New nalidixic acid–1,3-thiazolidin-4-one hybrids: Design, synthesis and in vitro antimicrobial activity

Article abstract of DOI:10.1080/10426507.2016.1217212

In this paper, 14 new nalidixic acid–1,3-thiazolidin-4-one hybrid compounds (17–30)were synthesized by the cyclization reaction of corresponding N-substituted nalidixic acid hydrazones (3–16) with mercaptoacetic acid in the presence of 1,4-dioxane. The structures of the obtained compounds were confirmed by means of¹H NMR and¹³C NMR spectroscopy. All newly synthesized hybrids were screened in vitro for antimicrobial activity. The antimicrobial activity assay indicated that compounds 17–30 showed good to moderate antimicrobial activity, especially against Gram-positive bacteria. Moreover, compound 29 inhibited growth of reference strains of Gram-negative bacteria belonging to Enterobacteriaceae family.

Full text of DOI:10.1080/10426507.2016.1217212

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
New nalidixic acid–1,3-thiazolidin-4-one hybrids:
Design, synthesis and in vitro antimicrobial activity
Łukasz Popiołek & Anna Biernasiuk
To cite this article: Łukasz Popiołek & Anna Biernasiuk (2017) New nalidixic acid–1,3-
thiazolidin-4-one hybrids: Design, synthesis and in vitro antimicrobial activity,
Phosphorus, Sulfur, and Silicon and the Related Elements, 192:1, 23-27, DOI:
10.1080/10426507.2016.1217212
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1217212
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Date: 16 December 2016, At: 08:57

PHOSPHORUS, SULFUR, AND SILICON
, VOL. , NO. , –
http://dx.doi.org/./..
New nalidixic acid–,-thiazolidin--one hybrids: Design, synthesis and
in vitro antimicrobial activity
Łukasz Popiołeka and Anna Biernasiukb
aDepartment of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland; bDepartment of Pharmaceutical Microbiology,
Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland
ABSTRACT
ARTICLE HISTORY
Received  May 
Accepted  July 
In this paper, 14 new nalidixic acid–1,3-thiazolidin-4-one hybrid compounds (17–30) were synthesized by the
cyclization reaction of corresponding N-substituted nalidixic acid hydrazones (3–16) with mercaptoacetic
acid in the presence of 1,4-dioxane. The structures of the obtained compounds were confirmed by means
of 1H NMR and 13C NMR spectroscopy. All newly synthesized hybrids were screened in vitro for antimicro-
bial activity. The antimicrobial activity assay indicated that compounds 17–30 showed good to moderate
antimicrobial activity, especially against Gram-positive bacteria. Moreover, compound 29 inhibited growth
of reference strains of Gram-negative bacteria belonging to Enterobacteriaceae family.
KEYWORDS
,-Thiazolidin--one
derivatives; antimicrobial
activity; MIC; MBC; nalidixic
acid
GRAPHICAL ABSTRACT
due to the interaction with MurB enzyme which inhibits the
biosynthesis of the peptidoglycan—a polymer essential for cell
wall of bacteria13–15. The 1,3-thiazolidin-4-one derivatives also
show other interesting activities such as: anticonvulsant,16 anti-
cancer17,18 and antiviral activity19.
Based on the facts mentioned above in this paper, we would
like to report the synthesis, spectral characterization, and in vitro
antimicrobial study of new nalidixic acid–1,3-thiazolidin-4-one
hybrids.
Introduction
The introduction of nalidixic acid for the treatment of bacterial
infections has begun the era of antibiotics collectively known
as quinolones1,2. Quinolone antibiotics are still important as
anti-infective agents and are widely prescribed for various infec-
tions3. Their activity is connected with the inhibition of bacterial
DNA gyrase/topoisomerase IV system3–5
.
Our recent review and literature findings concerning the
impact of modifying the chemical structure of nalidixic acid
on antimicrobial activity indicated and confirmed that the car-
boxylic acid group at C-3 position is essential for antibacterial
activity6–9. In an earlier paper, we synthesized new nalidixic
Results and discussion
acid hydrazones and screened them for in vitro antimicro- Chemistry
bial activity10. In this paper, we decided to modify the struc-
New derivatives of nalidixic acid were obtained in a three-step
ture of nalidixic acid by combining it with substituted 1,3-
thiazolidin-4-one derivatives using the previously obtained
hydrazones10.
synthesis. First, nalidixic acid hydrazide (2) was obtained
by the reaction of nalidixic acid methyl ester (1) with 100%
hydrazide hydrate. This reaction was conducted according
to the procedure described earlier10,20. Then nalidixic acid
The 1,3-thiazolidin-4-one derivatives are interesting group
of compounds exhibiting significant antibacterial activity11,12
CONTACT Łukasz Popiołek
– Lublin, Poland.
lukasz.popiolek@umlub.pl
Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, A Chodz´ki Street,
Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article can be accessed on the publisher’s website at http://dx.doi.org/./...
©  Taylor & Francis Group, LLC

24
Ł. POPIOŁEK AND A. BIERNASIUK
Scheme . Synthetic route to new nalidixic acid–,-thiazolidin--one hybrids (17–30).
hydrazones were synthesized by the condensation reaction
of nalidixic acid hydrazide with corresponding substituted
(hetero)aromatic aldehydes. This reaction was performed
according to the procedure reported earlier by our group10.
Finally, new hybrid compounds were prepared by the cycliza-
tion of N-substituted nalidixic acid hydrazones (3–16) with
mercaptoacetic acid. This reaction begins by nucleophilic
attack of anion of mercaptoacetic acid upon the carbon atom
of hydrazone, followed by the capture of proton by nitrogen
and subsequent cyclization with removal of water molecule15.
All nalidixic acid hybrid derivatives (17–30) are new and their
synthesis and structures are presented for the first time in the
literature.
Experimental
Chemistry
All chemicals and solvents used in this study were pur-
chased from Sigma-Aldrich (Munich, Germany) and Merck
Co. (Darmstadt, Germany). Melting points are uncorrected and
were marked with Fisher-Johns blocks (Fisher Scientific, Ger-
many). The 1H NMR and 13C NMR spectra were recorded on
a Bruker Avance 300 apparatus (Bruker BioSpin GmbH, Ger-
many) in DMSO-d6 with TMS as internal standard. The chem-
ical shifts are given in δ (ppm) scale using TMS as the stan-
dard reference. The coupling constants (J) are given in Hertz.
The progress of the reaction and purity of obtained compounds
were monitored by TLC on precoated aluminum sheets 60 F254
plates (Merck Co., USA), in a CHCl3/C2H5OH (10:1, v/v) sol-
vent system. The spots were detected by exposure to a UV lamp
at 254 nm. Elemental analysis of synthesized compounds was
1
The H NMR spectra of compounds (17–30) showed fol-
lowing signals corresponding to the specific group in 1,3-
thiazolidin-4-one ring. The NH group gave a typical singlet sig-
nal in the range of δ 11.25–11.94 ppm, the singlet signals for
CH2 and CH groups were found in the range of δ 3.37–3.86 ppm
and δ 5.25–6.51 ppm, respectively. In the 13C NMR spectra of
compounds (17–30), signals for CH2 and CH groups for the
thiazolidine system appeared in the range of δ 31.9–33.5 ppm
and δ 60.9–67.9 ppm, respectively. The signal for C═O group
was observed at δ 171.1–174.5 ppm. All other aliphatic and aro-
matic signals were found at usual regions. Based on the obtained
spectral data, we successfully confirmed the formation of the
expected hybrid compounds (17–30). The hybrid derivatives
(17–30) were synthesized according to the reactions presented
in Scheme 1.
´
performed on AMZ 851 CHX analyser (PG, Gdansk, Poland).
The results of elemental analysis (C, H, N) were within 0.4%
of the calculated values.
Synthesis of nalidixic acid hydrazide ()
The compound was prepared according to a literature proce-
dure10,20. Analytical and spectral data were consistent with those
reported in the literature10.
Synthesis of nalidixic acid hydrazones (–)
The synthesized compounds (17–30) were in vitro screened
for antibacterial and antifungal activity.
Compounds (3–16) were prepared according to a literature pro-
cedure reported earlier by our group10. Compound 2 (2.46 g,
10 mmol) was dissolved in methanol (15 mL). The mixture was
stirred until a clear solution was obtained. After that, the appro-
priate (hetero)aromatic aldehydes were added (11 mmol) and
the solution was stirred at room temperature for 3 h. The pre-
cipitate obtained was filtered off, dried, and recrystallized from
ethanol.
Microbiology
The results of our antimicrobial activity study indicated that
all synthesized substances had no inhibitory effect on the
growth of reference strains of yeasts Candida spp. How-
ever, our assays showed that the tested compounds exhibited
some influence on the growth of reference strains of bacte-
ria. Detailed results and discussion of antimicrobial screen-
ing together with the table (Table S1) with the activity data
The analytical and spectral data of compounds (3–16) were
reported earlier10.
of compounds 17–30 expressed as MIC (µg/mL) against the Synthesis of hybrid compounds (–)
reference strains of bacteria are presented in Supplemental To a solution of the corresponding nalidixic acid hydrazones
Materials.
3–16 (10 mmol) in 1,4-dioxane (15 mL), mercaptoacetic acid

PHOSPHORUS, SULFUR, AND SILICON
25
(0.92 g, 10 mmol) was slowly added. The mixture was stirred and N-[2-(4-methoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-1-
heated under reflux for 12–24 h. Subsequently, the solvent was ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
removed under reduced pressure and after that a 10% aquous carboxamide (20). Yield: 69%; m.p.: 229–231°C. Time of
solution of sodium bicarbonate (20 mL) was added. The precip- reaction: 16h. 1H NMR (DMSO-d6) δ (ppm) = 1.38–1.43 (t, J =
itate formed was filtered off, dried, and purified by recrystalliza- 6 Hz, J = 9 Hz, 3H, CH3), 2.69 (s, 3H, CH3), 3.57 (s, 3H, CH3),
tion from ethanol.
3.74 (s, 2H, CH2), 4.57–4.65 (q, J = 9 Hz, 2H, CH2), 5.97 (s, 1H,
CH), 6.92–6.95 (d, J = 9 Hz, 1H, ArH), 7.40–7.43 (d, J = 9 Hz,
1H, ArH), 7.47–7.49 (d, J = 6 Hz, 1H, ArH), 7.51–7.54 (d, J =
9 Hz, 1H, ArH), 8.47–8.50 (d, J = 9 Hz, 1H, ArH), 8.55 (s, 1H,
N-[2-(3-bromo-4-hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-
yl]-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxamide (17). Yield: 70%; m.p.: 148–150°C. Time of
reaction: 24h. 1H NMR (DMSO-d6) δ (ppm) = 1.38–1.43
(t, J = 6 Hz, J = 9 Hz, 3H, CH3), 2.69 (s, 3H, CH3), 3.57 (s,
2H, CH2), 4.58–4.65 (q, J = 6 Hz, J = 9 Hz, 2H, CH2), 5.83
(s, 1H, CH), 6.92–6.95 (d, J = 9 Hz, 1H, ArH,), 7.20–7.33 (m,
1H, ArH), 7.47–7.49 (m, 1H, ArH), 7.51–7.54 (m, J = 9 Hz,
1H, ArH), 8.58–8.61 (d, J = 9 Hz, 1H, ArH), 9.05 (s, 1H, ArH),
10.90 (s, 1H, OH), 11.25 (s, 1H, NH); 13C NMR (DMSO) δ
ArH), 8.58–8.61 (d, J = 9 Hz, 1H, ArH), 11.25 (s, 1H, NH); 13
C
NMR (DMSO) δ (ppm) = 12.4 (CH3), 24.3 (CH3), 33.5 (CH2),
45.8 (CH2), 56.0 (CH3), 67.6 (CH), 105.1, 114.0, 119.3, 121.9,
126.7, 135.5, 137.3, 145.8, 159.8, 160.8, 161.8 (13Car), 163.8
=
=
=
(C O), 172.4 (C O), 180.6 (C O). Analysis for C22H22N4O4S
(438.49) Calculated: C: 60.26%, H: 5.06%, N: 12.78%; Found: C:
60.31%, H: 5.08%, N: 12.76%.
(ppm) = 12.4 (CH3), 24.3 (CH3), 33.3 (CH2), 45.5 (CH2), 67.9 N-[2-(2,3-dimethoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-
(CH), 105.0, 107.4, 115.3, 119.3, 121.9, 126.6, 134.2, 145.8, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
=
=
156.4, 159.0, 160.5 (13Car), 163.4 (C O), 172.4 (C O), 180.1 carboxamide (21). Yield: 76%; m.p.: 222–224°C. Time of
(C O). Analysis for C21H19BrN4O4S (503.37) Calculated: C: reaction: 16h. 1H NMR (DMSO-d6) δ (ppm) = 1.35–1.37
=
50.11%, H: 3.80%, N: 11.13%; Found: C: 50.16%, H: 3.76%, (t, J = 6 Hz, 3H, CH3), 2.66 (s, 3H, CH3), 3.55 (s, 2H, CH2),
N: 11.16%.
3.71 (s, 3H, CH3), 3.76 (s, 3H, CH3), 4.54–4.62 (q, J = 6 Hz, J
= 9 Hz, 2H, CH2), 6.22 (s, 1H, CH), 7.05–7.14 (dd, J = 6 Hz,
2H, ArH), 7.47–7.50 (d, J = 9 Hz, 1H, ArH), 8.50–8.54 (d, J =
12 Hz, 1H, ArH), 8.59–8.62 (d, J = 9 Hz, 1H, ArH), 9.01 (s,
1H, ArH), 11.39 (s, 1H, NH); 13C NMR (DMSO) δ (ppm) =
12.4 (CH3), 24.3 (CH3), 33.3 (CH2), 45.8 (CH2), 56.8 (CH3),
60.6 (CH3), 62.1 (CH), 105.1, 115.6, 119.3, 119.9, 121.6, 121.9,
127.7, 137.3, 144.1, 145.8, 151.8, 159.9, 160.7 (13Car), 163.8
N-[2-(5-bromo-2-hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-
yl]-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxamide (18). Yield: 65%; m.p.: 205–207°C. Time of
reaction: 24h. 1H NMR (DMSO-d6) δ (ppm) = 1.38–1.43
(t, J = 6 Hz, J = 9 Hz, 3H, CH3), 2.70 (s, 3H, CH3), 3.57 (s,
2H, CH2), 4.58–4.65 (q, J = 6 Hz, J = 9 Hz 2H, CH2), 5.57 (s,
1H, CH), 6.90–6.93 (d, J = 9 Hz, 1H, ArH), 7.27–7.32 (m, 1H,
ArH), 7.39–7.40 (d, J = 3 Hz, 1H, ArH), 7.45–7.54 (m, 1H,
ArH), 8.53–8.61 (m, 1H, ArH,), 9.03 (s, 1H, ArH), 10.94 (s, 1H,
OH), 11.38 (s, 1H, NH); 13C NMR (DMSO) δ (ppm) = 12.2
=
=
=
(C O), 172.3 (C O), 180.6 (C O). Analysis for C23H24N4O5S
(468.52) Calculated: C: 58.96%, H: 5.16%, N: 11.96%; Found: C:
58.91%, H: 5.14%, N: 11.99%.
(CH3), 24.2 (CH3), 33.2 (CH2), 45.5 (CH2), 61.8 (CH), 105.3, N-[2-(3-bromo-4-methoxyphenyl)-4-oxo-1,3-thiazolidin-3-
110.9, 118.8, 119.3, 121.9, 124.9, 129.9, 130.8, 137.3, 145.8, yl]-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
=
=
150.1, 159.1, 160.6 (13Car), 160.3 (C O), 171.1 (C O), 180.1 carboxamide (22). Yield: 75%; m.p.: 124–126°C. Time of
1
=
(C O). Analysis for C21H19BrN4O4S (503.37) Calculated: C: reaction: 20h. H NMR (DMSO-d6) δ (ppm) = 1.38–1.42 (t,
50.11%, H: 3.80%, N: 11.13%; Found: C: 50.09%, H: 3.85%, J = 6 Hz, 3H, CH3), 2.69 (s, 3H, CH3), 3.85 (s, 3H, CH3),
N: 11.15%.
3.91 (s, 2H, CH2), 4.57–4.63 (q, J = 6 Hz, 2H, CH2), 5.25 (s,
1H, CH), 7.09–7.12 (d, J = 9 Hz, 1H, ArH), 7.21–7.24 (d, J =
9 Hz, 1H, ArH), 7.37–7.40 (dd, J = 3 Hz, 1H, ArH), 7.47–7.57
(m, 2H, ArH), 7.73–7.76 (dd, J = 3 Hz, 1H, ArH), 11.27 (s,
1H, NH); 13C NMR (DMSO) δ (ppm) = 12.5 (CH3), 24.2
(CH2), 33.4 (CH2), 45.8 (CH2), 56.9 (CH3), 67.9 (CH), 106.1,
111.3, 112.7, 119.3, 121.9, 125.8, 135.0, 136.4, 137.3, 145.8,
N-[2-(3-ethoxy-4-hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-
yl]-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxamide (19). Yield: 75%; m.p.: 219–221°C. Time of
reaction: 16h. 1H NMR (DMSO-d6) δ (ppm) = 1.17–1.21
(t, J = 6 Hz, 3H, CH3), 1.38–1.42 (t, 3H, CH3, J = 6 Hz), 2.59 (s,
3H, CH3), 3.39 (s, 2H, CH2), 3.94–4.00 (q, J = 6 Hz, 2H, CH2),
4.29–4.35 (q, J = 6 Hz, 2H, CH2), 5.75 (s, 1H, CH), 6.56–6.58
(d, J = 6 Hz, 1H, ArH), 6.74–6.81 (m, 2H, ArH), 7.09–7.11 (d,
J = 6 Hz, 1H, ArH), 8.15–8.17 (d, J = 6 Hz, 1H, ArH), 8.37
(s, 1H, ArH), 10.63 (s, 1H, OH), 11.54 (s, 1H, NH); 13C NMR
=
=
159.9, 160.75, 161.2 (13Car), 163.8 (C O), 172.3 (C O), 180.6
=
(C O). Analysis for C22H21BrN4O4S (517.39) Calculated: C:
51.07%, H: 4.09%, N: 10.83%; Found: C: 51.11%, H: 4.07%,
N: 10.84%.
(DMSO) δ (ppm) = 12.4 (CH3), 13.8 (CH3), 24.3 (CH3), 33.3 N-[2-(2-chloro-3-methoxyphenyl)-4-oxo-1,3-thiazolidin-3-
(CH2), 45.7 (CH2), 64.5 (CH2), 67.9 (CH), 105.1, 111.8, 117.1, yl]-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
117.8, 119.3, 121.9, 132.3, 137.3, 145.5, 145.8, 147.2, 159.1, 160.7 carboxamide (23). Yield: 63%; m.p.: 237–239°C. Time of
(13Car), 163.7 (C O), 172.3 (C O), 180.6 (C O). Analysis reaction: 12h. 1H NMR (DMSO-d6) δ (ppm) = 1.36–1.40
for C23H24N4O5S (468.52) Calculated: C: 58.96%, H: 5.16%, N: (t, J = 6 Hz, 3H, CH3), 3.57 (s, 2H, CH2), 3.84 (s, 3H, CH3),
=
=
=
11.96%; Found: C: 58.92%, H: 5.14%, N: 11.94%.
3.88 (s, 3H, CH3), 4.56–4.62 (q, J = 6 Hz, 2H, CH2), 6.32 (s,

26
Ł. POPIOŁEK AND A. BIERNASIUK
1H, CH), 6.73–6.75 (d, J = 6 Hz, 1H, ArH), 7.13–7.22 (m, 1H, N-[2-(1H-pyrrol-2-yl)-4-oxo-1,3-thiazolidin-3-yl]-1-ethyl-7-
ArH), 7.29–7.38 (m, 1H, ArH), 8.17 (s, 1H, ArH), 8.50–8.52 methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(d, J = 6 Hz, 1H, ArH), 9.03 (s, 1H, ArH), 11.48 (s, 1H, NH); (27). Yield: 62%; m.p.: 228–230°C. Time of reaction: 16h.
13C NMR (DMSO) δ (ppm) = 12.4 (CH3), 24.2 (CH3), 33.2 1H NMR (DMSO-d6) δ (ppm) = 1.17–1.21 (t, J = 6 Hz, 3H,
(CH2), 45.4 (CH2), 56.8 (CH3), 64.9 (CH), 105.1, 116.2, 117.9, CH3), 2.52 (s, 3H, CH3), 3.35 (s, 2H, CH2), 3.96–4.02 (q, J =
119.3, 121.6, 121.9, 126.5, 137.3, 140.9, 145.8, 157.2, 159.8, 160.7 6 Hz, 2H, CH2,), 5.98 (s, 1H, CH), 6.08–6.10 (m, 2H, ArH),
=
=
=
(13Car), 163.1 (C O), 172.4 (C O), 180.6 (C O). Analysis for 6.86–6.89 (m, 1H, ArH), 7.01–7.03 (d, J = 6 Hz, 1H, ArH),
C22H21ClN4O4S (472.94) Calculated: C: 55.87%, H: 4.48%, N: 8.03–8.05 (d, J = 6 Hz, 1H, ArH), 8.30 (s, 1H, ArH), 11.24 (s,
11.85%; Found: C: 55.91%, H: 4.50%, N: 11.83%.
1H, NH), 14.14 (s, 1H, NH); 13C NMR (DMSO) δ (ppm) = 12.4
(CH3), 14.2 (CH3), 31.9 (CH2), 45.5 (CH2), 64.9 (CH), 105.3,
107.8, 112.1, 119.3, 119.9, 121.9, 137.3, 139.0, 145.8, 159.1, 160.5
N-[2-(2-bromo-5-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxamide (24). Yield: 63%; m.p.: 111–113°C. Time of
reaction: 16h. 1H NMR (DMSO-d6) δ (ppm) = 1.17–1.21 (t, J =
6 Hz, 3H, CH3), 2.61 (s, 3H, CH3), 3.37 (s, 2H, CH2), 4.37–4.43
=
=
=
(13Car), 163.4 (C O), 174.4 (C O), 180.3 (C O). Analysis
for C19H19N5O3S (397.45) Calculated: C: 57.42%, H: 4.82%, N:
17.62%; Found: C: 57.46%, H: 4.85%, N: 17.59%.
(q, J = 6 Hz, 2H, CH2), 5.83 (s, 1H, CH), 6.85–6.87 (m, 2H, N-[2-(5-chlorofuran-2-yl)-4-oxo-1,3-thiazolidin-3-yl]-1-
ArH), 7.10–7.12 (d, J = 6 Hz, 1H, ArH), 7.48–7.51 (d, J = ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
6 Hz, 1H, ArH), 8.18–8.20 (d, J = 6 Hz, 1H, ArH), 8.34 (s, 1H, carboxamide (28). Yield: 78%; m.p.: 189–191°C. Time of
ArH), 11.94 (s, 1H, NH); 13C NMR (DMSO) δ (ppm) = 12.4 reaction: 16h. 1H NMR (DMSO-d6) δ (ppm) = 1.38–1.43 (t, J =
(CH3), 24.2 (CH3), 33.3 (CH2), 45.7 (CH2), 66.3 (CH), 105.0, 6 Hz, J = 9 Hz, 3H, CH3), 2.69 (s, 3H, CH3), 3.57 (s, 2H, CH2),
113.6, 118.4, 119.3, 119.8, 121.9, 135.0, 137.3, 142.8, 145.8, 4.58–4.64 (q, J = 6 Hz, 2H, CH2), 5.51 (s, 1H, CH), 6.46–6.50
=
=
159.1, 160.4, 160.7 (13Car), 163.8 (C O), 172.9 (C O), 180.1 (m, 1H, ArH), 6.60–6.68 (m, 1H, ArH), 7.49–7.54 (m, 1H, ArH),
=
(C O). Analysis for C21H18BrFN4O3S (505.36) Calculated: 8.55–8.61 (m, 1H, ArH), 9.05 (s, 1H, ArH), 11.84 (s, 1H, NH);
C: 49.91%, H: 3.59%, N: 11.09%; Found: C: 49.95%, H: 3.60%, 13C NMR (DMSO) δ (ppm) = 12.2 (CH3), 24.2 (CH3), 31.9
N: 11.06%.
(CH2), 45.7 (CH2), 62.1 (CH), 104.9, 108.6, 117.7, 119.3, 121.9,
=
137.3, 145.8, 158.9, 160.2, 160.7 (13Car), 163.2 (C O), 174.5
=
=
(C O), 180.9 (C O). Analysis for C19H17ClN4O4S (432.88)
Calculated: C: 52.72%, H: 3.96%, N: 12.94%; Found: C: 52.76%,
H: 3.97%, N: 12.92%.
N-[2-(2-chloro-6-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxamide (25). Yield: 71%; m.p.: 206–208°C. Time of
reaction: 24h. H NMR (DMSO-d6) δ (ppm) = 1.40–1.44 (t,
1
3H, CH3, J = 6 Hz), 2.68 (s, 3H, CH3), 3.52 (s, 2H, CH2), N-[2-(1H-indol-3-yl)-4-oxo-1,3-thiazolidin-3-yl]-1-ethyl-7-
4.56–4.64 (q, 2H, CH2, J = 6 Hz), 6.51 (s, 1H, CH), 7.33–7.43 methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(m, 1H, ArH), 7.46–7.57 (m, 1H, ArH), 8.50–8.52 (d, 1H, ArH, J (29). Yield: 75%; m.p.: 197–199°C. Time of reaction: 20h. 1H
= 6 Hz), 8.56–8.62 (m, 1H, ArH), 9,03 (s, 1H, ArH). 9.13 (s, 1H, NMR (DMSO-d6) δ (ppm) = 1.41–1.45 (t, J = 6 Hz, 3H, CH3),
ArH), 11.53 (s, 1H, NH); 13C NMR (DMSO) δ (ppm) = 12.7 2.70 (s, 3H, CH3), 3.66 (s, 2H, CH2), 4.60–4.68 (q, J = 9 Hz,
(CH3), 24.7 (CH3), 33.2 (CH2), 45.6 (CH2), 61.5 (CH), 105.2, 2H, CH2), 5.63 (s, 1H, CH), 6.92–7.17 (m, 1H, ArH), 7.33–7.55
116.9, 119.3, 121.8, 126.9, 127.5, 130.7, 134.2, 137.3, 145.8, (m, 1H, ArH), 7.63–7.71 (m, 1H, ArH), 7.82–7.83 (d, J = 3 Hz,
=
=
159.6, 160.1, 160.7 (13Car), 163.7 (C O), 172.1 (C O), 180.2 1H, ArH), 8.26–8.29 (d, J = 9 Hz, 1H, ArH), 8.55 (s, 1H, ArH),
=
(C O). Analysis for C21H18ClFN4O3S (460.91) Calculated: C: 8.60–8.63 (d, J = 9 Hz, 1H, ArH), 9.09 (s, 1H, ArH), 11.58 (s,
54.72%, H: 3.94%, N: 12.16%; Found: C: 54.76%, H: 3.96%, N: 1H, NH), 12.85 (s, 1H, NH); 13C NMR (DMSO) δ (ppm) = 12.5
12.13%.
(CH3), 24.4 (CH3), 31.9 (CH2), 45.7 (CH2), 60.9 (CH), 103.8,
105.0, 112.4, 119.3, 119.6, 119.7, 121.9, 123.2, 127.4, 136.5,
=
=
137.3, 145.8, 159.0, 160.7 (14Car), 163.8 (C O), 174.4 (C O),
N-[2-(2,3-difluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-1-
ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxamide (26). Yield: 76%; m.p.: 179–181°C. Time of
reaction: 24h. 1H NMR (DMSO-d6) δ (ppm) = 1.35–1.40 (t, J =
9 Hz, J = 6 Hz, 3H, CH3), 2.68 (s, 3H, CH3), 3.86 (s, 2H, CH2),
=
180.4 (C O). Analysis for C23H21N5O3S (447.51) Calculated:
C: 61.73%, H: 4.73%, N: 15.65%; Found: C: 61.78%, H: 4.75%,
N: 15.62%.
4.54–4.61 (q, J = 6 Hz, J = 9 Hz, 2H, CH2), 6.24 (s, 1H, CH), N-[2-(6-chloro-benzo[1,3]dioxol-5-yl)-4-oxo-1,3-thiazolidin-
7.24–7.31 (m, 1H, ArH), 7.41–7.56 (m, 2H, ArH), 8.49–8.52 3-yl]-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-
(d, J = 9 Hz, 1H, ArH), 8.59–8.61 (m, 1H, ArH), 9.01 (s, 1H, 3-carboxamide (30). Yield: 69%; m.p.: 168–170°C. Time of
ArH), 11.43 (s, 1H, NH); 13C NMR (DMSO) δ (ppm) = 12.6 reaction: 24h. 1H NMR (DMSO-d6) δ (ppm) = 1.17–1.21 (t, J
(CH3), 24.2 (CH3), 33.2 (CH2), 45.6 (CH2), 65.0 (CH), 105.0, = 6 Hz, 3H, CH3), 2.58 (s, 3H, CH3), 3.42 (s, 2H, CH2), 4.59–
118.6, 119.3, 121.9, 122.9, 124.4, 128.9, 137.3, 145.8, 148.4, 4.65 (q, J = 6 Hz, 2H, CH2,), 4.85 (s, 2H, CH2), 5.97 (s, 1H,
=
=
152.5, 159.6, 160.8 (13Car), 163.8 (C O), 172.3 (C O), 180.6 CH), 6.78 (s, 1H, ArH), 6.84 (s, 1H, ArH), 7.11–7.13 (d, J =
=
(C O). Analysis for C21H18F2N4O3S (444.45) Calculated: C: 6 Hz, 1H, ArH), 7.90 (s, 1H, ArH), 8.17–8.19 (d, J = 6 Hz, 1H,
56.75%, H: 4.08%, N: 12.61%; Found: C: 56.78%, H: 4.06%, ArH), 11.31 (s, 1H, NH); 13C NMR (DMSO) δ (ppm) = 12.4
N: 12.65%.
(CH3), 24.4 (CH3), 33.5 (CH2), 45.8 (CH2), 65.1 (CH), 102.1,

PHOSPHORUS, SULFUR, AND SILICON
27
105.1, 111.1, 119.4, 120.8, 121.9, 132.9, 137.3, 145.8, 146.8,
3. Mitscher, L. A. Chem. Rev. 2005, 105, 559-592.
4. Shen, L. L.; Pernet, A.G. Proc. Natl. Acad. Sci. 1985, 82, 307-311.
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6. Popiołek, Ł.; Gawron´ska-Grzywacz, M. Int. Res. J. Pure Appl. Chem.
2015, 7(4), 191-202.
=
=
149.8, 159.7, 160.8 (13Car), 160.7 (C O), 163.4 (C O), 172.4
=
(C O). Analysis for C22H19ClN4O5S (486.93) Calculated: C:
54.27%, H: 3.93%, N: 11.51%; Found: C: 54.32%, H: 3.96%, N:
11.53%.
7. Aggarwal, N.; Kumar, R.; Dureja, P.; Khurana, J. M. Eur. J. Med. Chem.
2011, 46, 4089-4099.
8. Aggarwal, N.; Kumar, R.; Dureja, P.; Kuharna, J. M. Chem. Biol. Drug.
Des. 2012, 79, 384-397.
Microbiology
In vitro antimicrobial assay
9. Abdelmoty, S. G.; Heta, H. F. Bull. Pharm. Sci. 2009, 32(1), 125-140.
10. Popiołek, Ł.; Biernasiuk, A.; Malm, A. J. Het. Chem. [online] 2015,
DOI: 10.1002/jhet.2468
The examined compounds 17–30 were screened in vitro for
antibacterial and antifungal activities. Detailed information
concerning procedure of antimicrobial assay is presented in the
Supplemental Materials.
11. Omar, K.; Geronikaki, A.; Zoumpoulakis, P.; Camoutsis, Ch.; Sokovic´,
´
M.; Ciric´, A.; Glamocˆlija, J. Bioorg. Med. Chem. 2010, 18, 426-432.
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S.; Samadi, N.; Faramazrzi, M. A.; Saniee, P.; Siavoishi, F.; Abadian,
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Chem. Res. 2013, 22, 2293-2302.
Conclusions
13. Anders, C.; Bronson, J.; D’Andrea, S. V.; Deshpande, M.; Falk, P.; Grant-
Young, K.; Harte, W.; Ho, H.; Misco, P.; Robertson, J.; Stock, D.; Sun,
Y.; Walsh, A. Bioorg. Med. Chem. Lett. 2000, 10, 715-717.
14. Jain, A. K.; Vaidya, A.; Ravichandran, V.; Kashaw, S.K.; Agrawal, R. K.
Bioorg. Med. Chem. 2012, 20, 3378-3395.
In conclusion, in this paper we design, synthesized, identified,
and evaluated for in vitro antimicrobial activity 14 new nalidixic
acid–1,3-thiazolidin-4-one hybrids (17–30). Our results indi-
cated that newly synthesized compounds 17–30 showed good
to moderate antimicrobial activity, especially against Gram- 15. Tripathi, A. C.; Gupta, S. J.; Fatima, G. N.; Sonar, P. K.; Verma, A.; Saraf,
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positive bacteria. Moreover, compound 29 inhibited growth of
16. Archana, S. V. K.; Kumar, A. Eur. J. Med. Chem. 2002, 37, 873-882.
reference strains of Gram-negative bacteria belonging to Enter-
17. Havrylyuk, D.; Zimenkovsky, B.; Vasylenko, O.; Day, C. W.; Smee, D.
obacteriaceae family.
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