virus
virus
B4
Toro
virus
Fever
virus
(µM)
virus
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
112
5a
5c
5e
5g
5h
5k
5m
5n
5o
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>250
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>250
0.4
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
38
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
8.9
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
20
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.8
5p
5q
DS-10.000
Ribavirin
Mycophenolic
acid
>250
11.7
>250
>100
126
1.4
>250
0.8
0.4
a Required to cause a microscopically detectable alteration of normal cell morphology.
b Required to reduce virus-induced cytopathogenicity by 50 %.
Table 5. Antiviral activity and cytotoxicity of selected compounds in MDCK cell cultures.
c
Antiviral EC50
Cytotoxicity
Minimum
Influenza
A/H1N1
A/Ned/378/05
visual MTS visual MTS visual
CPE
Influenza
A/H3N2
A/HK/7/87
Influenza B
B/Ned/537/05
Com. Code
cytotoxic
MTS
a
conc.b
CPE
score
CPE
score
CC
50
(µM)
score
(µM)
>100
>100
>100
>100
>100
>100
>100
>100
>100
5a
5c
5e
5g
5h
5k
5m
5n
5o
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
18

5p
5q
>100
>100
>100
>100
>100
>200
>100
>100
>100
≥100
>100
>200
>100
>100
0.8
8.9
>100
0.3
>100
>100
0.04
9.8
>100
0.1
>100
>100
1.8
8.9
0.4
>100
>100
1.2
1.5
0.3
>100
>100
0.4
2.1
>100
>200
>100
>100
0.02
1.2
>100
>200
Zanamivir
Ribavirin
Amantadine
Rimantadine
0.03
0.09
a50% Cytotoxic concentration, as determined by measuring the cell viability with the colorimetric
formazan-based MTS assay.
bMinimum compound concentration that causes a microscopically detectable alteration of normal cell
morphology.
c50% Effective concentration, or concentration producing 50% inhibition of virus-induced cytopathic
effect, as determined by visual scoring of the CPE, or by measuring the cell viability with the
colorimetric formazan-based MTSassay.
MDCK cells: Madin Darby canine kidney cells
Highlights
19

1. Novel substituted phenyl azetidine-2-one sulphonyl derivatives were developed as
antimicrobial and antiviral agents
2. Compounds 5d, 5e, 5f, 5i and 5j showed most potent antibacterial activity.
3. Compounds5h, 5i, 5j and 5q showed good activity against fungal strains.
4. Antiviral study of selected derivatives had shown moderate activity against various DNA
and RNA viruses.
Declaration of Interest Statement: None
20