Facile synthesis, antimicrobial and antiviral evaluation of novel substituted phenyl 1,3-thiazolidin-4-one sulfonyl derivatives

Article abstract of DOI:10.1016/j.bioorg.2021.105153

A series of novel substituted phenyl 1, 3-thiazolidin-4-one sulfonyl derivatives 5 (a-t) were synthesized and screened for their in-vitro anti-microbial and anti-viral activity. The result of the anti-microbial assay demonstrated compounds 5d, 5f, 5g, 5h,

Full text of DOI:10.1016/j.bioorg.2021.105153

Bioorganic Chemistry 114 (2021) 105153
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Facile synthesis, antimicrobial and antiviral evaluation of novel substituted
phenyl 1,3-thiazolidin-4-one sulfonyl derivatives
Milan Kumar Mandala, Swagatika Ghoshb, Lieve Naesensc, Hans Raj Bhatd,
,
*
Udaya Pratap Singha
a Drug 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 Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium
d Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
A series of novel substituted phenyl 1, 3-thiazolidin-4-one sulfonyl derivatives 5 (a-t) were synthesized and
screened for their in-vitro anti-microbial and anti-viral activity. The result of the anti-microbial assay demon-
strated compounds 5d, 5f, 5g, 5h, 5i, 5j showed prominent inhibitory activity against all the tested Gram-
positive and Gram-negative bacterial strains, while compounds 5g, 5j, 5o, 5p, 5q showed significant activity
against the entire set of fungal strains as compared to standard drug Ampicillin and Clotrimazole, respectively.
The antimicrobial study revealed that compounds having electron-withdrawing groups showed significant
antimicrobial potency. The most active antibacterial compound 5j showed potent inhibition of S. aureus DNA
Gyrase enzyme as a possible mechanism of action for antimicrobial activity. Moreover, the antiviral testing of
selected compounds showed considerable activity against Herpes simplex virus-1(KOS), Herpes simplex virus-2
(G), Herpes simplex virus-1(TK- KOS ACVr), Vaccinia virus, Human Coronavirus (229E), Reovirus-1, Sindbis
virus, Coxsackie virus B4, Yellow Fever virus and Influenza A, B virus. Compounds 5h exhibited low anti-viral
activity against HIV-1(strain IIIB) and HIV-2 (strain ROD). The study clearly outlined that synthesized com-
pounds endowed with good antimicrobial property together with considerable antiviral activity.
Thiazolidine
Sulfonamides
Schiff base
Antimicrobial
Antiviral
1. Introduction
antioxidant, cytotoxic, analgesic, antiviral, anti-tubercular, anti-in-
flammatory, and anti-HIV [11–17]. Thiazolidin-4-one biological activity
In the age of dramatic medical advancement, microbial infection is
still the leading global killer. Lower respiratory tract infections, diar-
rhea, HIV/AIDS, tuberculosis, and malaria have become a major threat
due to the development of drug-resistant strains [1–3]. Mainly drug
resistivity has been evolved due to the irrational use of antibiotics thus,
the development of newer analogs is urgently needed [4,5]. European
Centre for Disease Prevention and Control (ECDC), the European Union
reported that more than 33,000 people die every year due to infections
with antibiotic-resistant bacteria. Thiazolidin-4-ones are five-membered
heterocyclic compounds, gifted with a wide range of therapeutic prop-
erties [6–10]. It offers enormous scope towards the development of new
drug candidates and can prove instrumental in the fight against micro-
bial resistance. This ring is also known as wonder nuclei due to their
broad range of biological activities i.e. antibacterial, antifungal,
is directly dependent on the type of substitution at C-2 and N-3 positions.
The thiazolidine-4-one ring plays an important role in commercially
available drugs like Pioglitazone, Teneligliptin, Etozoline, Penicillin G,
Cloxacillin, Amoxicillin, Carbenicillin, Piperacillin, and Tazobactam
[18,19].
On the contrary, Sulfonamides have significantly contributed to
chemotherapy either alone or in combination with other drugs. A
literature survey has revealed that sulfonamide derivatives showed
multifunctional and multi-targeting action in drug therapy [20]. It also
showed significant biological activity such as antibacterial, antifungal,
antioxidant, anticancer, antiviral, antitubercular, and diuretics. The
versatile range of commercial drugs like antitubercular drug Dapsone,
COX-2 inhibitors Celecoxib, uricosurics Probenecid, nonsteroidal anti-
androgen
Bicalutamide,
and
antiviral
drugs
Amprenavir,
* Corresponding author.
E-mail addresses: udaysingh98@gmail.com, udaya.singh@shiats.edu.in (U.P. Singh).
https://doi.org/10.1016/j.bioorg.2021.105153
Received 26 February 2021; Received in revised form 2 July 2021; Accepted 3 July 2021
Available online 9 July 2021
0045-2068/© 2021 Elsevier Inc. All rights reserved.

M.K. Mandal et al.
Bioorganic Chemistry 114 (2021) 105153
Fig. 1. Chemical structures of commercially available drugs containing Thiazolidine and benzenesulfone moieties.
Fosamprenavir, Darunavir contain benzene sulfonamides (Fig. 1) skel-
eton [21–25].
recorded by FTIR-8400S, Shimadzu, Japan using KBr pellets, and fre-
1
quencies are described in wave numbers cmꢀ 1. H NMR spectra were
Prompted by the above, we hypothesized to develop a single skeleton
that comprises thiazolidine-4-one and benzene sulfonyl derivatives in a
search of potent anti-infective compounds. It was envisaged that hy-
bridizing these two rings into a single molecule with suitable substitu-
tion might give rise to new antibacterial, antifungal, and antiviral
scaffold [26,27]. Thus, in the present study, we have synthesized a series
of novel 2-(R-phenyl)-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidin-4-
one 5 (a-t) derivatives and subsequently evaluated for inhibitory ac-
tivity against various human disease-causing bacteria, fungi, and
viruses.
recorded by Bruker Avance 400/AvIII HD-300 (FT NMR) with a low and
◦
◦
high-temperature facility (ꢀ 150 C–+180 C) in the solvents CDCl3
&
DMF using Tetramethylsilane (TMS) as an internal standard. Chemical
shifts are reported in parts per million (δ) and the signals are described
as singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). Mass
spectra were performed on Agilent 6520 Q-TOF (ESI-MS). Elemental
analysis was carried out by Elemental Analyzer: Vario EL-III
2.1.1. General procedure for the synthesis of N-[(R-phenyl)methylidene]-4-
methylbenzenesulfonamide 3 (a-t) [28]
An equimolar quantity of corresponding aromatic aldehyde 2 (a-t)
(0.01 mol) and 4-methylbenzenesulfonamide (1) (1.12 g, 0.01 mol) in
the presence of 20 ml of absolute ethanol was refluxed for 5–6 h. The
completion of the reaction was ascertained by TLC (carbon tetrachlo-
ride/methanol, 2:1). The whole reaction mixture was transferred into a
beaker containing crushed ice in boiling condition and filtered after
attaining room temperature. Then the product was kept overnight,
dried, and recrystallized using ethanol to get corresponding pure N-[(R-
phenyl)methylidene]-4-methylbenzenesulfonamide derivatives 3 (a-t).
2. Materials & method
2.1. Chemistry
All the reagents and solvents used for synthesis and other experi-
mental work were obtained from SD Fine India and Sigma-Aldrich, USA,
and were used without purification unless otherwise stated. The melting
point was determined in an open capillary tube using a Temp Star Pvt.
Ltd. India, apparatus and is uncorrected. The completion of the reaction
was monitored by thin-layer chromatography (TLC) performed on Silica
gel G plates using appropriate solvents and the spots were visualized by
exposure to ultraviolet light or Iodine vapors. Infra-red spectra were
2.1.2. General procedure for the synthesis of 2-(R-phenyl)-3-[(4-
methylphenyl) sulfonyl]-1,3-thiazolidin-4-one 5 (a-t) [8]
An equimolar quantity of corresponding compounds 3 (a-t) was
2

M.K. Mandal et al.
Bioorganic Chemistry 114 (2021) 105153
refluxed with thioglycolic acid (4) in anhydrous ethanol in the presence
of DCC (N,N-dicyclohexylcarbodimide) for 9–10 h. The reaction mixture
was cooled and poured into ice-cold water. The resultant precipitate was
filtered off and washed several times with distilled water, air-dried, and
recrystallized from ethanol to obtain final derivatives of 2-(R-phenyl)-3-
[(4-methylphenyl) sulfonyl]-1,3-thiazolidin-4-one 5 (a-t).
3.81; found C 52.25, H 3.85, N 3.83.
2.1.2.7. 2-(4-Chlorophenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazoli-
din-4-one (5g). Yield 65%; white crystals; m.p. 174.1–175.1 ◦C; IR (KBr,
cmꢀ 1): 3158(Ar C H str), 2978(N CH S str), 2942(CH2 S str), 1695
–
– –
–
–
–
–
–
–
– –
(C O str), 1610(C C str), 1369(C N str), 1390( SO2 str), 690
1
– –
(C
S C str), 665 (C-Cl str); H NMR (CDCl3, 400 MHz): 2.43(s, 3H,
2.1.2.1. 3-[(4-Methylphenyl)sulfonyl]-2-phenyl-1,3-thiazolidin-4-one
CH3), 3.49 (s, 1H, N-CH), 3.74(s, 2H, S-CH2), 3.91(t, 2H, CH2, J = 2.5
Hz), 7.50–7.58(m, 5H, Ar-H), 9.45(s, 1H, –CONH). ESI-MS (m/z):
368.38 [M + H]+; anal. calcd. for C16H14ClNO3S2: C 52.24, H 3.84, N
3.81; found C 52.26, H 3.84, N 3.82.
(5a). Yield 69%; white crystals; m.p. 138.9–139.8 ◦C; IR (KBr, cmꢀ 1):
–
–
–
– –
–
–
3081(Ar C H str), 2972(N CH S str), 2940(CH2 S str), 1700(C
O
–
–
– –
– –
–
str), 1610(C C str), 1358(C N str), 1390( SO2 str), 690(C S C
1
str) ; H NMR (CDCl3, 400 MHz): 2.40(s, 3H, CH3), 3.50(s, 1H, N CH),
–
3.75(s, 2H, S CH2), 3.95(t, 2H, CH2, J = 2.5 Hz), 7.58–7.65(m, 6H,
2.1.2.8. 2-(2-Fluorophenyl)-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidin-
+
◦
–
–
Ar H), 9.40(s, 1H, CONH). ESI-MS (m/z): 334.81 [M + H] ; anal.
calcd. For C16H15NO3S2: C 57.64, H 4.53, N 4.20; found C 57.63, H 4.56,
N 4.21.
4-one (5h). Yield 59%; white crystals; m.p. 175.6–176.2 C; IR (KBr,
–
– –
–
–
– –
cm-1): 3125(Ar C H str), 2978(N CH S str), 2948(CH2 S str), 1710
–
–
–
–
(C O str), 1650(C C str), 1358(C N str), 1395( SO2 str), 700
S
C str), 590(C-F str); 1H NMR (CDCl3, 400 MHz): 2.43(s, 3H,
– –
(C
2.1.2.2. 2-(2-Bromophenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazoli-
CH3), 3.55(s, 1H, N-CH), 3.75(s, 2H, S-CH2), 3.91(t, 2H, CH2, J = 2.5
Hz), 7.55–7.62(m, 5H, Ar-H), 9.41(s, 1H, –CONH). ESI-MS (m/z):
352.01 [M + H]+; anal. calcd. for C16H14FNO3S2: C 54.68, H 4.02, N
3.99; found C 54.69, H 4.05, N 3.99.
din-4-one (5b). Yield 61%; brown crystals; m.p. 149.6–150.4 ◦C; IR
(KBr, cmꢀ 1): 3092(Ar C H str), 2954(N CH S str), 2969(CH2 S str),
–
– –
–
–
–
–
–
–
– –
1690(C O str), 1626(C C str), 1334(C N str), 1344( SO2 str), 694
S
C str), 540(C-Br str); 1H NMR (CDCl3, 400 MHz): 2.41(s, 3H,
– –
(C
CH3), 3.52(s, 1H, N-CH), 3.80(s, 2H, S-CH2), 3.95(t, 2H, CH2, J = 2.5
Hz), 7.60–7.80(m, 5H, Ar-H), 9.42(s, 1H, –CONH). ESI-MS (m/z):
413.18 [M + H]+; anal. calcd. for C16H14BrNO3S2: C 46.61, H 3.42, N
3.40; found C 46.63, H 3.41, N 3.44.
2.1.2.9. 2-(3-Fluorophenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazoli-
din-4-one (5i). Yield 68%; white crystals; m.p. 180.1–180.6 ◦C; IR (KBr,
-1
–
– –
–
–
– –
cm ): 3142(Ar C H str), 2962(N CH S str), 2935(CH2 S str), 1716
–
–
–
(C O str), 1653(C C str), 1346(C N str), 1389( SO2 str), 704
–
(C
S
C str), 597(C-F str); 1H NMR (CDCl3, 400 MHz): 2.40(s, 3H,
– –
–
CH3), 3.55(s, 1H, N-CH), 3.85(s, 2H, S CH2), 3.91(t, 2H, CH2, J = 2.5
2.1.2.3. 2-(3-Bromophenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazoli-
din-4-one (5c). Yield 69%; brown crystals; m.p. 158.2–158.6 ◦C; IR
Hz), 7.61–7.69(m, 5H, Ar H), 9.43(s, 1H, CONH). ESI-MS (m/z):
352.11 [M + H]+; anal. calcd. for C16H14FNO3S2: C 54.68, H 4.02, N
3.99; found C 54.69, H 4.02, N 3.98.
–
–
(KBr, cmꢀ 1): 3085(Ar C H str), 2974(N CH S str), 2940(CH2 S str),
–
– –
–
–
–
–
–
–
– –
1710(C O str), 1610(C C str), 1358(C N str), 1390( SO2 str), 689
1
– –
(C
S C str), 545(C-Br str) ; H NMR (CDCl3, 400 MHz): 2.43(s, 3H,
CH3), 3.49(s, 1H, N-CH), 3.78(s, 2H, S-CH2), 3.99(t, 2H, CH2, J = 2.5
Hz), 7.53–7.59(m, 5H, Ar-H), 9.44(s, 1H, –CONH). ESI-MS (m/z):
413.39 [M + H]+; anal. calcd. for C16H14BrNO3S2: C 46.61, H 3.42, N
3.40; found C 46.62, H 3.44, N 3.41.
2.1.2.10. 2-(4-Fluorophenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazoli-
din-4-one (5j). Yield 60%; white crystals; m.p. 181.7–182.4 ◦C; IR (KBr,
-1
–
– –
–
–
– –
cm ): 3151(Ar C H str), 2966(N CH S str), 2951(CH2 S str), 1706
–
–
–
(C O str), 1652(C C str), 1346(C N str), 1391( SO2 str), 711
–
S
(C
C str), 560(C-F str); 1H NMR (CDCl3, 400 MHz): 2.41(s, 3H,
– –
CH3), 3.52(s, 1H, N-CH), 3.80(s, 2H, S-CH2), 3.95(t, 2H, CH2, J = 2.5
2.1.2.4. 2-(4-Bromophenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazoli-
din-4-one (5d). Yield 67%; light brown crystals; m.p. 168.6–169.4 ◦C; IR
Hz), 7.60–7.65(m, 5H, Ar-H), 9.42(s, 1H, CONH). ESI-MS (m/z):
–
(KBr, cmꢀ 1): 3079(Ar C H str), 2968(N CH S str), 2938(CH2 S str),
352.16 [M + H]+; anal. calcd. for C16H14FNO3S2: C 54.68, H 4.02, N
–
– –
–
–
–
–
–
–
– –
1694(C O str), 1630(C C str), 1348(C N str), 1382( SO2 str), 710
3.99; found C 54.67, H 4.03, N 3.99.
S
C str), 560(C-Br str); 1H NMR (CDCl3, 400 MHz): 2.40(s, 3H,
– –
(C
CH3), 3.55(s, 1H, N-CH), 3.77(s, 2H, S-CH2), 3.90(t, 2H, CH2, J = 2.5
Hz), 7.63–7.69(m, 5H, Ar-H), 9.48(s, 1H, –CONH). ESI-MS (m/z):
413.32 [M + H]+; anal. calcd. for C16H14BrNO3S2: C 46.61, H 3.42, N
3.40; found C 46.63, H 3.41, N 3.40.
2.1.2.11. 2-(2-Hydroxyphenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazo-
lidin-4-one (5k). Yield72 %; pale white powder; m.p. 183.2 – 184.1 ◦C;
–
–
–
– –
S
IR (KBr, cm-1): 3521(Ar-OH str), 3059(Ar C H str), 2982(N CH
–
–
–
str), 2940(CH2 S str), 1695(C O str), 1640(C C str), 1358(C N str),
–
1
– –
– –
1395( SO2 str), 690(C
S C str); H NMR (CDCl3, 400 MHz): 2.41(s,
2.1.2.5. 2-(2-Chlorophenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazoli-
3H, CH3), 3.52(s, 1H, N-CH), 3.80(s, 2H, S-CH2), 3.95(t, 2H, CH2, J =
din-4-one (5e). Yield 62%; white crystals; m.p. 172.3–173.0 ◦C; IR (KBr,
2.5 Hz), 7.60–7.66(m, 5H, Ar-H), 9.42(s, 1H, CONH), 10.02(s, 1H,
–
cmꢀ 1): 3158(Ar C H str), 2972(N CH S str), 2942(CH2 S str), 1665
OH). ESI-MS (m/z): 350.15 [M + H]+; anal. calcd. for C16H15NO4S2: C
–
– –
–
–
–
–
–
–
– –
(C O str), 1628(C C str), 1359(C N str), 1392( SO2 str), 700
55.00, H 4.33, N 4.01; found C 55.02, H 4.34, N 4.01.
1
– –
(C
S C str), 650 (C-Cl str) ; H NMR (CDCl3, 400 MHz): 2.44(s, 3H,
CH3), 3.48(s, 1H, N-CH), 3.82(s, 2H, S-CH2), 3.95(t, 2H, CH2, J = 2.5
Hz), 7.61–7.70(m, 5H, Ar-H), 9.41(s, 1H, –CONH). ESI-MS (m/z):
369.36 [M + H]+; anal. calcd. for C16H14ClNO3S2: C 52.24, H 3.84, N
3.81; found C 52.26, H 3.85, N 3.82.
2.1.2.12. 2-(3-Hydroxyphenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazo-
lidin-4-one (5l). Yield 76%; pale white powder; m.p. 184.2–184.6 ◦C; IR
-1
–
– –
–
(KBr, cm ): 3516(Ar-OH str), 3128(Ar C H str), 2992(N CH S str),
–
–
–
–
2948(CH2 S str), 1700(C O str), 1645(C C str), 1359(C N str),
–
1
– –
– –
1360( SO2 str), 701(C
S C str); H NMR (CDCl3, 400 MHz): 2.40(s,
2.1.2.6. 2-(3-Chlorophenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazoli-
3H, CH3), 3.51(s, 1H, N-CH), 3.84(s, 2H, S-CH2), 3.91(t, 2H, CH2, J =
din-4-one (5f). Yield 60%; white crystals; m.p. 169.9–170.5 ◦C; IR (KBr,
2.5 Hz), 7.61–7.64(m, 5H, Ar-H), 9.45(s, 1H, CONH), 10.01(s, 1H,
–
cm-1): 3182(Ar C H str), 2969(N CH S str), 2948(CH2 S str), 1700
OH). ESI-MS (m/z): 350.10 [M + H]+; anal. calcd. for C16H15NO4S2: C
–
– –
–
–
–
–
–
–
– –
(C O str), 1610(C C str), 1358(C N str), 1395( SO2 str), 710
55.00, H 4.33, N 4.01; found C 55.03, H 4.35, N 4.02.
1
– –
(C
S C str), 668 (C-Cl str); H NMR (CDCl3, 400 MHz): 2.42(s, 3H,
CH3), 3.50(s, 1H, N-CH), 3.81(s, 2H, S-CH2), 3.94(t, 2H, CH2, J = 2.5
Hz), 7.59–7.67(m, 5H, Ar-H), 9.41(s, 1H, –CONH). ESI-MS (m/z):
369.41 [M + H]+; anal. calcd. for C16H14ClNO3S2: C 52.24, H 3.84, N
2.1.2.13. 2-(4-Hydroxyphenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazo-
lidin-4-one (5m). Yield 75%; pale white powder; m.p. 179.8–180.1 ◦C;
IR (KBr, cmꢀ 1): 3552(Ar-OH str), 3165(Ar C H str), 2995(N CH
–
– –
S
3

M.K. Mandal et al.
Bioorganic Chemistry 114 (2021) 105153
–
–
–
–
–
str), 2936(CH2 S str), 1686(C O str), 1643(C C str), 1366(C N str),
H 4.93, N 4.03; found C 58.78, H 4.94, N 4.03.
–
1
– –
– –
1392( SO2 str), 698(C
S C str); H NMR (CDCl3, 400 MHz): 2.41(s,
3H, CH3), 3.52(s, 1H, N-CH), 3.80(s, 2H, S-CH2), 3.95(t, 2H, CH2, J =
2.5 Hz), 7.60–7.67(m, 5H, Ar-H), 9.42(s, 1H, –CONH), 10.02(s, 1H, OH).
ESI-MS (m/z): 350.11 [M + H]+; anal. calcd. for C16H15NO4S2: C 55.00,
H 4.33, N 4.01; found C 55.01, H 4.35, N 4.02.
2.1.2.20. 2-(4-Methylphenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazoli-
◦C; IR
– –
din-4-one (5t). Yield 51%; white powder; m.p. 174.8 – –175.1–
(KBr, cmꢀ 1): 3180(Ar C H str), 2910(C CH3 str), 2976(N CH S str),
–
–
–
–
–
2942(CH2 S str), 1690(C O str), 1630(C C str), 1385(C N str),
–
1
– –
– –
1395( SO2 str), 700(C
S C str); H NMR (CDCl3, 400 MHz): 2.40(s,
2.1.2.14. 3-[(4-Methylphenyl)sulfonyl]-2-[4-(propan-2-yl)phenyl]-1,3-
3H, CH3), 2.42(s, 3H, CH3), 3.45 (s, 1H, N-CH), 3.73(s, 2H, S-CH2), 3.94
–
thiazolidin-4-one (5n). Yield 62%; pale white powder; m.p. 181.6 –
(t, 2H, CH2, J = 2.5 Hz), 7.51–7.59(m, 5H, Ar-H), 9.41(s, 1H, CONH).
ꢀ 1
182.3 C; IR (KBr, cm ): 3080(Ar C H str), 2900(C CH3 str), 2975
ESI-MS (m/z): 348.30 [M + H]+; anal. calcd. for C17H17NO3S2: C 58.77,
◦
– –
–
–
–
–
–
–
–
(N CH S str), 2940(CH2 S str), 1665(C O str), 1620(C C str), 1358
H 4.93, N 4.03; found C 58.77, H 4.95, N 4.04.
–
1
– –
– –
(C N str), 1395( SO2 str), 690(C S C str); H NMR (CDCl3, 400
MHz): 1.32(s, 6H, 2xCH3), 2.42(s, 3H, CH3), 3.50(s, 1H, N-CH), 3.86(s,
2.2. In-vitro antimicrobial screening
2H, S-CH2), 3.95(t, 2H, CH2, J = 2.5 Hz), 7.60–7.66(m, 6H, Ar-H), 9.42
+
–
(s, 1H, CONH). ESI-MS (m/z): 376.02 [M + H] ; anal. calcd. for
2.2.1. Determination of the inhibition zone
C19H21NO3S2: C 60.77, H 5.64, N 3.73; found C 60.75, H 5.63, N 3.74.
The newly synthesized compounds 5 (a-t) were screened for their
antimicrobial potency against pathogenic bacteria and fungi. Gram-
negative bacteria Pseudomonas aeruginosa (MCCB 0035), Escherichia
coli (ATCC 8739), Salmonella typhimurium (NCIM-2501), Klebsiella aer-
ogenes (NCIM-2098) and Gram-positive bacteria Staphylococcus aureus
(ATCC 29213), Bacillus cereus (NCIM-2458), Lactobacillus casei (NCIM-
2651), and Streptococcus pneumonia (ATCC 49619) were used to evaluate
antibacterial activity. The antifungal activity was evaluated against
fungal strains Aspergillus fumigatus (NCIM 2081), Aspergillus niger (NCIM
2191), Candida albicans (NCIM 2087), and Cryptococcus neoformans
(ATCC 9011) [29,30]. The preliminary screening for antibacterial and
antifungal activities was carried out by the agar disk diffusion technique.
Mueller-Hinton agar (MHA) Petri plates and Whatman filter paper disc
(8 mm) were prepared and sterilized. Stock solutions of test compounds
and standard compounds (Ampicillin, Clotrimazole) were prepared in
DMSO and diluted with distilled water to get a final concentration of
100 µg/mL. The filter paper disks were soaked in standard and test so-
lutions. After this, the disks were placed in MHA Petri plates seeded with
standard microbial suspensions in a triplicate manner and were incu-
bated at 35 ◦C for 24 h for bacterial strains and 48 h for fungal strains.
The results were recorded in ‘mm’ as the average diameter of the inhi-
bition zones of microbial growth around each disk for each test
compound.
2.1.2.15. 3-[(4-Methylphenyl)sulfonyl]-2-(2-nitrophenyl)-1,3-thiazolidin-
◦
4-one (5o). Yield 59%; yellow crystal; m.p. 149.6–150.1 C; IR (KBr,
cmꢀ 1): 3100(Ar C H str), 2972(N CH S str), 2940(CH2 S str), 1710
–
– –
–
–
–
–
–
–
(C O str), 1420(C-NO str), 1626(C C str), 1360(C N str), 1395
2
1
– –
– –
S C str); H NMR (CDCl3, 400 MHz): 2.45(s, 3H,
(
SO2 str), 695(C
CH3), 3.48(s, 1H, N-CH), 3.85(s, 2H, S-CH2), 3.95(t, 2H, CH2, J = 2.5
Hz), 7.61–7.65(m, 5H, Ar-H), 9.41(s, 1H, –CONH). ESI-MS (m/z):
379.11 [M + H]+; anal. calcd. for C16H14N2O5S2: C 50.78, H 3.73, N
7.40; found C 50.79, H 3.74, N 7.41.
2.1.2.16. 3-[(4-Methylphenyl)sulfonyl]-2-(3-nitrophenyl)-1,3-thiazolidin-
◦
4-one (5p). Yield 63%; yellow crystal; m.p. 157.6–158.3 C; IR (KBr,
cmꢀ 1): 3106(Ar C H str), 2981(N CH S str), 2955(CH2 S str), 1706
–
– –
–
–
–
–
–
–
(C O str), 1434(C-NO str), 1619(C C str), 1366(C N str), 1398
2
1
– –
– –
S C str); H NMR (CDCl3, 400 MHz): 2.42(s, 3H,
(
SO2 str), 696(C
CH3), 3.51(s, 1H, N-CH), 3.81(s, 2H, S-CH2), 3.94(t, 2H, CH2, J = 2.5
Hz), 7.54–7.59(m, 5H, Ar-H), 9.46(s, 1H, –CONH). ESI-MS (m/z):
379.09 [M + H]+; anal. calcd. for C16H14N2O5S2: C 50.78, H 3.73, N
7.40; found C 50.79, H 3.74, N 7.42.
2.1.2.17. 3-[(4-Methylphenyl)sulfonyl]-2-(4-nitrophenyl)-1,3-thiazolidin-
◦
4-one (5q). Yield 56%; yellow crystal; m.p. 168.8–169.2 C; IR (KBr,
cmꢀ 1): 3120(Ar C H str), 2975(N CH S str), 2938(CH2 S str), 1700
–
– –
–
2.2.2. Determination of MIC
–
–
–
–
–
(C O str), 1451(C-NO str), 1610(C C str), 1359(C N str), 1365
2
1
Minimal Inhibitory Concentrations (MICs, µg/mL) were determined
by following the Broth Micro dilution procedure as per CLSI. For the
growth of bacterial strains and fungal strains, Mueller–Hinton Broth and
saboraud liquid medium were used, respectively. Two-fold serial dilu-
tion of all synthesized compounds and standard drugs of various con-
centrations were prepared in a suitable medium ranging from 512 to
0.25 µg/mL. Bacterial broth culture was incubated for 2–6 h, while
fungal broth culture was incubated for 24 h at 35 ◦C to achieve the
turbidity of a 0.5 McFarland standard. The bacterial and fungal sus-
pension was adjusted with a sterile solution to obtain a final concen-
tration of 5x105 CFU/mL and 0.5–2.5 × 103 CFU/mL, respectively.
MIC’s were defined as the lowest concentration of the substance that
gave no visible turbidity and completely inhibited the microbial growth.
– –
– –
S C str); H NMR (CDCl3, 400 MHz): 2.40(s, 3H,
(
SO2 str), 690(C
CH3), 3.49 (s, 1H, N-CH), 3.79(s, 2H, S-CH2), 3.91(t, 2H, CH2, J = 2.5
–
Hz), 7.50–7.54(m, 5H, Ar-H), 9.45(s, 1H, CONH). ESI-MS (m/z):
379.14 [M + H]+; anal. calcd. for C16H14N2O5S2: C 50.78, H 3.73, N
7.40; found C 50.80, H 3.75, N 7.42.
2.1.2.18. 2-(2-Methylphenyl)-3-[(4-methylphenyl)sulfonyl]-1,3-thiazoli-
din-4-one (5r). Yield 57%; white powder; m.p. 172.6–173.4 ◦C; IR (KBr,
cmꢀ 1): 3080(Ar C H str), 2920(C CH3 str), 2970(N CH S str), 2945
–
–
– –
–
–
–
–
–
–
(CH2 S str), 1700(C O str), 1625(C C str), 1380(C N str), 1390
1
– –
– –
(
SO2 str), 695(C
S C str); H NMR (CDCl3, 400 MHz): 2.41(s, 3H,
CH3), 2.44(s, 3H, CH3), 3.46 (s, 1H, N-CH), 3.74(s, 2H, S-CH2), 3.92(t,
–
2H, CH2, J = 2.5 Hz), 7.50–7.56(m, 5H, Ar-H), 9.42(s, 1H, CONH).
ESI-MS (m/z): 348.26 [M + H]+; anal. calcd. for C17H17NO3S2: C 58.77,
2.2.3. DNA Gyrase inhibition assay
H 4.93, N 4.03; found C 58.79, H 4.94, N 4.04.
The S. aureus DNA gyrase purification, Supercoiling, and decatena-
tion were executed as reported by F. Blanche.[31] The IC50
determined from the dose response curve.
(μM) was
2.1.2.19. 2-(3-Methylphenyl)-3-[(4-methylphenyl) sulfonyl]-1,3-thiazoli-
din-4-one (5s). Yield 62%; white powder; m.p. 170.3–170.7 ◦C; IR (KBr,
cmꢀ 1): 3120(Ar C H str), 2935(C CH3 str), 2980(N CH S str), 2948
–
–
– –
–
2.2.4. Antiviral activity assays
–
–
–
–
–
(CH2 S str), 1720(C O str), 1650(C C str), 1375(C N str), 1390
Eleven final derivatives were screened for their antiviral activity
using a Cytopathic effect (CPE) reduction assay. Antiviral potency was
determined against human coronavirus, adeno virus-2, Vaccina virus
using Human embryonic lung (HEL) cells and Parainfluenza-3virus,
Reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, and
1
– –
– –
(
SO2 str), 710(C
S C str); H NMR (CDCl3, 400 MHz): 2.42(s, 3H,
CH3), 2.43(s, 3H, CH3), 3.46 (s, 1H, N-CH), 3.74(s, 2H, S-CH2), 3.92(t,
–
2H, CH2, J = 2.5 Hz), 7.50–7.55(m, 5H, Ar-H), 9.42(s, 1H, CONH).
ESI-MS (m/z): 348.28 [M + H]+; anal. calcd. for C17H17NO3S2: C 58.77,
4

M.K. Mandal et al.
Bioorganic Chemistry 114 (2021) 105153
Scheme 1. Scheme for the synthesis of 2-(R-phenyl)-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidin-4-one derivatives 5 (a-t). Reagents and Condition: (a) C2H5OH,
reflux, 80 ◦C, 5–6 h.; (b) DCC (N,N-dicyclohexylcarbodimide), C2H5OH, reflux 120 ◦C, 9–10 h.
Yellow fever virus using African green monkey kidney Viro cells. Madin-
Darby Canine Kidney (MDCK) cells were used to evaluate Influenza A/
H1N1A/Ned/378/05, Influenza A/H3N2A/HK/7/87, and Influenza B
B/Ned/537/05 viruses. The anti-HIV activity was also performed using
MT4 cells against HIV-1 (strain IIIB) virus and HIV-2 (strain ROD) virus.
To evaluate the antiviral activity, the viruses were added to sub-
confluent cell cultures in 96 well plates. Two-fold serial dilutions of
test compounds were prepared and added to the cell cultures. Virus
entry inhibitor dextran sulfate (MW-10000), mycophenolic acid (an
inhibitor of cellular IMP dehydrogenase), broad-spectrum antiviral
agent Ribavirin, Acyclovir, Amantadine, Rimantadine, antiherpetic
agents Ganciclovir and Brivudin were used as reference compounds. The
cell cultures were incubated for 3–6 days at 37 ◦C (35 ◦C in case of
Influenza viruses). Antiviral and cytotoxic effects of test compounds
were assessed by light microscopy or by MTS cell viability assay.
Antiviral activity was reported as EC50 (50% effective concentration)
based on the inhibitory effect of test compounds on virus-induced
cytopathic effect (CPE). Cytotoxicity was expressed as MCC (Minimal
Cytotoxic Concentration) and CC50 (Cytotoxic concentration) assessed
by colorimetric formazan-based MTS assay.
3. Result & discussion
3.1. Chemistry
The synthetic approach for final derivatives was depicted in Scheme
1. The synthesis was accomplished in two different steps. The first step
corresponds to the formation of Schiff’s base (reactive imine) by
nucleophilic addition of an amine to the carbonyl group of aromatic
aldehyde. While in the second step, the Nitrogen atom of Schiff’s base
Table 1
Minimum inhibitory concentration (MIC) in µg/ml of 5 (a-t) against pathogenic bacterial and fungal strains.a.
Comp. Code
R
Bacterial Strainsb
Fungal Strainsc
EC
PA
ST
KA
SA
BC
LC
SP
AN
CA
AF
CN
5a
5b
5c
5d
5e
5f
H
64
16
16
4
128
32
16
4
>256
32
>256
64
64
32
32
16
64
32
4
128
64
64
64
16
8
128
128
64
32
64
32
32
32
16
8
64
32
32
16
32
16
8
64
64
32
16
64
64
16
16
8
128
128
64
2-Br
3-Br
32
16
32
4-Br
16
8
32
64
32
2-Cl
16
8
32
16
8
64
32
64
16
16
16
4
64
16
3-Cl
16
8
32
8
32
5g
5h
5i
4-Cl
4
32
32
8
32
16
2-F
4
8
16
64
8
16
64
32
32
8
32
16
4
8
3-F
16
2
32
2
64
32
16
4
16
8
32
16
5j
4-F
8
16
8 s
64
4
64
4
4
5k
5l
2-OH
3-OH
4-OH
4-CH(CH3)2
2-NO2
3-NO2
4-NO2
2-CH3
3-CH3
4-CH3
Stand. drug
Stand. drug
32
16
16
>256
16
32
16
64
16
64
1
32
32
16
>256
32
64
32
64
64
128
4
64
32
64
64
32
>256
16
32
32
64
128
64
2
64
32
16
>256
32
32
16
64
64
>256
2
128
64
32
64
64
>256
16
8
16
16
32
>256
8
32
64
128
>512
16
8
64
64
16
128
64
128
64
5m
5n
5o
5p
5q
5r
32
64
32
>256
64
>256
32
>256
64
>256
64
>512
2
32
16
64
128
64
4
2
64
32
32
4
4
4
2
128
64
128
128
>256
8
128
64
128
128
>256
8
64
128
128
–
64
64
128
–
128
64
64
–
128
128
>256
5s
5t
>256
8
>256
4
AA
CL
–
–
–
–
–
–
–
–
16
4
1
2
Where AA is Ampicillin and CL is Clotrimazole.
a
Minimum inhibitory concentration was determined by the micro-broth dilution method.
b
Escherichia coli (EC), Pseudomonas aeruginosa (PA), Salmonella typhimurium (ST), Klebsiella aerogenes (KA), Staphylococcus aureus (SA), Bacillus cereus (BC),
Lactobacillus casei (LC), Streptococcus pneumonia (SP).
c
Aspergillus fumigatus (AF), Aspergillus niger (AN), Candida albicans (CA), Cryptococcus neoformans (CN).
5

M.K. Mandal et al.
Bioorganic Chemistry 114 (2021) 105153
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 strains.
Com.
R
*Diameter of growth inhibition zone (mm)a
Bacterial Strainsb
Codea
Fungal Strainsc
EC
PA
ST
KA
SA
BC
LC
SP
AN
CA
AF
CN
5a
5b
5c
5d
5e
5f
H
13.2 ±
1.1
12.5 ±
0.6
07 ± 1.5
07 ±
13.8 ±
0.9
08 ± 0.4
10 ± 0.4
08 ± 0.8
10.1 ±
1.1
10.8 ±
2.3
10.2 ±
1.2
8.2 ±
0.5
1.74
2-Br
3-Br
4-Br
2-Cl
3-Cl
4-Cl
2-F
14 ± 0.56
15 ± 0.93
12 ± 0.7
10 ± 0.5
16 ± 1.1
10 ±
0.34
10 ± 0.6
08 ± 0.7
10 ± 0.9
10 ± 1.6
10.8 ±
0.51
11.6 ±
0.65
10 ± 0.9
7.2 ±
0.3
19 ± 0.53
20 ± 0.9
19 ± 0.69
18 ± 0.23
23 ± 0.32
16 ± 1.5
20 ± 1.1
18 ± 0.55
18 ± 0.56
24 ± 1.5
20 ± 0.6
18 ± 0.23
25 ± 1.5
12 ±
14 ± 0.6
18 ± 0.3
12 ± 0.5
17 ± 1.2
21 ± 2.3
17 ± 3.6
20 ± 1.2
12 ±
0.32
14 ±
0.43
12 ± 0.6
12.1 ±
0.9
11 ± 1.5
9.8 ± 0.5
9.6 ± 1.2
7.5 ±
0.5
0.32
14 ± 0.6
12 ± 0.4
18 ±
0.44
11.8 ±
0.66
12.9 ±
0.5
17 ±
1.0
10 ±
10 ± 0.7
12 ± 2.2
14 ± 0.3
10 ±
10.2 ±
0.9
10.8 ±
1.5
12 ±
0.9
0.72
1.32
14 ± 0.2
18 ±
0.23
14 ± 0.6
14 ± 0.4
19 ± 1.2
18 ± 0.7
11.2 ±
0.6
12 ± 0.35
11.8 ±
1.5
10 ±
0.7
5g
5h
5i
12 ± 0.9
14 ± 1.3
12 ±
0.12
22 ±
18 ±
0.33
12 ±
18 ± 1.1
20 ± 1.5
15 ± 0.56
15 ± 0.32
21 ± 0.9
16 ± 0.32
17 ± 0.5
15 ± 0.35
9 ± 1.5
13 ±
12 ±
1.8
0.63
1.43
0.63
23.8 ±
0.9
10 ± 0.5
19 ± 1.1
14 ±
0.62
10 ± 1.7
12 ± 0.66
11 ± 0.9
19 ± 0.6
15 ± 0.93
14 ± 1.5
13 ± 0.6
10 ± 1.2
19 ± 1.5
20 ± 0.9
22 ± 0.46
9.8 ± 0.9
15 ± 1.2
19 ±
1.1
3-F
22.8 ±
0.63
10 ±
12 ± 0.4
17 ±
14 ± 0.9
18 ±
12 ± 0.4
10 ± 0.6
08 ± 0.3
10 ± 0.5
12 ± 2.1
07 ± 0.6
10 ± 1.5
15 ± 0.6
19 ± 1.2
13 ± 1.5
12 ± 2.3
10 ± 1.2
9.5 ± 0.9
18 ± 0.9
20 ± 1.1
14 ±
1.3
0.76
0.53
1.62
5j
4-F
25.9 ±
0.32
18 ± 0.3
14 ±
0.94
23 ± 1.1
18 ± 0.5
10 ± 0.3
08 ± 0.5
10 ± 0.6
07 ± 0.1
10 ± 0.6
10 ± 0.4
12 ± 0.6
08 ± 0.4
10 ± 0.2
19 ± 0.5
13 ±
1.5
5k
5l
2-OH
3-OH
4-OH
18.8 ±
0.9
17.5 ±
0.6
10 ± 0.8
10 ± 0.3
12 ± 0.4
07 ± 1.5
10 ± 0.8
12 ± 0.1
10 ± 1.1
08 ± 0.6
10 ± 0.4
07 ± 0.7
18
12 ±
0.48
16 ±
10 ±
11 ±
1.2
0.32
1.25
17.8 ±
1.1
16 ± 1.5
14 ± 0.4
14 ± 1.2
12 ± 1.6
12 ±
1.4
5m
5n
5o
5p
5q
5r
15.9 ±
0.23
15.2 ±
0.96
10 ± 0.4
07 ± 0.7
13 ±
14 ±
0.64
13 ±
1.4
0.63
4-CH
08 ± 0.65
8.5 ± 1.5
0.7 ± 1.2
07 ±
0.30
5 ± 0.3
(CH3)2
2-NO2
16 ± 0.9
16 ± 0.69
17 ± 1.2
15 ± 0.69
17 ± 1.5
12 ± 1.2
18
15 ± 1.1
14 ± 1.1
18 ± 1.2
16 ± 1.9
15 ± 0.32
11 ± 0.65
17
12 ±
0.34
15 ± 1.5
16 ± 0.9
18 ± 1.2
14 ± 1.1
13 ± 1.5
12 ± 1.9
21
12 ±
0.66
20 ± 1.1
22 ± 1.2
23 ± 1.2
10 ± 0.6
10 ± 1.1
19 ±
1.2
3-NO2
4-NO2
2-CH3
3-CH3
4-CH3
14 ±
0.75
12 ±
1.56
08 ±
0.87
19 ±
1.0
12 ± 0.4
14 ± 0.4
10 ±
0.45
21 ±
19 ±
1.3
0.63
08 ± 0.3
08 ± 1.3
07 ± 0.6
17
10 ± 0.7
10 ± 0.6
08 ± 0.5
20
08 ± 0.8
9.6 ± 0.9
11 ±
0.7
5s
5t
08 ± 0.4
07 ± 0.7
17
9.6 ±
9.2 ± 1.5
9 ± 0.5
0.63
07 ±
0.84
19
9.5 ± 0.9
9.8 ±
0.23
–
09 ± 1.5
10 ±
0.9
–
AA
CL
Stand.
Drug
–
–
Stand.
Drug
–
–
–
–
–
–
–
–
23
24
22
19
a
b
Agar Disk diffusion assay with standard and test solutions of (100 µg/8mm disk) in triplicate, Mean ( ) standard deviation.
Escherichia coli (EC), Pseudomonas aeruginosa (PA), Salmonella typhimurium (ST), Klebsiella aerogenes (KA), Staphylococcus aureus (SA), Bacillus cereus (BC),
Lactobacillus casei (LC), Streptococcus pneumonia (SP).
c
Aspergillus fumigatus (AF), Aspergillus niger (AN), Candida albicans (CA), Cryptococcus neoformans (CN).
undergoes attack by a sulfur nucleophile (thioglycolic acid) followed by
intramolecular cyclization and elimination of water in the presence of
DCC (N,N′-Dicyclohexylcarbodiimide). The DCC is used to accelerate the
intramolecular cyclization which results in faster reaction and improved
yield [32,33].
3.2. In-vitro antimicrobial activity
The newly synthesized final derivatives were screened for their
antimicrobial activity and results are presented in Tables 1 & 2. The
entire set of target compounds 5 (a-t) showed significant inhibitory
activities against pathogenic microbes used in the anti-microbial assay
as compared to standard drug ampicillin and clotrimazole. It has been
found that compounds with halogen substitution, especially Flouro and
Chloro substitution at phenyl ring connected to thiazolidine moiety (5d,
5f, 5g, 5h, 5j) exhibited significant to substantial activity against all the
tested bacterial strains. Especially compounds 5d, 5g, 5h, and 5j showed
significant activity against gram-negative E. coli and gram-positive
L. casei. In continuation, compounds 5j, 5g, and 5d displayed potent
activity against P. aeruginosa. Similarly against S. aureus, B. cereus
compound 5g, 5j, and against S. typhimurium compound 5j displayed
prominent inhibitory activity as compared to ampicillin. Introduction of
The structures of final derivatives 5 (a-t) were ascertained based on
FT-IR, 1H NMR, mass spectra, and elemental analysis. The data found for
the title compounds in the elemental analysis (C, H, and N) were found
near their calculated values. In IR spectra, significant stretching bands
were observed at 1706–1710 cmꢀ 1, 689–700 cmꢀ 1, and 2954–2982
cmꢀ 1 due to C O, C
–
– – –
S C, and NH which showed evidence of ring
–
closure. 1H NMR spectra displayed three broad singlets at δ 9.40–9.48
–
–
ppm due to CONH protons, δ 3.50–3.55 ppm due to N-CH protons,
–
and δ 3.74–3.77 ppm for S CH2 protons confirming the formation of
condensed products, while all other aromatic protons were found in the
expected region. Mass spectra of final derivatives showed molecular ion
peaks in full agreement with their molecular weight.
–
–
NO2 and OH group substitution at phenyl ring (5k, 5l, 5m, 5p, 5q,
6

M.K. Mandal et al.
Bioorganic Chemistry 114 (2021) 105153
Fig. 2. General prototype structure and structure–activity relationship study of compounds 5 (a-t) against bacterial and fungal strains.
5r) showed mild to moderate activity against tested pathogenic mi-
crobes. Meanwhile, a steep decline in activity was reported by com-
pounds with methyl group substitution (5r, 5 s, 5 t) at phenyl ring
connected to core 1,3-thiazolidin-4-one moiety. The rest of the com-
pounds were found moderate to weakly active against the same pool of
bacterial strains in comparison to standard drug. It has been also noted
that analog with bulkier substitution (5n) attached to phenyl ring had
nil antibacterial activity.
3.3. Structure-activity relationship
Structure-activity relationship studies, as shown in Fig. 2 clearly
outlined that the presence of electron-withdrawing group on phenyl ring
attached to 1,3-thiazolidin-4-one moiety greatly influenced the inhibi-
tory activity against all the tested bacterial strains (5g, 5j, 5d, 5f, 5p,
5q) and fungal strains (5g, 5j, 5o, 5p, 5q) in comparison to their
electron-donating counterparts (5k, 5l, 5m, 5n, 5r, 5 s, 5 t). It is
noteworthy to consider that replacement of halogen by non-halogen
substituents led to the dramatic reduction in antimicrobial activity.
These observations suggest the necessity of an electron-withdrawing
group for the generation and escalation of antimicrobial activity. The
activity might be influenced may be due to ease of penetration of mol-
ecules across the bacterial cell wall resulting in cell wall damage and
interrupting cell membrane function with loss of important cellular
constituents (potassium ion and amino acids), in the case of fungi, these
molecules may cause modulation of steric effect on the phenyl ring.
According to the antifungal activity profile, compounds containing
nitro substitution (5o, 5p, 7q) and halogen substitution (5g, 5j) at
phenyl ring displayed significant antifungal activity against all the
tested fungal strains. Compounds 5q, 5p, 5g, and 5j exhibited more
potent activity against A. niger, while the compounds 5o, 5p, 5q, 5g, and
5j showed more prominent activity against C. albicans, and compounds
5j, 5p, 5q displayed significant activity against A. fumigatus in com-
parison to standard drug clotrimazole. Against C. neoformans, com-
pounds 5e, 5g, 5h, 5j, 5o, 5p, and 5q showed excellent activity as
compared to other compounds. Moreover, compound 5n showed the
least activity against all fungal strains.
Table 3
Antiviral activity and cytotoxicity of selected compounds in HEL cell cultures.
Com. Code
Minimum cytotoxic
Antiviral EC50b (µM)
conc.a (µM)
Herpes simplex virus-
1 (KOS)
Herpes simplex
virus-2 (G)
Herpes simplex virus-1 TK-
KOS ACVr
Vaccinia
virus
Adeno
virus-2
Human Coronavirus
(229E)
5a
>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
0.9
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
3.5
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
–
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
–
5c
5e
5g
5h
5k
5m
5n
5o
5p
5q
Brivudin
Cidofovir
Acyclovir
Ganciclovir
Zalcitabine
Alovudine
Ribavirin
3.4
10
7.2
–
0.1
0.2
22
>250
>100
–
–
–
–
–
–
0.05
–
–
–
0.05
–
–
–
0.4
–
–
50
–
–
1.4
–
–
–
>250
a
b
Required to cause a microscopically detectable alteration of normal cell morphology.
Required to reduce virus-induced cytopathogenicity by 50%.
7

M.K. Mandal et al.
Bioorganic Chemistry 114 (2021) 105153
Table 4
Antiviral activity and cytotoxicity of selected compounds in Vero cell cultures.
Com. Code
Minimum cytotoxic conc.a(µM)
Antiviral EC50 (µM)
Para- influenza-3virus
Reovirus-1
Sindbis virus
CoxsackievirusB4
Punta Torovirus
YellowFevervirus
5a
>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
112
>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
5c
5e
5g
5h
5k
5m
5n
5o
5p
5q
DS-10.000
Ribavirin
Mycophenolic acid
>250
11.7
>250
>100
126
>250
0.8
0.4
1.4
Required to reduce virus-induced cytopathogenicity by 50%.
a
Required to cause a microscopically detectable alteration of normal cell morphology.
Table 5
Antiviral activity and cytotoxicity of selected compounds in MDCK cell cultures.
c
Com. Code
Antiviral EC50
Cytotoxicity
CC50a(µM)
Influenza A/H1N1 A/Ned/378/05
Influenza A/H3N2 A/HK/7/87
Influenza B B/Ned/537/05
Minimum cytotoxic conc.b (µM)
visual CPE score
MTS
visual CPE score
MTS
visual CPE score
MTS
5a
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>200
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
≥100
>100
>200
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.8
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.04
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
1.8
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
1.2
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.4
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.02
5c
5e
5g
5h
5k
5m
5n
5o
5p
5q
Zanamivir
Ribavirin
Amantadine
Rimantadine
8.9
9.8
8.9
1.5
2.1
1.2
>100
0.3
>100
0.1
0.4
0.3
>100
>200
>100
>200
0.03
0.09
MDCK cells: Madin Darby canine kidney cells.
a
50% Cytotoxic concentration, as determined by measuring the cell viability with the colorimetric formazan-based MTS assay.
Minimum compound concentration that causes a microscopically detectable alteration of normal cell morphology.
b
c
50% 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 MTS assay.
3.4. DNA Gyrase inhibition study
5o, 5p, 5q) were evaluated for their antiviral efficacy against a diverse
panel of RNA and DNA viruses using cytopathic effect (CPE) reduction
assays inappropriate cell cultures (HEL cell, Vero cell, MDCK cells, and
MT4 cell lines). From the antiviral data Table 3, 4, 5 & 6, it has been
observed that almost all the tested compounds displayed a very marginal
level of antiviral activity. However, compounds 5h exhibited some
antiviral potency among all the synthesized compounds in MT4 cell lines
against HIV-1(strain IIIB) and HIV-2(strain ROD). In HEL cell cultures
against Vaccinia virus and Human Coronavirus (229E), a very low level
of activity was observed but no activity was noted in the case of Herpes
simplex virus-1 (KOS), Herpes simplex virus-2 (G), and Herpes simplex
virus-1 (TKKOS ACVr). In Vero cell cultures, the same set of synthesized
compounds displayed negligible activity against Sindbis virus, Cox-
sackie virus B4, and Yellow Fever virus, but some activity exhibited
against Influenza B (B/Ned/537/05) strain in MDCK cell lines.
Impressed by the exceptional antibacterial activity of synthesized
compounds, we intend to define the probable mechanism of action of
most potent compound 5j. Thus, the inhibitory activity of compound 5j
was studied against S. aureus DNA gyrase enzyme. It has been found that
DNA Gyrase responsible for supercoiling into the bacterial DNA, and
induces initiation and elongation during replication and transcription
stages of the bacterial organisms. Therefore, its inhibition possibly offers
selective advantage to limit the bacterial population via introduction of
negative supercoils in DNA and traps the chromosome in a positively
supercoiled state that may have a downstream impact on cell physiology
and division. In the present study, compound 5j showed IC50 of 4.26 µM.
Thus, it might be suggested that compound 5j inhibit the bacterial
growth by potent inhibition of DNA Gyrase, and it also be the possible
target for other synthesized derivatives due to common structural
scaffold.
This antiviral study suggests that a straight forward structur-
e–activity relationship could not be derived as all the synthesized
compounds showed the similar intensity of activity. The broad pool of
virus testing panels allowed estimating the cytotoxicity of compounds in
various mammalian cell lines. All the tested compounds were found non-
3.5. Antiviral activity
cytotoxic at 100 μM, the highest concentration tested. Thus, it could be
Some of the synthesized compounds (5a, 5c, 5e, 5g, 5h, 5k, 5m, 5n,
8

M.K. Mandal et al.
Bioorganic Chemistry 114 (2021) 105153
Acknowledgments
Table 6
Anti-HIV activity and cytotoxicity of selected compounds in MT4 cells cultures.
The author (MKM) would like to sincerely thank the University Grant
Commission (UGC), New Delhi, Government of India for the Rajiv
Gandhi National Fellowship (RGNF/2013-14-SC-ORI-36328), and
SHUATS for providing necessary infrastructural facilities.
Com. Code
Antiviral EC50
Minimum cytotoxic conc.b
HIV-1(strain
IIIB)
HIV-2(strain
ROD)
(µM)
5a
>125
>125
>125
>125
111
>125
>125
>125
>125
111
>125
>125
>125
>125
111
5c
Appendix A. Supplementary material
5e
5g
5h
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.105153.
5k
>125
>125
>125
>125
>125
>125
>4
>125
>125
>125
>125
>125
>125
0.075
0.58
>125
>125
>125
>125
>125
>125
>4
5m
5n
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5p
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