Synthesis, Dissociation Constants, and Antimicrobial Activity of Novel 2,3-Disubstituted-1,3-thiazolidin-4-one Derivatives

DOI: 10.1002/jhet.2418

Source and publish data:

Journal of Heterocyclic Chemistry p. 393 - 402 (2016)

Update date:2022-08-04

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Authors:

Popiolek, Lukasz

Stefaska, Joanna

Kielczykowska, Malgorzata

Musik, Irena

Biernasiuk, Anna

Malm, Anna

Wujec, Monika

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Article abstract of DOI:10.1002/jhet.2418

In this article, a new series of 2,3-disubstituted-1,3-thiazolidin-4-one derivatives have been designed, synthesized, and evaluated as antimicrobial agents. New compounds were prepared by the cyclization reaction of N-substituted carboxylic acid hydrazide derivatives with mercaptoacetic acid. The structures of the obtained compounds were confirmed by means of IR, ¹H NMR, and ¹³C NMR spectra. The dissociation constants were determined using spectrophotometric method. All synthesized compounds were tested for their in vitro antibacterial and antifungal activities using the broth microdilution method.

Full text of DOI:10.1002/jhet.2418

March 2016

Synthesis, Dissociation Constants, and Antimicrobial Activity of Novel

2,3-Disubstituted-1,3-thiazolidin-4-one Derivatives

393

Łukasz Popiołek, Joanna Stefańska, Małgorzata Kiełczykowska, Irena Musik,

Anna Biernasiuk,^dAnna Malm,^dand Monika Wujec^a

^aDepartment of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093

Lublin, Poland

^bDepartment of Pharmaceutical Microbiology, Faculty of Pharmacy, Warsaw Medical University, 3 Oczki Street, 02-007

Warsaw, Poland

^cDepartment of Medical Chemistry, Faculty of Medicine, Medical University of Lublin, 4A Chodzki Street, 20-093

Lublin, Poland

^dDepartment of Pharmaceutical Microbiology, Faculty of Pharmacy, Medical University of Lublin, 1 Chodzki Street,

20-093 Lublin, Poland

E-mail: lukasz.popiolek@umlub.pl

Additional Supporting Information may be found in the online version of this article.

Received October 3, 2014

DOI 10.1002/jhet.2418

Published online 7 April 2015 in Wiley Online Library (wileyonlinelibrary.com).

In this article, a new series of 2,3-disubstituted-1,3-thiazolidin-4-one derivatives have been designed,

synthesized, and evaluated as antimicrobial agents. New compounds were prepared by the cyclization

reaction of N-substituted carboxylic acid hydrazide derivatives with mercaptoacetic acid. The structures of

the obtained compounds were conﬁrmed by means of IR, ¹H NMR, and ¹³C NMR spectra. The dissociation

constants were determined using spectrophotometric method. All synthesized compounds were tested for

their in vitro antibacterial and antifungal activities using the broth microdilution method.

J. Heterocyclic Chem., 53, 393 (2016).

INTRODUCTION

are shown in Scheme 1. The yields, melting points, and

spectral data of compounds 1a–1g, 2a–2g, 3a–3g, 4a–4g,

5a–5g, and 6a–6g are given in the Experimental section.

In the past few years, the incidence of microbial infec-

tions and pathogen resistance to existing drugs grows to

an alarming level. These infections are a major cause of

increasing mortality, especially in patients with low levels

of immunity [1]. Therefore, discovery of a new class of

antimicrobial agents is needed to combat multiresistance

infections and in the prevention and treatment of certain

infection complications [1].

In a wide variety of heterocyclic structures, the 1,3-

thiazolidin-4-one nucleus constitutes an important class

displaying a broad spectrum of biological activities [2]. It

was found that the 1,3-thiazolidin-4-one system, which is

a core structure in various synthetic pharmaceuticals, dis-

plays antibacterial [3–5], antifungal [6,7], antiviral [8–15],

antitumor [16], and anticonvulsant [17] properties.

The IR, H NMR, and ¹³C NMR spectra, and elemental

analyses were in full agreement with the proposed

structures of all the compounds (1a–1g, 2a–2g, 3a–3g,

4a–4g, 5a–5g, and 6a–6g).

The key intermediates N-substituted carboxylic acid

hydrazide derivatives (1a–1g, 2a–2g, and 3a–3g) were

synthesized by the fusion of three different carboxylic acid

hydrazides (1, 2, and 3) with appropriate aliphatic or

aromatic aldehydes in ethanol in the presence of glacial

acetic acid for 4h under reﬂux (Scheme 1).

The formation of the Schiff base hydrazone derivatives

(1a–1g, 2a–2g, and 3a–3g) was conﬁrmed by IR, ¹H NMR,

and ¹³C NMR spectra and elemental analyses. The IR spectra

of synthesized N-substituted carboxylic acid hydrazide deriv-

atives conﬁrmed the presence of C¼O and NH groups. The

¹H NMR spectra of the compounds (1a–1g, 2a–2g, and

3a–3g) showed two singlets at δ 7.82–9.03ppm and δ

9.50–11.91ppm corresponding to ¼CH and NH protons,

respectively, whereas in ¹³C NMR spectra, we observed sig-

nals for ¼CH group at δ 149.0–160.9 ppm and for the C¼O

group in the range of δ 172.7–177.4 ppm. All other aliphatic

and aromatic signals were displayed at expected regions.

In view of these facts and in continuation of our work de-

voted to search new antimicrobial compounds, we design, syn-

thesize, and evaluate for in vitro antimicrobial activity a new

series of 2,3-disubstituted-1,3-thiazolidin-4-one derivatives.

RESULTS AND DISCUSSION

Chemistry. The reaction sequences employed for the

synthesis of title compounds (4a–4g, 5a–5g, and 6a–6g)

394

Ł. Popiołek, J. Stefańska, M. Kiełczykowska, I. Musik, A. Biernasiuk, A. Malm, and M. Wujec

Vol 53

Scheme 1. Reactions leading to new 1,3-thiazolidin-4-one derivatives 4a-4g, 5a-5g, 6a-6g.

The cyclization reaction of N-substituted carboxylic

The spectra of neutral molecules and monoanion forms

acid hydrazide derivatives (1a–1g, 2a–2g, and 3a–3g)

with mercaptoacetic acid in the presence of 1,4-dioxane

afforded new 2,3-disubstituted-1,3-thiazolidin-4-one de-

rivatives 4a–4g, 5a–5g, and 6a–6g in good yield

(Scheme 1).

(Figure 1S. and Figure 2S. in the Supporting Information)

of the studied compounds generally were not affected by

the structure, which is consistent with the fact that in all

compounds, the same conjugated system of double bond

occurs.

All 2,3-disubstituted-1,3-thiazolidin-4-one derivatives

displayed (4a–4g, 5a–5g, and 6a–6g) IR, H NMR, and

On the basis of obtained pK values, we can also con-

clude that the increase of antimicrobial activity can be con-

nected with the increase of pK value. For example, the

tested linear cyclopropane (R₁) carboxylic acid hydrazide

derivatives (1e and 1g) had the lowest pK values and had

no antimicrobial activity compared with the linear cyclo-

hexane (R₁) carboxylic acid hydrazide derivatives that

showed some antimicrobial activity (3e and 3g). On the

other hand, the activity of N-substituted cyclopentane

(R₁) carboxylic acid hydrazide derivatives strongly de-

pends on the nature of substituent R₂in the structure of

compound (2e and 2g).

Microbiology. The results of our study indicated that

all the newly synthesized compounds had no inhibitory

effect on the growth of reference strains of Gram-

negative bacteria. According to the data presented in

Tables 1 and 2, the compounds 1a–1g, 2a, 2b, 3b, 3d,

3g, 4b, 5b, 5c, 5e, and 6d had no inﬂuence also on

the growth of Gram-positive bacteria. On the basis of

minimal inhibitory concentration (MIC) values obtained

by the broth microdilution method, it was shown that

among the examined compounds, the widest spectrum

of antibacterial activity possessed 2c, 2g, 3c, and 6e.

These compounds were found to be active against

Gram-positive bacteria, both pathogenic staphylococci,

that is, Staphylococcus aureus ATCC 25923 with

MIC = 64–500 μg/mL and S. aureus ATCC 6538 with

MIC = 128–500μg/mL, and opportunistic bacteria, such as

Staphylococcus epidermidis ATCC 12228, Micrococcus

¹³C NMR spectra and elemental analyses consistent with

the assigned structures. The IR spectra of synthesized

2,3-disubstituted-1,3-thiazolidin-4-one derivatives con-

ﬁrmed the presence of C¼O and NH groups. The ¹H

NMR spectra showed three signals corresponding to the

following: CH group in the range of δ 4.41–9.02 ppm,

CH₂group at δ 2.58–3.81ppm, and NH group at δ 8.59–

12.01 ppm. In the ¹³C NMR spectra, we observed charac-

teristic signals for CH₂group at about 30 ppm, for CH

group at about 70 ppm, and for two C¼O groups at δ

168ppm and δ 174ppm, respectively. All other aliphatic

and aromatic signals were observed at expected regions.

Dissociation constants.

The studied acid–base

equilibrium is connected with the dissociation of NH

group from hydrazide part. As the phenyl group forms

the conjugated system with the CH¼N bond, the

substituents occurring in this ring should exert the

inﬂuence on pK value. The obtained results (Table 1S. in

the Supporting Information) conﬁrm this suggestion that

electronegative bromine in position 4 causes distinct

increase in pK value when compared with the respective

compound containing methyl. Cycloalkane group does

not show so considerable effect although the bromine

inﬂuence decreases in the following series:

cyclopropane derivatives < cyclopentane derivatives

< cyclohexane derivatives:

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

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Synthesis, Dissociation Constants, and Antimicrobial Activity of Novel 2,

3-Disubstituted-1,3-thiazolidin-4-one Derivatives

395

Table 1

The activity data expressed as MIC [μg/mL] for tested N-substituted carboxylic acid hydrazide derivatives (2c, 2d, 2e, 2f, 2g, 3c, 3f, 3g) against the

reference strains of bacteria and fungi.

Compound number/species

CIP/FLU*

Staphylococcus aureus ATCC 25923

S. aureus ATCC 6538

S. aureus NCTC 4163

256

128

256

128

256

128

1000

250

1000

500

1000

250

1000

500

1000

500

1000

0.488

0.244

0.25

250

S. aureus ATCC 29213

0.5

Staphylococcus epidermidis ATCC 12228

S. epidermidis ATCC 35984

Bacillus subtilis ATCC 6633

Bacillus cereus ATCC 10876

B. cereus ATCC 11778

Micrococcus luteus ATCC 10240

M. luteus ATCC 9341

Candida albicans ATCC 2091

C. albicans ATCC 10231

0.122

0.125

0.031

0.061

1.000

0.976

2.000

0.244

0.976

1.953

1000

500

1000

Candida parapsilosis ATCC 22019

-, no activity; nt, not tested.

Table 2

The activity data expressed as MIC [μg/mL] for tested 2,3-disubstituted-1,3-thiazolidin-4-one derivatives (4g, 5c, 5d, 5g, 6b, 6c, 6e, 6g) against the

reference strains of bacteria and fungi.

Compound number/species

1000

CIP/FLU*

Staphylococcus aureus ATCC 25923

S. aureus ATCC 6538

S. aureus NCTC 4163

500

1000

250

1000

0.488

0.244

0.25

S. aureus ATCC 29213

0.5

Staphylococcus epidermidis ATCC 12228

S. epidermidis ATCC 35984

Bacillus subtilis ATCC 6633

Bacillus cereus ATCC 10876

B. cereus ATCC 11778

Micrococcus luteus ATCC 10240

M. luteus ATCC 9341

Candida albicans ATCC 2091

C. albicans ATCC 10231

0.122

0.125

0.031

0.061

1.000

0.976

2.000

0.244

0.976

1.953

1000

Candida parapsilosis ATCC 22019

500

The standard antibiotics used as positive controls: ciproﬂoxacin (CIP) for bacteria and ﬂuconazole (FLU) for fungi. -, no activity; nt, not tested.

luteus ATCC 10240, M. luteus ATCC 9341, Bacillus

subtilis ATCC 6633, and Bacillus cereus ATCC 11778

with MIC = 32–1000μg/mL. Moreover, the highest good

bioactivity against S. epidermidis ATCC 12228 and M.

luteus ATCC 9341 with MIC = 32 μg/mL showed 3c and

6e. Compounds 3c and 6e also showed good activity

against M. luteus ATCC 10240 and B. cereus with

MIC =32–64 μg/mL. The remaining compounds exhibited

some bacteriostatic activity or no activity to reference

strains of Gram-positive bacteria. The minimal

bactericidal concentration (MBC) of these compounds

was >1000μg/mL.

concentration of 3c, 3e, 3f, 3g, 5g, and 6e, which inhibited

the growth of some of these yeasts, was 1000 μg/mL. The

minimal fungicidal concentration (MFC) for tested com-

pounds was >1000μg/mL. Most of the examined com-

pounds had no inhibitory effect on the growth of

reference yeasts belonging to Candida spp.

In general, both linear and cyclic cyclopropane (R₁) car-

boxylic acid derivatives (1a–1g and 4a–4f) did not show

any antimicrobial activity irrespective of the nature of sub-

stituent R₂presented in the structure of tested compounds.

Linear cyclopentane (R₁) carboxylic acid hydrazide deriv-

atives had higher activity than their corresponding cyclic

1,3-thiazolidin-4-one derivatives (5a–5g). The inﬂuence

of the substituent R₂is especially signiﬁcant in the case

of compound 2c, which had 2–OH–Ph group and showed

the best activity among all linear cyclopentane derivatives

It was showed also that some of the tested compounds,

especially 2e, 2g, 4g, 5c, and 6g, showed fungistatic

activity with MIC = 250–500μg/mL against all or some

of Candida spp. ATCC strains. Moreover, the minimum

Journal of Heterocyclic Chemistry

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Vol 53

(CH₂-cyclopropyl), 1410 (C–N). ¹H NMR (DMSO-d₆): δ

(ppm) = 0.77–0.84 (m, 2H, CH₂-cyclopropyl), 1.09–1.14 (m, 2H,

CH₂-cyclopropyl), 1.39 (d, 6H, 2xCH₂), 1.89–1.94 (m, 1H, CH-

cyclopropyl), 2.26–2.29 (m, 1H, CH), 7.88 (s, 1H,¼CH), 10.04

(s, 1H, NH). ¹³C NMR: δ (ppm) = 10.7 (2xCH₂-cyclopropyl),

15.9 (CH-cyclopropyl), 18.2 (2xCH₃), 29.7 (CH), 150.9 (¼CH),

173.8 (C¼O). Anal. Calcd for C₈H₁₄N₂O (154.21): C, 62.31; H,

9.15; N, 18.17; Found: C, 62.51; H, 9.11; N, 18.09%.

(2a–2g). In the midst of linear cyclohexane (R₁) carboxylic

acid derivatives (3a–3g), the best activity showed the

compound (3c) with 2–OH–Ph substituent as R₂, whereas

among cyclic 1,3-thiazolidin-4-one derivatives (6a–6g),

the most signiﬁcant activity was connected with the

4–CH₃–Ph substituent in the compound (6e).

In conclusion, our results indicate that some of the

obtained compounds showed mild or moderate activity

with bacteriostatic or fungistatic effect against Gram-

positive bacteria or yeasts belonging to Candida spp.

N-(Phenylmethylidene)cyclopropanecarbohydrazide (1b).

CAS Registry Number: 91350-09-3. Yield: 1.65 g (87.5%), mp.

140–142°C (dec.). IR (KBr), ν (cm^ꢀ1): 3055 (CH aromatic),

3030, 1460 (CH aliphatic), 1715 (C¼O), 1590 (C¼N), 1596

(N–H), 1442 (CH₂–cyclopropyl), 1396 (C–N). ¹H NMR

(DMSO-d₆): δ (ppm) = 1.24–1.47 (m, 2H, CH₂-cyclopropyl),

1.67–1.77 (m, 2H, CH₂-cyclopropyl), 2.17–2.25 (m, 1H, CH-

cyclopropyl), 7.41–7.69 (m, 4H, Ar–H), 8.18 (s, 1H,¼CH),

EXPERIMENTAL

Chemistry. General.

All reagents were purchased from

Sigma-Aldrich (Munich, Germany) and Merck Co. (Darmstadt,

Germany) and used without further puriﬁcation. Melting points

were determined in Fisher-Johns blocks (Fisher Scientiﬁc,

Schwerte, Germany) and presented without any corrections.

The IR spectra (ν, cm^ꢀ1) were recorded in KBr tablets

using a Specord IR-75 spectrophotometer (VEB Carl Zeiss,

Jena, Germany). The ¹H NMR spectra were recorded on a

Bruker Avance 300 apparatus (Bruker BioSpin GmbH,

Rheinstetten/Karlsruhe, Germany) in DMSO-d₆with TMS

as internal standard. The ¹³C NMR spectra were recorded on a

Bruker Avance 300 apparatus. Chemical shifts are given in

ppm (δ-scale). The purity of obtained compounds was checked

by TLC on aluminium oxide 60 F254 plates (Merck Co.

Whitehouse Station, NJ), in a CHCl₃/C₂H₅OH (10:1, v/v)

solvent system. The spots were detected by exposure to a UV

lamp at 254 nm. Elemental analyses of the obtained compounds

were performed for C, H, and N on AMZ 851 CHX analyser

(PG, Gdańsk, Poland). The maximum percentage differences

between the calculated and found values for each element were

within the error and amounted to 0.4%.

11.32 (s, 1H, NH). ¹³C NMR:

δ (ppm) = 10.7 (2xCH₂-

cyclopropyl), 15.9 (CH-cyclopropyl), 127.0, 128.7, 129.1, 134.7

(6C_ar), 149.4 (¼CH), 172.7 (C¼O). Anal. Calcd for C₁₁H₁₂N₂O

(188.22): C, 70.19; H, 6.43; N, 14.88; Found: C, 70.23; H,

6.45; N, 14.93%.

N-[(2-Hydroxyphenyl)methylidene]cyclopropanecarbohydrazide

(1c).

CAS Registry Number: 444049-35-8. Yield: 1.39 g

(68.1%), mp. 176–178°C (dec.). IR (KBr), ν (cm^ꢀ1): 3055

(CH aromatic), 3030, 1460 (CH aliphatic), 1715 (C¼O),

1590 (C¼N), 1596 (N–H), 1442 (CH₂–cyclopropyl), 1396

(C–N). ¹H NMR (DMSO-d₆): δ (ppm) = 0.79–0.89 (m, 2H,

CH₂–cyclopropyl), 1.62–1.70 (m, 2H, CH₂–cyclopropyl),

2.54–2.63 (m,1H, CH–cyclopropyl), 6.84–773 (m, 4H, Ar–H),

8.37 (s, 1H,¼CH), 9.03 (s, 1H, OH), 11.90 (s, 1H, NH). ¹³C

NMR:

δ (ppm) = 10.8 (2xCH₂–cyclopropyl), 15.9 (CH–

cyclopropyl), 117.4, 120.4, 121.2, 128.5, 129.7 (5C_ar), 152.1

(¼CH), 158.3 (C_ar), 173.7 (C¼O). Anal. Calcd for

C₁₁H₁₂N₂O₂(204.22): C, 64.69; H, 5.92; N, 13.72; Found: C,

64.68; H, 5.95; N, 13.70%.

N-[(3-Nitrophenyl)methylidene]cyclopropanecarbohydrazide

Synthesis of carboxylic acid hydrazide (1, 2, 3). To the

solution of appropriate ethyl ester of carboxylic acid (10 mmol)

in ethanol (15 mL), an equimolar of 100% hydrazine hydrate

was added. The solution was heated under reﬂux for 3 h. After

that, the solution was cooled to room temperature. The obtained

precipitate was ﬁltered and crystallized from ethanol.

(1d).

CAS Registry Number: 35559-15-0. Yield: 2.26 g

(97.1%), mp. 196–198°C (dec.). IR (KBr), ν (cm^ꢀ1): 3032 (CH

aromatic), 3011, 1448 (CH aliphatic), 1702 (C¼O), 1611

(C¼N), 1600 (N–H), 1442 (CH₂–cyclopropyl), 1410 (C–N). H

NMR (DMSO-d₆):

δ (ppm) = 0.82–0.96 (m, 2H, CH₂–

cyclopropyl), 1.65–1.72 (m, 2H, CH₂–cyclopropyl), 2.65–2.73

(m, 1H, CH–cyclopropyl), 7.72–8.52 (m, 4H, Ar–H), 8.93 (s,

1H,¼CH), 11.91 (s, 1H, NH). ¹³C NMR: δ (ppm) = 7.7, 8.6

(2xCH₂–cyclopropyl), 10.2 (CH–cyclopropyl), 121.4, 124.3,

130.9, 133.3, 134.9, 141.1 (6C_ar), 143.4 (¼CH), 175.3 (C¼O).

Anal. Calcd for C₁₁H₁₁N₃O₃(233.22): C, 56.65; H, 4.75; N,

18.02; Found: C, 56.68; H, 4.78; N, 18.06%.

Cyclopropane carboxylic acid hydrazide (1). CAS Registry

Number: 6952-93-8. Yield: 78.4%, mp. 98–99°C (dec.).

Cyclopentane carboxylic acid hydrazide (2). CAS Registry

Number: 3400-07-5. Yield: 94.2%, mp. 108–109°C (dec.).

Cyclohexane carboxylic acid hydrazide (3). CAS Registry

Number: 38941-47-8. Yield: 90.1%, mp. 158–159°C (dec.).

Synthesis of N-substituted carboxylic acid hydrazide

derivatives (1a–1g, 2a–2g, 3a–3g), General method. To a

suspension of hydrazides (1–3) (10 mmol) in ethanol (20 mL),

an equimolar amount of various aliphatic or aromatic aldehydes

(10 mmol) was added. The suspension was heated until clear

solution was obtained. Then few drops of glacial acetic acid

were added as a catalyst. The solution was reﬂuxed for 4 h.

After the completion of the reaction, the solution was cooled to

room temperature. The obtained precipitate was ﬁltered and

crystallized from ethanol.

N-[(4-Methylphenyl)methylidene]cyclopropanecarbohydrazide

(1e).

CAS Registry Number: 443975-38-0. Yield: 1.42 g

(70.2%), mp. 146–148°C (dec.). IR (KBr), ν (cm^ꢀ1): 3011 (CH

aromatic), 2990, 1450 (CH aliphatic), 1710 (C¼O), 1615

(C¼N), 1605 (N–H), 1442 (CH₂–cyclopropyl), 1396 (C–N). H

NMR (DMSO-d₆):

δ (ppm) = 0.78–0.88 (m, 2H, CH₂–

cyclopropyl), 1.60–1.68 (m, 2H, CH₂–cyclopropyl), 2.34 (s, 3H,

CH₃), 2.63–2.71 (m, 1H, CH–cyclopropyl), 7.24–7.26 (dd, 2H,

J = 6Hz, Ar–H), 7.57–7.59 (dd, 2H, J = 6Hz, Ar–H), 8.14 (s,

1H,¼CH), 11.58 (s, 1H, NH). ¹³C NMR: δ (ppm) = 10.8

(2xCH₂–cyclopropyl); 15.9 (CH–cyclopropyl), 21.1 (CH₃),

127.3, 129.1, 131.9, 138.5 (6C_ar), 149.0 (¼CH), 173.8 (C¼O).

Anal. Calcd for C₁₂H₁₄N₂O (202.25): C, 71.26; H, 6.98; N,

13.85; Found: C, 72.33; H, 6.97; N, 13.81%.

N-(2-Methylpropylidene)cyclopropanecarbohydrazide (1a).

CAS Registry Number: 545346-60-9. Yield: 1.38 g (98.9%),

mp. 90–92°C (dec.). IR (KBr), ν (cm^ꢀ1): 3020, 1448 (CH

aliphatic), 1710 (C¼O), 1580 (C¼N), 1590 (N–H), 1442

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N-[(4-Methoxyphenyl)methylidene]cyclopropanecarbohydrazide

128.5, 129.7 (5C_ar), 152.1 (¼CH), 158.3 (C_ar), 176.2 (C¼O).

Anal. Calcd for C₁₃H₁₆N₂O₂(232.28): C, 67.22; H, 6.94; N,

12.06; Found: C, 67.25; H, 6.96; N, 12.10%.

(1f).

CAS Registry Number: 468102-53-6. Yield: 1.91 g

(87.7%), mp. 176–178°C (dec.). IR (KBr), ν (cm^ꢀ1): 3089

(CH aromatic), 3050, 1442 (CH aliphatic), 1714 (C¼O), 1622

(C¼N), 1590 (N–H), 1442 (CH₂–cyclopropyl), 1402 (C–N).

¹H NMR (DMSO-d₆): δ (ppm) = 0.77–0.87 (m, 2H, CH₂–

cyclopropyl), 1.59–1.67 (m, 2H, CH₂–cyclopropyl), 2.62–2.70

(m, 1H, CH–cyclopropyl), 3.80 (s, 3H, CH₃), 6.98–7.02 (m,

4H, Ar–H), 8.13 (s, 1H,¼CH), 11.51 (s, 1H, NH). ¹³C NMR:

N-[(3-Nitrophenyl)methylidene]cyclopentanecarbohydrazide

(2d). Yield: 2.57 g (98.4%), mp. 171–173°C (dec.). IR (KBr), ν

(cm^ꢀ1): 3040 (CH aromatic), 3035, 1441 (CH aliphatic), 1710

(C¼O), 1633 (C¼N), 1615 (N–H), 1455 (CH₂–cyclopentyl),

1404 (C–N). ¹H NMR (DMSO-d₆): δ (ppm) = 1.54–1.90 (m,

8H, CH₂–cyclopentyl), 2.64–2.74 (m, 1H, CH–cyclopentyl),

7.70–8.52 (m, 4H, Ar–H), 8.31 (s, 1H,¼CH), 11.63 (s, 1H,

NH). ¹³C NMR: δ (ppm) = 26.2, 26.3, 29.8, 30.4 (4xCH₂–

cyclopentyl), 43.6 (CH–cyclopentyl), 121.3, 124.3, 130.9,

133.1, 140.5, 143.8 (6C_ar), 148.7 (¼CH), 172.3 (C¼O). Anal.

Calcd for C₁₃H₁₅N₃O₃(261.28): C, 59.76; H, 5.79; N, 16.08;

Found: C, 59.77; H, 5.80; N, 16.12%.

(ppm) = 7.9, 8.2 (2xCH₂–cyclopropyl), 10.2 (CH–

cyclopropyl), 55.8 (–CH₃), 114.8, 127.4, 128.7, 128.9, 143.2,

145.7 (6C_ar), 160.9 (¼CH), 174.8 (C¼O). Anal. Calcd for

C₁₂H₁₄N₂O₂(218.25): C, 66.04; H, 6.47; N, 12.84; Found: C,

66.10; H, 6.44; N, 12.79%.

N-[(4-Bromophenyl)methylidene]cyclopropanecarbohydrazide

(1g).

CAS Registry Number: 468102-56-9. Yield: 2.14 g

N-[(4-Methylphenyl)methylidene]cyclopentanecarbohydrazide

(2e). Yield: 1.09g (47.2%), mp. 152–154°C (dec.). IR (KBr), ν

(cm^ꢀ1): 3035 (CH aromatic), 2996, 1459 (CH aliphatic), 1715

(C¼O), 1612 (C¼N), 1604 (N–H), 1455 (CH₂–cyclopentyl),

(80.2%), mp. 166–168°C (dec.). IR (KBr), ν (cm^ꢀ1): 3070

(CH aromatic), 3025, 1458 (CH aliphatic), 1718 (C¼O), 1611

(C¼N), 1605 (N–H), 1442 (CH₂–cyclopropyl), 1408 (C–N).

¹H NMR (DMSO-d₆): δ (ppm) = 0.80–0.89 (m, 2H, CH₂–

cyclopropyl), 1.61–1.70 (m, 2H, CH₂–cyclopropyl), 2.63–2.71

(m, 1H, CH–cyclopropyl), 7.61–8.16 (m, 4H, Ar–H), 8.72 (s,

1H,¼CH), 11.72 (s, 1H, NH). ¹³C NMR: δ (ppm) = 10.8

(2xCH₂–cyclopropyl), 15.9 (CH–cyclopropyl), 123.9, 129.3,

132.3, 132.5 (6C_ar), 149.0 (¼CH), 173.8 (C¼O). Anal. Calcd

for C₁₁H₁₁BrN₂O (267.12): C, 49.46; H, 4.15; N, 10.49;

Found: C, 49.49; H, 4.17; N, 10.51%.

1395 (C–N). H NMR (DMSO-d₆): δ (ppm) = 1.55–1.88 (m, 8H,

CH₂cyclopentyl), 2.34 (s, 3H, CH₃), 2.61–2.66 (m, 1H, CH–

cyclopentyl), 7.23–7.58 (m, 4H, Ar–H), 8.15 (s, 1H,¼CH), 11.29

(s, 1H, NH). ¹³C NMR: δ (ppm) = 21.1 (CH₃), 26.1, 32.9

(4xCH₂–cyclopentyl), 46.3 (CH–cyclopentyl), 127.3, 129.1,

131.9, 138.5 (6C_ar), 149.5 (¼CH), 176.2 (C¼O). Anal. Calcd for

C₁₄H₁₈N₂O (230.30): C, 73.01; H, 7.88; N, 12.16; Found: C,

73.06; H, 7.82; N, 12.14%.

N-(2-Methylpropylidene)cyclopentanecarbohydrazide (2a).

Yield: 1.54 g (84.5%), mp. 102–104°C (dec.).IR (KBr), ν (cm^ꢀ1):

2990, 1451 (CH aliphatic), 1703 (C¼O), 1618 (C¼N), 1598

(N–H), 1455 (CH₂–cyclopentyl), 1396 (C–N). ¹H NMR

(DMSO-d₆): δ (ppm) = 1.32 (s, 6H, 2xCH₃), 1.57–1.59 (m, 4H,

2xCH₂–cyclopentyl), 1.64–1.66 (m, 4H, 2xCH₂–cyclopentyl),

2.22–2.25 (m, 1H, CH), 2.55–2.59 (m, 1H, CH–cyclopentyl),

7.86 (s, 1H,¼CH), 10.07 (s, 1H, NH). ¹³C NMR: δ (ppm) = 18.2

(2xCH₃), 26.1 (2xCH₂–cyclopentyl), 29.7 (CH), 32.9 (2xCH₂–

cyclopentyl), 32.9 (2xCH₂–cyclopentyl), 46.7 (CH–cyclopentyl),

150.9 (¼CH), 176.2 (C¼O). Anal. Calcd for C₁₀H₁₈N₂O

(182.26): C, 65.90; H, 9.95; N, 15.37; Found: C, 65.92; H, 9.91;

N, 15.39%.

N-[(4-Methoxyphenyl)methylidene]cyclopentanecarbohydrazide

(2f).

CAS Registry Number: 1030511-26-2. Yield: 0.83 g

(33.9%), mp. 134–136°C (dec.). IR (KBr), ν (cm^ꢀ1): 3046

(CH aromatic), 3025, 1442 (CH aliphatic), 1708 (C = O), 1610

(C = N), 1600 (N–H), 1455 (CH₂-cyclopentyl), 1412 (C–N).

¹H NMR (DMSO-d₆): δ (ppm) = 1.56–1.83 (m, 8H, CH₂-

cyclopentyl), 2.58–2.68 (m, 1H, CH-cyclopentyl), 6.97–7.63

(m, 4H, Ar–H), 8.13 (s, 1H, ¼CH), 11.22 (s, 1H, NH). ¹³C

NMR: δ (ppm) = 26.2, 26.3, 29.8, 30.5 (4xCH₂-cyclopentyl),

43.6 (CH-cyclopentyl), 55.7 (CH₃), 114.7, 127.5, 127.5, 128.6,

128.9, 160.9 (6C_ar), 146.9 (¼CH), 177.4 (C¼O). Anal. Calcd

for C₁₄H₁₈N₂O₂(246.30): C, 68.27; H, 7.37; N, 11.37; Found:

C, 68.33; H, 7.36; N, 11.41%.

N-(Phenylmethylidene)cyclopentanecarbohydrazide (2b).

CAS Registry Number: 5547-59-1. Yield: 2.12 g (98.1%), mp.

158–160°C (dec.). IR (KBr), ν (cm^ꢀ1): 2990, 1451 (CH

aliphatic), 1703 (C¼O), 1618 (C¼N), 1598 (N–H), 1455 (CH₂–

cyclopentyl), 1396 (C–N). ¹H NMR (DMSO-d₆): δ (ppm)

= 1.55–1.88 (m, 8H, CH₂–cyclopentyl), 2.60–2.70 (m, 1H, CH–

cyclopentyl), 7.42–7.70 (m, 5H, Ar–H), 8.19 (s, 1H,¼CH),

11.35 (s, 1H, NH). ¹³C NMR: δ (ppm) = 26.1, 32.9 (4xCH₂–

cyclopentyl), 46.3 (CH–cyclopentyl), 127.0, 128.7, 129.1, 134.7

(6C_ar), 149.0 (¼CH), 176.2 (C¼O). Anal. Calcd for C₁₃H₁₆N₂O

(216.28): C, 72.19; H, 7.46; N, 12.95; Found: C, 72.23; H,

7.48; N, 12.98%.

N-[(4-Bromophenyl)methylidene]cyclopentanecarbohydrazide

(2g). Yield: 2.92 g (98.9%), mp. 180–182°C (dec.). IR (KBr),

ν (cm^ꢀ1): 3050 (CH aromatic), 3015, 1454 (CH aliphatic), 1710

(C¼O), 1622 (C¼N), 1590 (N–H), 1455 (CH₂-cyclopentyl),

1415 (C–N). ¹H NMR (DMSO-d₆): δ (ppm) = 1.55–1.88 (m,

8H, CH₂-cyclopentyl), 2.60–2.74 (m, 1H, CH-cyclopentyl),

7.59–7.86 (m, 4H, Ar–H), 8.16 (s, 1H, ¼CH), 11.43 (s, 1H,

NH). ¹³C NMR: δ (ppm) = 26.1, 32.9 (4xCH₂-cyclopentyl),

46.32 (CH-cyclopentyl), 123.9, 129.3, 132.4, 132.5 (6C_ar),

149.0 (¼CH), 176.2 (C¼O). Anal. Calcd for C₁₃H₁₅BrN₂O

(295.17): C, 52.90; H, 5.12; N, 9.49; S, Found: C, 52.93; H,

5.15; N, 9.47%.

N-[(2-Hydroxyphenyl)methylidene]cyclopentanecarbohydrazide

N-(2-Methylpropylidene)cyclohexanecarbohydrazide (3a).

CAS Registry Number: 541518-82-5. Yield: 0.63 g (32.2%),

mp. 116–118°C (dec.). IR (KBr), ν (cm^ꢀ1): 3010, 1460 (CH

aliphatic), 1698 (C¼O), 1624 (C¼N), 1595 (N–H), 1452 (CH₂-

(2c).

CAS Registry Number: 1030556-24-1. Yield: 0.79 g

(34.1%), mp. 204–206°C (dec.). IR (KBr), ν (cm^–1): 3055 (CH

aromatic), 3011, 1459 (CH aliphatic), 1701 (C¼O), 1614 (C¼N),

1595 (N–H), 1455 (CH₂–cyclopentyl), 1410 (C–N). ¹H NMR

(DMSO-d₆): δ (ppm) = 1.05–1.23 (m, 6H, CH₂–cyclopentyl),

1.67–1.71 (m, 2H, CH₂–cyclopentyl), 2.09–2.11(m 1H, CH–

cyclopentyl), 6.91–7.72 (m, 4H, Ar–H), 8.37 (s, 1H,¼CH), 9.02

(s,1H, OH), 11. 16 (s, 1H, OH). ¹³C NMR: δ (ppm) = 26.1, 32.9

(4xCH₂–cyclopentyl), 46.3 (CH–cyclopentyl), 117.4, 120.4, 121.2,

cyclohexyl), 1410 (C–N). H NMR (DMSO-d₆): δ (ppm) = 1.33

(s, 6H, 2xCH₃), 1.58–1.60 (m, 8H, CH₂-cyclohexyl), 2.05–2.07

(m, 2H, CH₂-cyclohexyl), 2.23–2.26 (m, 1H, CH), 2.44–2.47

(m, 1H, CH-cyclohexyl), 7.82 (s, 1H, ¼CH), 10.08 (s, 1H,

NH). ¹³C NMR: δ (ppm) = 18.2 (2xCH₃), 25.1, 27.9 (5xCH₂-

cyclohexyl), 29.7 (CH), 41.8 (CH-cyclohexyl), 150.9 (¼CH),

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

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Ł. Popiołek, J. Stefańska, M. Kiełczykowska, I. Musik, A. Biernasiuk, A. Malm, and M. Wujec

Vol 53

174.7 (C¼O). Anal. Calcd for C₁₁H₂₀N₂O (196.29): C, 67.31; H,

10.27; N, 14.27; Found: C, 67.35; H, 10.22; N, 14.30%.

N-(Phenylmethylidene)cyclohexanecarbohydrazide (3b).

CAS Registry Number: 340295-32-1. Yield: 1.54 g (67.1%),

CH₃), 6.99–7.93 (m, 4H, Ar–H), 8.65 (s, 1H, ¼CH), 11.18 (s,

1H, NH). ¹³C NMR: δ (ppm) = 25.1, 25.9, 27.9 (5xCH₂-

cyclohexyl), 41.8 (CH-cyclohexyl), 56.0 (CH₃), 114.3, 127.0,

129.1 (5C_ar), 149.0 (¼CH), 160.1 (C_ar), 174.7 (C¼O). Anal.

Calcd for C₁₅H₂₀N₂O₂(260.33): C, 69.20; H, 7.74; N, 10.76;

Found: C, 69.23; H, 7.78; N, 10.80%.

mp. 152–153°C (dec.). IR (KBr),

(cm^ꢀ1): 3070 (CH

aromatic), 3024, 1451 (CH aliphatic), 1701 (C¼O), 1612

(C¼N), 1602 (N–H), 1452(CH₂-cyclohexyl), 1390 (C–N). ¹H

N-[(4-Bromophenyl)methylidene]cyclohexanecarbohydrazide

NMR (DMSO-d₆):

(ppm) = 1.53–1.56 (m, 6H, 3xCH₂-

(3g).

CAS Registry Number: 468102-70-7. Yield: 2.36 g

cyclohexyl), 1.66–1.68 (m, 2H, CH₂-cyclohexyl), 1.83–1.85 (m,

2H, CH₂-cyclohexyl), 2.61–2.65 (m, 1H, CH-cyclohexyl), 7.33–

7.36 (m, 3H, ArH), 7.55–7.58 (m, 2H, ArH) 8.40 (s, 1H, ¼CH),

9.50 (s, 1H, NH). ¹³C NMR: δ (ppm) = 25.1, 25.9, 27.9

(5xCH₂-cyclohexyl), 41.8 (CH-cyclohexyl), 127.0, 128.7, 129.1,

134.7 (6C_ar), 149.0 (¼CH), 176.7 (C¼O). Anal. Calcd for

C₁₄H₁₈N₂O (230.30): C, 73.01; H, 7.88; N, 12.16; Found: C,

73.08; H, 7.81; N, 12.18%.

(76.3%), mp. 181–183°C (dec.). IR (KBr), ν (cm^ꢀ1): 3032 (CH

aromatic), 3008, 1454 (CH aliphatic), 1690 (C¼O), 1632 C¼N),

1598 (N–H), 1452 (CH₂-cyclohexyl), 1398 (C–N). ¹H NMR

(DMSO-d₆): δ (ppm) = 1.24–1.77 (m, 10H, CH₂-cyclohexyl),

2.17–2.25 (m, 1H, CH-cyclohexyl), 7.58–7.86 (m, 4H, Ar–H),

8.73 (s, 1H, CH), 11.40 (s, 1H, NH). ¹³C NMR: δ (ppm) = 25.8,

25.8, 26.1, 28.9, 29.5 (5xCH₂-cyclohexyl), 43.4 (CH-

cyclohexyl), 128.9, 129.2, 132.3, 134.2 (6C_ar), 149.1 (¼CH),

174.7 (C¼O). Anal. Calcd for C₁₄H₁₇BrN₂O (309.20): C, 54.38;

H, 5.54; N, 9.06; Found: C, 54.34; H, 5.58; N, 9.10%.

Preparation of 2,3-disubstituted-1,3-thiazolidin-4-one

derivatives (4a–4g, 5a–5g, and 6a–6g). General method.

To a solution of corresponding N-substituted carboxylic acid

hydrazide derivatives 1a–1g, 2a–2g, and 3a–3g (10 mmol) in

15 mL of 1,4-dioxane, mercaptoacetic acid (0.92 g, 10 mmol)

was added dropwise. The mixture was stirred under reﬂux for

6 h at room temperature. Then the solvent was removed under

reduced pressure; after that, 15 mL of 10% water solution of

sodium bicarbonate was added. The precipitate was ﬁltered and

puriﬁed by recrystallization from ethanol.

N-[(2-Hydroxyphenyl)methylidene]cyclohexanecarbohydrazide

(3c).

CAS Registry Number: 468102-83-2. Yield: 0.85 g

(34.5%), mp. 148–150°C (dec.). IR (KBr), ν (cm^ꢀ1): 3061 (CH

aromatic), 3045, 1440 (CH aliphatic), 1710 (C¼O), 1618

(C¼N), 1605 (N–H), 1452 (CH₂-cyclohexyl), 1400 (C–N). ¹H

NMR (DMSO-d₆):

δ (ppm) = 1.04–1.78 (m, 10H, CH₂-

cyclohexyl), 2.19–2.26 (m, 1H, CH-cyclohexyl), 6.88–7.73

(m,4H, Ar–H), 8.26 (s, 1H, ¼CH), 9.03 (s, 1H, OH), 11.58 (s,

1H, NH). ¹³C NMR: δ (ppm) = 25.1, 25.9, 27.9 (5xCH₂-

cyclohexyl), 41.8 (CH-cyclohexyl), 117.4, 120.4, 121.2, 128.5,

129.7 (5C_ar), 152.1 (¼CH), 158.3 (C_ar), 174.7 (C¼O). Anal.

Calcd for C₁₄H₁₈N₂O₂(246.30): C, 68.27; H, 7.37; N, 11.37;

Found: C, 68.32; H, 7.41; N, 11.39%.

N-[4-Oxo-2-(propan-2-yl)-1,3-thiazolidin-3-yl]cyclopropane-

N-[(3-Nitrophenyl)methylidene]cyclohexanecarbohydrazide

carboxamide (4a).

Yield: 0.99 g (43.2%), mp. 103–104°C

(3d).

CAS Registry Number: 468102-66-1. Yield: 2.71 g

(dec.). IR (KBr), ν (cm^ꢀ1): 3070, 1452 (CH aliphatic), 1710

(C¼O), 1600 (N–H), 1442 (CH₂-cyclopropyl), 1411 (C–N),

(98.6%), mp. 164–166°C (dec.). IR (KBr), ν (cm^ꢀ1): 3043

(CH aromatic), 3022, 1456 (CH aliphatic), 1716 (C¼O), 1635

648 (C–S). H NMR (DMSO-d₆): δ (ppm) = 0.77–0.79 (m, 2H,

(C¼N), 1610 (N–H), 1452 (CH₂-cyclohexyl), 1391 (C–N). H

CH₂-cyclopropyl), 1.08 (s, 6H, 2xCH₃), 1.09–1.11 (m, 2H,

CH₂-cyclopropyl), 1.83–1.86 (m, 1H, CH-cyclopropyl), 2.48–

2.53 (m, 1H, CH), 3.28 (s, 2H, CH₂), 4.42 (d, 1H, CH), 8.87 (s,

1H, NH). ¹³C NMR: δ (ppm) = 10.7 (2xCH₂-cyclopropyl), 17.7

(CH-cyclopropyl), 20.4 (2xCH₃), 30.8 (CH₂), 32.3 (CH), 78.2

(CH), 168.8 (C¼O), 176.4 (C¼O). Anal. Calcd for

C₁₀H₁₆N₂O₂S (228.31): C, 52.61; H, 7.06; N, 12.27; Found: C,

52,65; H, 7.04; N, 12.29%.

N-(4-Oxo-2-phenyl-1,3-thiazolidin-3-yl)cyclopropanecarboxamide

(4b). Yield: 1.41 g (53.6%), mp. 128–130°C (dec.). IR (KBr),

ν (cm^ꢀ1): 3080 (CH aromatic), 3055, 1452 (CH aliphatic),

1715 (C¼O), 1595 (N–H), 1442 (CH₂-cyclopropyl), 1390

(C–N), 654 (C–S). ¹H NMR (DMSO-d₆): δ (ppm) = 0.76–0.78

(m, 2H, CH₂-cyclopropyl), 1.10–1.12 (m, 2H, CH₂-

cyclopropyl), 1.41 (m, 1H, CH-cyclopropyl), 3.40 (s, 2H,

CH₂), 6.16 (s, 1H, CH), 7.26–7.32 (m, 5H, ArH), 9.04 (s,

1H, NH); ¹³C NMR: δ (ppm) = 10.7 (2xCH₂-cyclopropyl),

18.3 (CH-cyclopropyl), 33.2 (CH₂), 67.6 (CH), 126.7, 127.7,

128.9, 140.4 (6C_ar), 168.8 (C¼O), 172.1 (C¼O). Anal. Calcd

for C₁₃H₁₄N₂O₂S (262.33): C, 59.52; H, 5.38; N, 10.68;

Found: C, 59.56; H, 5.34; N, 10.72%.

NMR (DMSO-d₆):

δ (ppm) = 1.17–1.78 (m, 10H, CH₂-

cyclohexyl), 2.21–2.29 (m, 1H, CH-cyclohexyl), 7.71–8.50

(m, 4H, Ar–H), 8.94 (s, 1H, ¼CH), 11.59 (s, 1H, NH). ¹³C

NMR: δ (ppm) = 25.1, 25.9, 17.9 (5xCH₂-cyclohexyl), 41.8

(CH-cyclohexyl), 122.3, 124.1, 129.9, 132.6, 137.8, 147.4

(6C_ar), 148.2 (¼CH); 174.7 (C¼O). Anal. Calcd for

C₁₄H₁₇N₃O₃(275.30): C, 61.08; H, 6.22; N, 15.26; Found: C,

61.11; H, 6.25; N, 15.22%.

N-[(4-Methylphenyl)methylidene]cyclohexanecarbohydrazide

(3e).

CAS Registry Number: 468102-75-2. Yield: 1.52 g

(62.2%), mp. 130–132°C (dec.). IR (KBr), ν (cm^ꢀ1): 3090 (CH

aromatic), 3047, 1451 (CH aliphatic), 1711 (C¼O), 1641

(C¼N), 1611 (N–H), 1452 (CH₂-cyclohexyl), 1405 (C–N). ¹H

NMR (DMSO-d₆):

δ (ppm) = 1.24–1.76 (m, 10H, CH₂-

cyclohexyl), 2.13–2.24 (m, 1H, CH-cyclohexyl), 2.34 (s, 3H,

CH₃), 7.24–7.80 (m, 4H, Ar–H), 8.68 (s, 1H, ¼CH), 11.25 (s,

1H, NH). ¹³C NMR: δ (ppm) = 21.5, 25.7, 25.9, 26.1, 28.7

(5xCH₂-cyclohexyl), 39.9 (CH-cyclohexyl), 43.3 (CH₃), 127.4,

129.9, 130.0, 132.2, 140.0, 141.8 (6C_ar), 146.3 (¼CH); 177.3

(C¼O). Anal. Calcd for C₁₅H₂₀N₂O (244.33): C, 73.74; H, 8.25;

N, 11.47; Found: C, 73.76; H, 8.22; N, 11.51%.

N-[2-(2-Hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]

N-[(4-Methoxyphenyl)methylidene]cyclohexanecarbohydrazide

cyclopropanecarboxamide (4c).

Yield: 0.63 g (22.5%), mp.

(3f).

CAS Registry Number: 444767-02-6. Yield: 1.05 g

186–188°C (dec.). IR (KBr), ν (cm^ꢀ1): 3065 (CH aromatic),

3059, 1452 (CH aliphatic), 1720 (C¼O), 1611 (N–H), 1442

(40.5%), mp. 137–139°C (dec.). IR (KBr), ν (cm^ꢀ1): 3085 (CH

aromatic), 3067, 1452 (CH aliphatic), 1709 (C¼O), 1644

(C¼N), 1618 (N–H), 1452 (CH₂-cyclohexyl), 1410 (C–N). ¹H

(CH₂-cyclopropyl), 1410 (C–N), 648 (C–S). H NMR (DMSO-

d₆): δ (ppm) = 0.79–0.89 (m, 4H, 2xCH₂-cyclopropyl), 1.62–

1.70 (CH-cyclopropyl), 2.58 (s, 2H, CH₂), 6.83–6.92 (m, 2H,

Ar–H), 7.25–7.31 (m, 1H, Ar–H), 7.50–7.71 (m, 1H, Ar–H),

NMR (DMSO-d₆):

δ (ppm) = 1.23–1.26 (m, 10H, CH₂-

cyclohexyl), 2.15–2.23 (m, 1H, CH-cyclohexyl), 3.80 (s, 3H,

Journal of Heterocyclic Chemistry

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Synthesis, Dissociation Constants, and Antimicrobial Activity of Novel 2,

3-Disubstituted-1,3-thiazolidin-4-one Derivatives

399

8.36 (s, 1H, CH), 9.02 (s, 1H, OH), 11.46 (s, 1H, NH), ¹³C NMR:

δ (ppm) = 10.8 (2xCH₂-cyclopropyl), 18.3 (CH-cyclopropyl),

33.3 (CH₂), 61.3 (CH), 117.7, 120.4, 122.4, 128.4, 128.9, 149.7

(6C_ar), 168.8 (C¼O), 172.3 (C¼O). Anal. Calcd for

C₁₃H₁₄N₂O₃S (278.33): C, 56.10; H, 5.07; N, 10.0; Found: C,

56.12; H, 5.06; N, 9.97%.

(ppm) = 1.06 (s, 6H, 2xCH₃), 1.63–1.67 (m, 6H, 2xCH₂-

cyclopentyl), 1.90–1.92 (m, 2H, CH₂-cyclopentyl), 2.48–2.52

(m, 1H, CH), 2.66–2.69 (m, 1H, CH-cyclopentyl), 3.29 (s, 2H,

CH₂), 4.42 (s, 1H, CH), 8.54 (s, 1H, NH); ¹³C NMR: δ (ppm)

= 20.4 (2xCH₃), 26.1, 26.2 (2xCH₂-cyclopenty), 30.8 (CH₂),

32.3 (CH), 33.3 (2xCH₂-cyclopentyl), 45.8 (CH-cyclopentyl),

78.2 (CH) 168.9 (C¼O), 176.4 (C¼O). Anal. Calcd for

C₁₂H₂₀N₂O₂S (256.36): C, 56.22; H, 7.86; N, 10.93; Found: C,

56.26; H, 7.88; N, 10.93%.

N-[2-(3-Nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]cyclopropa-

necarboxamide (4d). Yield: 2.03 g (66.1%), mp. 194–196°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3065 (CH aromatic), 3059, 1452

(CH aliphatic), 1720 (C¼O), 1611 (N–H), 1442 (CH₂-

N-(4-Oxo-2-phenyl-1,3-thiazolidin-3-yl)cyclopentanecarboxa-

mide (5b). Yield: 2.69 g (92.5%), mp. 124–126°C (dec.). IR

cyclopropyl), 1410 (C–N), 648 (C–S). H NMR (DMSO-d₆): δ

(ppm) = 0.67–0.95 (m, 4H, 2xCH₂-cyclopropyl), 1.68–1.76

(CH-cyclopropyl), 3.45 (s, 2H, CH₂), 5.99 (s, 1H, CH), 7.65–

8.52 (m, 4H, Ar–H), 12.01 (s, 1H, NH). ¹³C NMR: δ (ppm)

= 10.8 (2xCH₂-cyclopropyl), 18.3 (CH-cyclopropyl), 33.3

(CH₂), 67.9 (CH), 119.4, 128.4, 130.8, 143.0, 148.3 (6C_ar),

168.8 (C¼O), 172.3 (C¼O). Anal. Calcd for C₁₃H₁₃N₃O₄S

(307.32): C, 50.81; H, 4.26; N, 13.67; Found: C, 50.85; H,

4.25; N, 13.65%.

(KBr), ν

(cm^ꢀ1): 3091(CH aromatic), 3076, 1460 (CH

aliphatic), 1710 (C¼O), 1602 (N–H), 1455 (CH₂-cyclopentyl),

1402 (C–N), 620 (C–S). H NMR (DMSO-d₆): δ (ppm) = 1.57–

1.66 (m, 6H, 3xCH₂-cyclopentyl), 1.90–1.92 (m, 2H, CH₂-

cyclopentyl), 2.64–2.68 (m,1H, CH-cyclopentyl), 3.40 (s, 2H,

CH₂), 6.11 (s, 1H, CH), 7.25–7.32 (m, 5H, Ar–H), 8.71 (s, 1H,

NH); ¹³C NMR: δ (ppm) = 26.1, 32.9 (4xCH₂-cyclopentyl),

33.3 (CH₂), 46.2 (CH-cyclopentyl), 67.6 (CH), 126.6, 127.7,

128.9, 140.4 (6C_ar), 168.8 (C¼O), 172.3 (C¼O). Anal. Calcd

for C₁₅H₁₈N₂O₂S (290.38): C, 62.04; H, 6.25; N, 9.65; Found:

C, 62.07; H, 6.22; N, 9.62%.

N-[2-(4-Methylphenyl)-4-oxo-1,3-thiazolidin-3-yl]cyclopro-

panecarboxamide (4e). Yield: 2.02 g (73.2%), mp. 130–132°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3076 (CH aromatic), 3046, 1448 (CH

aliphatic), 1745 (C¼O), 1620 (N–H), 1442 (CH₂-cyclopropyl),

N-[2-(2-Hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]

1401 (C–N), 656 (C–S). H NMR (DMSO-d₆): δ (ppm) = 0.70–

cyclopentanecarboxamide (5c).

Yield: 3.01 g (98.2%), mp.

0.88 (m, 4H, 2xCH₂-cyclopropyl), 1.48–1.70 (m, 1H, CH-

cyclopropyl), 3.41 (s, 2H, CH₂), 5.68 (s, 1H, CH), 7.21–7.60

(m, 4H, ArH), 11.33 (s, 1H, NH). ¹³C NMR: δ (ppm) = 10.8

(2xCH₂-cyclopropyl), 18.3 (CH-cyclopropyl), 21.1 (CH₃), 33.3

(CH₂), 67.6 (CH), 125.7, 129.6, 137.5, 138.5 (6C_ar), 168.3

(C¼O), 172.3 (C¼O). Anal. Calcd for C₁₄H₁₆N₂O₂S (276.35):

C, 60.85; H, 5.84; N, 10.14; Found: C, 60.82; H, 5.81; N,

10.10%.

203–205°C (dec.). IR (KBr), ν (cm^ꢀ1): 3084 (CH aromatic),

3068, 1459 (CH aliphatic), 1732 (C¼O), 1610 (N–H), 1455

(CH₂-cyclopentyl), 1400 (C–N), 645 (C–S). H NMR (DMSO-

d₆): δ (ppm) = 1.57–1.89 (m, 8H, 4xCH₂-cyclopentyl), 2.62–

2.68 (m, 1H, CH-cyclopentyl), 3.39 (s, 2H, CH₂), 6.51 (s, 1H,

OH), 6.91–7.06 (m, 2H, Ar–H), 7.36–7.39 (m, 1H, Ar–H),

7.69–7.73 (m, 1H, Ar–H), 9.02 (s, 1H, CH), 11.27 (s, 1H, NH).

¹³C NMR: δ (ppm) = 26.1, 32.9 (4xCH₂-cyclopentyl), 33.3

(CH₂), 46.2 (CH-cyclopentyl), 61.3 (CH), 117.7, 120.4, 122.4,

128.4, 128.9, 149.7 (6C_ar), 168.8 (C¼O), 172.3 (C¼O). Anal.

Calcd for C₁₅H₁₈N₂O₃S (306.38): C, 58.80; H, 5.92; N, 9.14;

Found: C, 58.82; H, 5.94; N, 9.16%.

N-[(4-Methoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]cyclopropa-

necarboxamide (4f).

Yield: 0.52 g (17.9%), mp. 82–84°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3046 (CH aromatic), 3038, 1455

(CH aliphatic), 1710 (C¼O), 1615 (N–H), 1442 (CH₂-

cyclopropyl), 1406 (C–N), 638 (C–S). H NMR (DMSO-d₆): δ

N-[2-(3-Nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]cyclopenta-

necarboxamide (5d). Yield: 3.28 g (97.9%), mp. 158–160°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3048 (CH aromatic), 3032, 1451

(CH aliphatic), 1734 (C¼O), 1620 (N–H), 1455 (CH₂-

(ppm) = 0.68–0.92 (m, 4H, 2xCH₂-cyclopentyl), 1.48–1.57 (CH-

cyclopentyl), 3.78 (s, 3H, CH₃), 3.81 (s, 2H, CH₂), 6.84–6.98

(m, 2H, Ar–H), 7.33–7.37 (m, 2H, Ar–H), 8.14 (s, 1H, CH),

11.56 (s, 1H, NH). ¹³C NMR:

(ppm) = 10.8 (2xCH₂-

cyclopentyl), 1390 (C–N), 664 (C–S). H NMR (DMSO-d₆): δ

cyclopropyl), 18.3 (CH-cyclopropyl), 33.3 (CH₂), 56.0 (CH₃),

67.6 (CH), 114.0, 126.7, 135.5 (5C_ar), 161.8 (C_ar), 168.8

(C¼O), 172.3 (C¼O). Anal. Calcd for C₁₄H₁₆N₂O₃S (292.35):

C, 57.52; H, 5.52; N, 9.58; Found: C, 57.55; H, 5.45; N, 9.56%.

N-[2-(4-Bromophenyl)-4-oxo-1,3-thiazolidin-3-yl]cyclopropa-

(ppm) = 1.57–1.66 (m, 6H, 3xCH₂-cyclopentyl), 1.89–1.91 (m,

2H, CH₂-cyclopentyl), 2.64–2.68 (m, 1H, CH-cyclopentyl),

3.41 (s, 2H, CH₂), 6.19 (s, 1H, CH), 7.56–7.60 (m, 2H, Ar–H),

8.15–8.17 (m, 1H, Ar–H), 8.31–8.33 (m, 1H, Ar–H), 8.69 (s,

1H, NH); ¹³C NMR: δ (ppm) = 26.1, 32.9 (4xCH₂-cyclopentyl),

33.3 (CH₂), 46.2 (CH-cyclopentyl), 67.9 (CH), 119.4, 128.4,

130.8, 143.1, 148.4 (6C_ar), 168.8 (C¼O), 172.3 (C¼O). Anal.

Calcd for C₁₅H₁₇N₃O₄S (335.40): C, 53.72; H, 5.11; N, 12.53;

Found: C, 53.74; H, 5.08; N, 12.55%.

necarboxamide (4g).

Yield: 3.32 g (97.2%), mp. 232–234°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3078 (CH aromatic), 3047, 1457

(CH aliphatic), 1722 (C¼O), 1608 (N–H), 1442 (CH₂-

cyclopropyl), 1412 (C–N), 656 (C–S). H NMR (DMSO-d₆): δ

(ppm) = 0.70–0.89 (m, 4H, 2xCH₂-cyclopropyl), 1.62–1.71

(CH-cyclopropyl), 3.58 (s, 2H, CH₂), 7.38–7.61 (m, 4H, Ar–H),

5.78 (s, 1H, CH), 11.57 (s, 1H, NH). ¹³C NMR: δ (ppm) = 10.8

(2xCH₂-cyclopropyl), 18.3 (CH-cyclopropyl), 33.3 (CH₂), 67.6

(CH), 121.3, 128.9, 132.7, 140.2 (6C_ar), 168.8 (C¼O), 172.3

(C¼O). Anal. Calcd for C₁₃H₁₃BrN₂O₂S (341.22): C, 45.76; H,

3.84; N, 8.21; Found: C, 45.79; H, 3.81; N, 8.23%.

N-[2-(4-Methylphenyl)-4-oxo-1,3-thiazolidin-3-yl]cyclopenta-

necarboxamide (5e).

Yield: 2.58 g (84.8%), mp. 130–132°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3089 (CH aromatic), 3060, 1450

(CH aliphatic), 1713 (C¼O), 1605 (N–H), 1455 (CH₂-

cyclopentyl), 1422 (C–N), 653 (C–S). H NMR (DMSO-d₆): δ

(ppm) = 1.57–1.66 (m, 6H, 3xCH₂-cyclopentyl), 1.87–1.90 (m,

2H, CH₂-cyclopentyl), 2.32 (s, 3H, CH₃), 2.64–2.67 (m, 1H,

CH-cyclopentyl), 3.40 (s, 2H, CH₂), 6.08 (s, 1H, CH), 7.19–

7.22 (dd, 2H, Ar–H, J = 7.5Hz), 7.25–7.28 (dd, 2H, Ar–H,

J = 7.5Hz), 8.70 (s, 1H, NH). ¹³C NMR: δ (ppm) = 21.1 (CH₃),

26.1, 32.9 (4xCH₂-cyclopentyl), 33.3 (CH₂), 46.2 (CH-

cyclopentyl), 67.6 (CH), 125.7, 129.6, 137.6, 138.5 (6C_ar),

N-[4-Oxo-2-(propan-2-yl)-1,3-thiazolidin-3-yl]cyclopentane-

carboxamide (5a).

Yield: 1.43 g (55.8%), mp. 111–113°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3078 (CH aromatic), 3047, 1457

(CH aliphatic), 1722 (C¼O), 1608 (N–H), 1442 (CH₂-

cyclopentyl), 1412 (C–N), 656 (C–S). H NMR (DMSO-d₆): δ

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

400

Ł. Popiołek, J. Stefańska, M. Kiełczykowska, I. Musik, A. Biernasiuk, A. Malm, and M. Wujec

Vol 53

168.8 (C¼O), 172.3 (C¼O). Anal. Calcd for C₁₆H₂₀N₂O₂S

(304.41): C, 63.13; H, 6.62; N, 9.20; Found: C, 63.15; H, 6.68;

N, 9.17%.

1413 (C–N), 645 (C–S). H NMR (DMSO-d₆): δ (ppm) = 1.36–

1.38 (m, 2H, CH₂-cyclohexyl), 1.60–1.66 (m, 6H, 3xCH₂-

cyclohexyl), 2.18–2.24 (m, 1H, CH-cyclohexyl), 2.52–2.54 (m,

2H, CH₂-cyclohexyl), 3.40 (s, 2H, CH₂), 6.45 (s, 1H, CH),

6.82–6.86 (m, 2H, Ar–H), 7.09–7.20 (m, 2H, Ar–H), 8.62 (s,

1H, OH), 8.95 (s, 1H, NH); ¹³C NMR: δ (ppm) = 25.1, 25.9,

27.9 (5xCH₂-cyclohexyl), 33.3 (CH₂), 42.7 (CH-cyclohexyl),

61.3 (CH), 117.7, 120.4, 122.4, 128.4, 128.9, 149.7 (6C_ar),

170.5 (C¼O), 172.3 (C¼O). Anal. Calcd for C₁₆H₂₀N₂O₃S

(320.41): C, 59.98; H, 6.29; N, 8.74; Found: C, 59.97; H, 6.27;

N, 8.75%.

N-[2-(4-Methoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]cyclopen-

tanecarboxamide (5f). Yield: 1.48 g (46.1%), mp. 118–120°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3032 (CH aromatic), 3010, 1462 (CH

aliphatic), 1722 (C¼O), 1613 (N–H), 1455 (CH₂-cyclopentyl),

1411 (C–N), 648 (C–S). H NMR (DMSO-d₆): δ (ppm) = 1.55–

1.66 (m, 6H, 3xCH₂-cyclopentyl), 1.89–1.92 (m, 2H, CH₂-

cyclopentyl), 2.64–2.68 (m, 1H, CH-cyclopentyl), 3.39 (s, 2H,

CH₂), 3.79 (s, 3H, CH₃), 6.10 (s, 1H, CH), 6.94–6.97 (dd, 2H,

Ar–H, J = 7.5 Hz), 7.27–7.30 (dd, 2H, Ar–H, J = 7.5 Hz), 8.65

N-[2-(3-Nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]cyclohexa-

necarboxamide (6d). Yield: 3.39 g (97.1%), mp. 116–118°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3076 (CH aromatic), 3035, 1448

(CH aliphatic), 1722 (C¼O), 1610 (N–H), 1452 (CH₂-

(s, 1H, NH). ¹³C NMR:

δ (ppm) = 26.1, 32.9 (4xCH₂-

cyclopentyl), 32.3 (CH₂), 46.2 (CH-cyclohexyl), 56.0 (CH₃),

67.6 (CH), 114.0, 126.7, 135.5, 161.8 (6C_ar), 168.8 (C¼O),

172.3 (C¼O). Anal. Calcd for C₁₆H₂₀N₂O₃S (320.41): C, 59.98;

H, 6.29; N, 8.74; Found: C, 59.96; H, 6.27; N, 8.76%.

cyclohexyl), 1415 (C–N), 649 (C–S). H NMR (DMSO-d₆): δ

(ppm) = 1.01–1.03 (m, 2H, CH₂-cyclohexyl), 1.49–.1.54 (m,

6H, 3xCH₂-cyclohexyl), 2.07–2.09 (m, 2H, CH₂-cyclohexyl),

2.11–2.14 (m, 1H, CH-cyclohexyl), 3.40 (s, 2H, CH₂), 6.27

(s, 1H, CH), 7.58–7.62 (m, 2H, Ar–H), 8.19–8.21 (m, 1H,

Ar–H), 8.28–8.33 (m, 1H, Ar–H), 8.59 (s, 1H, NH). ¹³C

NMR: δ (ppm) = 25.1, 25.9, 27.9 (5xCH₂-cyclohexyl), 33.3

(CH₂), 42.7 (CH-cyclohexyl), 67.8 (CH), 119.4, 118.4, 130.8,

143.0, 148.4 (6C_ar), 170.6 (C¼O), 173.3 (C¼O). Anal. Calcd

for C₁₆H₁₉N₃O₄S (349.40): C, 55.00; H, 5.48; N, 12.03;

Found: C, 55.04; H, 5.45; N, 12.06%.

N-[2-(4-Methylphenyl)-4-oxo-1,3-thiazolidin-3-yl]

cyclohexanecarboxamide (6e). Yield: 3.08 g (96.9%), mp.

134–136°C (dec.). IR (KBr), ν (cm^ꢀ1): 3068 (CH aromatic),

3034, 1456 (CH aliphatic), 1738 (C¼O), 1608 (N–H), 1452

(CH₂-cyclohexyl), 1408 (C–N), 653 (C–S). ¹H NMR

(DMSO-d₆): δ (ppm) = 0.94–0.96 (m, 2H, CH₂-cyclohexyl),

1.47–1.53 (m, 6H, 3xCH₂-cyclohexyl), 2.08–2.11 (m, 1H,

CH-cyclohexyl), 2.12–2.16 (m, 2H, CH₂-cyclohexyl), 2.34

(s, 3H, CH₃), 3.39 (s, 2H, CH₂), 6.17 (s, 1H, CH), 7.21–7.25

(m, 4H, Ar–H), 8.58 (s, 1H, NH); ¹³C NMR: δ (ppm) = 21.1

(CH₃), 25.1, 25.9, 27.9 (5xCH₂-cyclohexyl), 33.3 (CH₂),

67.6 (CH), 125.7, 129.6, 137.5, 138.5 (6C_ar), 170.5 (C¼O),

172.3 (C¼O). Anal. Calcd for C₁₇H₂₂N₂O₂S (318.43): C,

64.12; H, 6.96; N, 8.80; Found: C, 64.14; H, 6.98; N, 8.82%.

N-[2-(4-Methoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]

N-[2-(4-Bromophenyl)-4-oxo-1,3-thiazolidin-3-yl]cyclopen-

tanecarboxamide (5g). Yield: 3.63 g (98.2%), mp. 152–154°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3056 (CH aromatic), 3035, 1453 (CH

aliphatic), 1710 (C¼O), 1603 (N–H), 1455 (CH₂-cyclopentyl),

1415 (C–N), 635 (C–S). H NMR (DMSO-d₆): δ (ppm) = 1.57–

1.66 (m, 6H, 3xCH₂-cyclopentyl), 1.88–1.90 (m, 2H, CH₂-

cyclopentyl), 2.64–2.69 (m, 1H, CH-cyclopentyl), 3.39 (s, 2H,

CH₂), 6.09 (s, 1H, CH), 7.18–7.22 (dd, 2H, Ar–H, J = 7.5 Hz),

7.47–7.50 (dd, 2H, Ar-H, J = 7.5 Hz), 8.68 (s, 1H, NH). ¹³C

NMR: δ (ppm) = 26.1, 32.9 (4xCH₂-cyclopentyl), 46.2 (CH-

cyclopentyl), 67.9 (CH), 121.3, 128.9, 132.7, 140.2 (6C_ar),

168.8 (C¼O), 172.3 (C¼O). Anal. Calcd for C₁₅H₁₇BrN₂O₂S

(369.28): C, 48.79; H, 4.64; N, 7.59; Found: C, 48.82; H, 4.65;

N, 7.62%.

N-[4-Oxo-2-(propan-2-yl)-1,3-thiazolidin-3-yl]cyclohexane-

carboxamide (6a).

Yield: 1.64 g (60.7%), mp. 124–126°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3004, 1456 (CH aliphatic), 1715

(C¼O), 1595 (N–H), 1452 (CH₂-cyclohexyl), 1405 (C–N),

657 (C–S). ¹H NMR (DMSO-d₆): δ (ppm) = 1.06 (s, 6H,

2xCH₃), 1.47–1.53 (m, 2H, CH₂-cyclohexyl), 1.61–1.63 (m,

8H, 4xCH₂-cyclohexyl), 2.02–2.05 (m, 2H, CH₂-cyclohexyl),

2.47–2.49 (m, 1H, CH), 2.53–2.55 (m, CH-cyclohexyl), 3.29

(s, 2H, CH₂), 4.41 (d, 1H, CH), 8.52 (s, 1H, NH); ¹³C NMR: δ

(ppm) = 20.4 (2xCH₃), 25.1, 25.9, 28.1 (5xCH₂-cyclohexyl),

30.8 (CH₂), 32.3 (CH), 42.6 (CH-cyclohexyl), 48.2 (CH),

170.5 (C¼O), 176.5 (C¼O). Anal. Calcd for C₁₃H₂₂N₂O₂S

(270.39): C, 57.75; H, 8.20; N, 10.36; Found: C, 57.72; H,

8.18; N, 10.38%.

cyclohexanecarboxamide (6f).

Yield: 2.61 g (78.2%), mp.

156–158°C (dec.). IR (KBr), ν (cm^ꢀ1): 3068 (CH aromatic),

3022, 1455 (CH aliphatic), 1740 (C¼O), 1615 (N–H), 1452

(CH₂-cyclohexyl), 1410 (C–N), 655 (C–S). H NMR (DMSO-

N-(4-Oxo-2-phenyl-1,3-thiazolidin-3-yl)cyclohexanecarboxamide

(6b). Yield: 2.99 g (98.1%), mp. 130–132°C (dec.). IR (KBr),

ν (cm^ꢀ1): 3096 (CH aromatic), 3060, 1453 (CH aliphatic), 1735

(C¼O), 1619 (N–H), 1452 (CH₂-cyclohexyl), 1403 (C–N), 648

(C–S). ¹H NMR (DMSO-d₆): δ (ppm) = 1.31–1.33 (m, 2H,

CH₂-cyclohexyl), 1.57–1.59 (m, 8H, 4xCH₂-cyclohexyl), 1.80–

1.82 (m, 2H, CH₂-cyclohexyl), 2.42–2.46 (m, 1H, CH-

cyclohexyl), 3.39 (s, 2H, CH₂), 6.20 (s, 1H, CH), 7.27–7.33 (m,

5H, Ar–H), 8.76 (s, 1H, NH). ¹³C NMR: δ (ppm) = 25.1, 25.9,

27.9 (5xCH₂-cyclohexyl), 33.3 (CH₂), 42.7 (CH-cyclohexyl),

67.6 (CH), 126.6, 127.7, 128.9, 140.4 (6C_ar), 170.5 (C¼O),

172.3 (C¼O). Anal. Calcd for C₁₆H₂₀N₂O₂S (304.41): C,

63.13; H, 6.62; N, 9.20; Found: C, 63.15; H, 6.61; N, 9.22%.

N-[2-(2-Hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]cyclohe-

xanecarboxamide (6c). Yield: 3.14 g (97.9%), mp. 150–152°C

(dec.). IR (KBr), ν (cm^ꢀ1): 3085 (CH aromatic), 3055, 1458 (CH

aliphatic), 1714 (C¼O), 1602 (N–H), 1452 (CH₂-cyclohexyl),

d₆): δ (ppm) = 1.28–1.31 (m, 2H, CH₂-cyclohexyl), 1.57–1.59

(m, 6H, 3xCH₂-cyclohexyl), 1.79–1.81 (m, 2H, CH₂-

cyclohexyl), 2.41–2.44 (m, 1H, CH-cyclohexyl), 3.39 (s, 2H,

CH₂), 3.80 (s, 3H, CH₃), 6.12 (s, 1H, CH), 6.94–6.97 (dd, 2H,

Ar–H, J = 7.5 Hz), 7.27–7.30 (dd, 2H, Ar–H, J = 7.5 Hz), 8.56

(s, 1H, NH); ¹³C NMR: δ (ppm) = 25.1, 25.9, 27.9 (5xCH₂-

cyclohexyl), 33.3 (CH₂), 56.0 (CH₃), 67.6 (CH-cyclohexyl),

114.0, 126.7, 135.5, 161.8 (6C_ar), 170.5 (C¼O), 172.3 (C¼O).

Anal. Calcd for C₁₇H₂₂N₂O₃S (334.43): C, 61.05; H, 6.63; N,

8.38; Found: C, 61.08; H, 6.61; N, 8.37%.

N-[2-(4-Bromophenyl)-4-oxo-1,3-thiazolidin-3-yl]

cyclohexanecarboxamide (6g).

Yield: 2.81 g (73.4%), mp.

171–173°C (dec.). IR (KBr), ν (cm^ꢀ1): 3068 (CH aromatic),

3022, 1455 (CH aliphatic), 1740 (C¼O), 1615 (N–H), 1452

(CH₂-cyclohexyl), 1410 (C–N), 655 (C–S). H NMR (DMSO-

d₆): δ (ppm) = 0.95–0.97 (m, 2H, CH₂-cyclohexyl), 1.48–1.54

(m, 6H, 3xCH₂-cyclohexyl), 2.07–2.09 (m, 2H, CH₂-

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

March 2016

Synthesis, Dissociation Constants, and Antimicrobial Activity of Novel 2,

3-Disubstituted-1,3-thiazolidin-4-one Derivatives

401

cyclohexyl), 2.11–2.13 (m, 1H, CH-cyclohexyl), 3.38 (s, 2H,

CH₂), 6.18 (s, 1H, CH), 7.19–7.22 (dd, 2H, Ar–H, J = 7.5 Hz),

7.51–7.53 (dd, 2H, Ar–H, J = 7.5 Hz), 8.57 (s, 1H, NH). ¹³C

NMR: δ (ppm) = 25.1, 25.9, 27.9 (5xCH₂-cyclohexyl), 33.3

(CH₂), 42.7 (CH-cyclohexyl), 67.6 (CH), 121.3, 128.9, 132.7,

140.2 (6C_ar), 170.5 (C¼O), 172.4 (C¼O). Anal. Calcd for

C₁₆H₁₉BrN₂O₂S (383.30): C, 50.14; H, 5.00; N, 7.31; Found:

C, 50.12; H, 5.02; N, 7.28%.

Mueller-Hinton broth or Mueller-Hinton broth with 5% sheep

blood (for bacteria) and RPMI 1640 broth with MOPS (for fungi)

prepared in 96-well polystyrene plates. Final concentrations of the

compounds ranged from 1000 to 0.488 μg/mL. Each well

containing 198 μL broth and various concentrations of the exam-

ined compounds was added 2 μL of bacterial or fungal suspen-

sion. After incubation (35 or 30°C for 24 h for bacteria and

fungi, respectively), the MIC was assessed spectrophotometri-

cally as the lowest concentration of the samples showing com-

plete bacterial or fungal growth inhibition. The media with or

without tested substances and with or without microbial suspen-

sions incubated under the similar conditions were used as con-

trols. Moreover, ciproﬂoxacin, vancomycin, or ﬂuconazole

(Sigma) was used as reference antimicrobial agents.

The MBC or MFC are deﬁned as the lowest concentration of

the compounds that is required to kill a particular bacterial or fun-

gal species. It was determined by removing 20 μL of the culture

using for MIC determinations from each well and spotting onto

appropriate agar medium which does not contain the tested com-

pounds. After incubation, the lowest compound concentration

Dissociation constants.

dissociation constants is presented in the Supporting Information.

Microbiology. The examined compounds were screened

Methodology for determining the

in vitro for antibacterial and antifungal activities by using the

broth microdilution method according to European Committee

on Antimicrobial Susceptibility Testing (EUCAST) [18] and

Clinical and Laboratory Standards Institute (CLSI) guidelines

[19]. The reference strains of microorganisms came from

American Type Culture Collection (ATCC) and National

Collection of Type Cultures (NCTC) and included Gram-

positive bacteria (S. aureus ATCC 25923, S. aureus ATCC

6538, S. epidermidis ATCC 12228, Streptococcus pyogenes

ATCC 19615, Streptococcus pneumoniae ATCC 49619,

Streptococcus mutans ATCC 25175, B. subtilis ATCC 6633, B.

cereus ATCC 10876, M. luteus ATCC 10240, S. aureus NCTC

4163, S. aureus ATCC 29213, S. epidermidis ATCC 35984,

Enterococcus hirae ATCC 10541, Enterococcus faecalis ATCC

29212, B. cereus ATCC 11778, M. luteus ATCC 9341, M. luteus

ATCC 10541), Gram-negative bacteria (Escherichia coli ATCC

3521, E. coli ATCC 25922, Klebsiella pneumoniae ATCC

13883, Proteus mirabilis ATCC 12453, Bordetella

bronchiseptica ATCC 4617, Salmonella typhimurium ATCC

14028, Pseudomonas aeruginosa ATCC 9027, E. coli ATCC

10538, E. coli NCTC 8196, Proteus vulgaris NCTC 4635, P.

aeruginosa ATCC 15442, P. aeruginosa NCTC 6749, P.

aeruginosa ATCC 27863), fungi belonging to yeasts (Candida

albicans ATCC 2091, C. albicans ATCC 10231, Candida

parapsilosis ATCC 22019, C. albicans ATCC 90028). The

microbial cultures were ﬁrst subcultured on nutrient agar or

Sabouraud agar at 35°C for 18–24 h or 30°C for 24–48 h for

bacteria and fungi, respectively.

The surface of Mueller-Hinton agar or Mueller-Hinton agar

with 5% sheep blood (for bacteria) and RPMI 1640 with MOPS

(for fungi) were inoculated with the suspensions of bacterial or

fungal species. Microbial suspensions were prepared in sterile sa-

line (0.85% NaCl) with an optical density of McFarland standard

scale 0.5 approximately 1.5 × 10⁸colony forming units (CFU)/

mL for bacteria and 0.5 McFarland standard scale approximately

5 × 10⁵CFU/mL for fungi.

Samples containing the examined compounds were dissolved in

dimethyl sulfoxide (DMSO) and then diluted appropriately in liq-

uid media. Microbial suspensions were prepared in sterile saline

(0.85% NaCl) with an optical density of 0.5 McFarland standard

scale approximately 1.5 × 10⁸CFU/mL for bacteria and

5 × 10⁵CFU/mL for fungi. Furthermore, solid media Mueller-

Hinton or Mueller-Hinton with 5% sheep blood (for bacteria) and

RPMI 1640 with MOPS (for fungi) containing 2 mg/mL of the

tested compounds were inoculated with 10 μL bacterial or fungal

suspensions and followed incubation under the appropriate condi-

tions. The inhibition of microbial growth was judged by compari-

son with a control culture prepared without any sample tested.

with no visible growth observed was assessed as

bactericidal/fungicidal concentration [20].

In this study, no bioactivity was deﬁned as

MIC > 1000 μg/mL, mild bioactivity as a MIC in the range

501–1000 μg/mL, moderate bioactivity with MIC from 126 to

500 μg/mL, good bioactivity as a MIC in the range 26–

125 μg/mL, strong bioactivity with MIC between 10 and

25 μg/mL and very strong bioactivity as a MIC < 10 μg/mL

[21]. The MBC/MIC or MFC/MIC ratios were calculated in order

to determine bactericidal/fungicidal or bacteriostatic/fungistatic

effect of the tested compounds.

DECLARATION OF INTEREST

The authors declare no conﬂict of interest.

Acknowledgment. The project was partially supported by the

Research Grant for Young Scientists (MNmb25).

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