Next Article in Journal
Naphthalen-2-yl 1-(benzamido(diethoxyphosphoryl)methyl)-1H-1,2,3-triazole-4-carboxylate
Previous Article in Journal
2,2-Bis(phenylselanyl)-1-(p-tolyl)vinyl 2-Oxo-2-(p-tolyl)acetate
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Short Note

Synthesis and Characterization of Novel Thiazolidinones and Thioxothiazolidinones Derived from Substituted Indole

1
Laboratoire de Synthèse Organique Appliquée (LSOA), Department of Chemistry, Faculté des Sciences Exactes et Appliquées, Université Oran1 Ahmed Ben Bella, BP 1524 El M’Naouer, Oran 31000, Algeria
2
Hôpital Militaire Régional Universitaire d’Oran Dr. Amir Mohamed Benaissa, BP 35 Ahmed Medeghri, Oran 31000, Algeria
3
Department of Chemistry, Faculty of Exact Sciences, University of Mascara, Mascara 29000, Algeria
4
Laboratoire Synthèse et Isolement de Molécules BioActives (SIMBA, EA7502), Faculté des Sciences et Techniques, Université de Tours, Parc de Grandmont, 32 Av. Monge, 37200 Tours, France
*
Author to whom correspondence should be addressed.
Molbank 2021, 2021(4), M1284; https://doi.org/10.3390/M1284
Submission received: 24 August 2021 / Revised: 24 September 2021 / Accepted: 27 September 2021 / Published: 30 September 2021

Abstract

:
Based on recent discoveries concerning the numerous biological properties of thiazolidinones and thiosemicarbazones, new N-substituted heterocyclic derivatives have been designed by combining the indole ring with thioxothiazolidinone, thiazolidinone or thiosemicarbazone. Thus, a series of new thioxothiazolidinone, thiazolidinone, or thiosemicarbazone derivatives bearing indole-based moiety have been designed, synthesized, and developed in good yields.

Graphical Abstract

1. Introduction

The indolic nucleus is a heteroaromatic organic compound that is highly common in nature. This structural unit is present in many bioactive molecules, whether natural or synthetic. Indoles are an important class of heterocyclic compounds, and this kind of structure has been revealed to have antimicrobial [1,2], antifungal [3], anti-inflammatory and analgesic [4,5,6], anticonvulsant [7], anticancer [8,9], and anti-malarial properties [10]. The 4-thiazolidinone derivatives are one of the heterocyclic types which play an important role in therapeutical chemistry, due to their variety in biological activity, as antiviral [11], anti-inflammatory [12], anticancer [13], antimicrobial [14,15], antidiabetic [16], antioxidant [17], anti-HIV agents [18]. Moreover, the 5-arylidene-2-thioxothiazolidin-4-one or 5-arylidenerhodanine derivatives represent particularly privileged moieties in drug discovery because of their inherent tendency for biological activity [19,20,21]. For example, it was reported that the incorporation of indolyl moiety as in N′-[(1H-indol-3-yl)methylene]-isonicotinohydrazide derivative showed excellent to good anti-tubercular activity (compound I, Figure 1) [22]. Compound II displayed potent broad-spectrum antibacterial and antifungal activities [15]. Moreover, benzyl-1H-indole derivatives (indibulin III) also possess prominent antitumor activity, for example, acting as a novel synthetic microtubule inhibitor [23].
A new series of thiosemicarbazones 5ae was prepared by the reaction of substituted indole-3-carbaldehyde 3ae on 4-chlorophenylthiosemicarbazide in ethanol, with acetic acid as a catalyst. Substituted thiazolidinones compounds 7ae were prepared by a cycling reaction in ethanol with sodium acetate. The arylidenerhodanines 10ae were also prepared by condensation reactions of 2-thioxothiazolidin-4-one on several substituted indole-3-carbaldehyde compounds. In the previous work [24], we synthesized new indole derivatives of potential biological interest. The biological activity of this kind of compound will be interesting for further work. The synthesis of the target compounds (A, B, or C series) was carried out as outlined in Scheme 1. The spectral data and elemental analysis results of the synthesized compounds were in agreement with the proposed structures.

2. Results and Discussion

2.1. Synthesis of N-Benzylindole-3-carboaldehyde Derivatives

Substituted N-benzylindole-3-carboxaldehyde derivatives 3ae were prepared with 90–95% yield by the reaction of the indole-3-carboxaldehyde 1 with various substituted benzyl halides 2ae with K2CO3 as a base, in N,N-dimethylformamide (DMF) (Scheme 2) [25]. The structures of the synthesized compounds 3ae were confirmed by their 1H-NMR and 13C-NMR spectral data. The 1H-NMR spectrum of compounds 3ae shows characteristic signals near δ 5.70 and 10.00 assignable to CH2 and CHO. Further confirmation was achieved by the 13C-NMR spectrum, which showed signals at δ 49.78 and 185.0 due to CH2 and CHO, respectively (see Supporting Information).

2.2. Synthesis of Thiosemicarbazones

The reaction of 4-(4-chlorophenyl)-3-thiosemicarbazide 4 with indole-3-carbaldehyde derivatives 3ae with a few drops of acetic acid, stirred for 3 h at 80 °C, lead to the corresponding 4-(4-chlorophenyl)-3-thiosemicarbazone derivatives 5ae in good yields (Scheme 3). In the 1H-RMN spectrum, the most characteristic signals of thiosemicarbazones 5ae correspond to the CH=N and the N–H protons. The 1H-RMN studies show that the N–H protons of thiosemicarbazones 5ae are in the range of 9.62 to 11.68 ppm for the N–H adjacent to the mono-substituted phenyl ring and for the N–H adjacent to the CH=N fraction, while CH=N protons are in the range of 8.41 to 8.53 ppm. All synthesized compounds are in the E configuration, which was confirmed by the 1H-RMN spectroscopy, because the NH group signal is in the range of 9 to 12 ppm, compared to the Z isomer, which has a characteristic signal between 14 and 15 ppm [26,27].

2.3. Synthesis of Thiazolidin-4-One Derivatives

The resulting thiosemicarbazones 5ae were cyclized with ethyl bromoacetate in ethanol and sodium acetate under reflux for 3 h to give 1,3-thiazolidin-4-one derivatives 7ae, and final products were obtained in good yield (85–94%) (Scheme 4). The structures of new compounds 7ae were defined by their 1H-NMR and 13C-NMR data. The 1H-NMR spectra present resonances assigned to the SCH2 group of the thiazolidine ring, and this signal appears as a singlet at 4.08 ppm due to the methylene protons. The CH=N protons in these kinds of structures were observed at 8.45 and 8.46 ppm.
At the final step for the synthesis of products 10ae, the 2-thioxothiazolidin-4-one 9 has undergone a condensation with indole-3-carbaldehydes 3ae. The interaction was realized in boiling alcohol with piperidine as a base, and final products were obtained with moderate to good yields (85–73%) (Scheme 5).
In the 1H-NMR spectrum, a large singlet at δ = 13.57 ppm was assigned to the –NH group, and the 13C-NMR spectrum showed signals at δ = 169.1 and 194.6 ppm assigned to the (C=O) and (C=S) functionalities for the compound 10a. The arylidenerhodanines synthesis 10ae leads to two isomers, Z and E. Z-isomers are predominant (Z > 75%) and thermodynamically more stable [26,27]. The exocyclic C=CH double bond configuration can be determined by NMR spectroscopy. The Z-configuration of the 5-arylidene 10ae derivatives was confirmed by the signal for the C=CH methine proton with a higher chemical shift between 7.90 and 7.95 ppm in a singlet form [28,29,30,31,32,33].

3. Materials and Methods

3.1. General Information

The reagents were purchased from commercial suppliers and used without further purification. Melting points were determined on Büchi B-540 apparatus and are uncorrected. All solvents were dried following the procedure described by Armarego and Chai [34]. 1H-NMR and 13C-NMR spectra were recorded on a Bruker Avance 300 MHz at 300 and 75 MHz, respectively. 1H-NMR spectra were recorded in CDCl3 referenced to the residual CHCl3 at 7.26 ppm, and 13C-NMR spectra were referenced to the central peak of CDCl3 at 77.0 ppm. 19F-NMR was recorded at 282 MHz on the same instrument, using the CFCl3 as internal reference (δ 0.0). Chemical shifts were reported in parts per million (ppm, δ), and coupling constants (J) were given in Hertz (Hz). Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; dd, doublet of doublets; dq, doublet of quartets; m, multiplet. High-resolution mass spectra (HRMS) were obtained by electrospray ionization time-of-flight (ESI) mass spectrometry. Thin-layer chromatography (TLC) was performed on TLC silica gel 60 F254. Compounds were visualized with UV light (λ = 254 nm) and/or by immersion in a KMnO4 solution followed by heating. Products were purified by flash column chromatography on silica gel (0.04–0.063 mm) using various mixtures of EtOAc and petroleum ether (35–60 °C fraction) as eluent. Heating was performed using a magnetic stirrer hotplate and an appropriately sized heating block. The compound names follow the IUPAC recommendations.

3.2. Experimental Section

3.2.1. General Procedure for the Synthesis of 1-Substituted-1H-indole-3-carbaldehydes (3ae) (35)

1-Substituted-1H-indole-3-carbaldehyde was synthesized by reaction of 1H-indole-3-carbaldehyde 1 (1.45 g, 0.01 mol), the corresponding benzyl chloride 2ae (0.011 mol), and anhydrous K2CO3 (2.76 g, 0.02 mol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred at 90 °C for 6 h, and the reaction was monitored by thin-layer chromatography. The reaction was stopped and cooled at room temperature, and the mixture was poured into ice-cold water. The resulting precipitate was collected by filtration and washed with water. The crude product was purified by recrystallization from ethanol and dried under vacuum to give the desired compounds (3ae).
1-Benzyl-1H-indole-3-carbaldehyde (3a): White solid, 90%, 2.21 g. mp 107–109 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.99 (s, 1H, CHO), 8.36–8.32 (m, 1H, indole C7-H), 7.69 (s, 1H, indole C2-H), 7.36–7.29 (m, 6H), 7.21–7.15 (m, 2H), 5.34 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, CDCl3): δ = 184.7 (CHO), 138.6 (indole C2), 137.5 (Cquat), 135.4 (Cquat), 129.2 (2 CH), 128.5 (CH), 127.3 (2 CH), 125.6 (Cquat), 124.3 (CH), 123.1 (CH), 122.2 (CH), 118.6 (Cquat), 110.5 (indole C7), 51.0 (CH2) ppm.
1-(4-Fluorobenzyl)-1H-indole-3-carbaldehyde (3b): White solid, 93%, 2.35 g. mp 117–119 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.98 (s, 1H, CHO), 8.35–8.30 (m, 1H, indole C7-H), 7.69 (s, 1H, indole C2-H), 7.36–7.29 (m, 3H, indole C4-H, C5-H and C6-H), 7.18–7.14 (m, 2H, 2H phenyl), 7.03 (t, J = 8.6 Hz, 2H, 2H phenyl), 5.32 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, CDCl3): δ = 184.8 (CHO), 138.5 (indole C2), 137.4 (Cquat), 136.6 (Cquat), 131.6 (q, J = 32.5 Hz, Cquat), 130.4 (q, J = 1.1 Hz, CH), 129.9 (CH), 125.6 (Cquat), 125.4 (q, J = 3.7 Hz, CH), 124.6 (CH), 123.9 (q, J = 3.8 Hz, CH), 123.8 (q, J = 272 Hz, Cquat), 123.4 (CH), 122.4 (CH), 118.9 (Cquat), 110.3 (indole C7), 50.5 (CH2) ppm.
1-(4-(Trifluoromethyl)benzyl)-1H-indole-3-carbaldehyde (3c): White solid, 94%, 2.85 g. mp 133–13509 °C. 1H-NMR (300 MHz, CDCl3): δ = 10.02 (s, 1H, CHO), 8.37–8.32 (m, 1H, indole C7-H), 7.74 (s, 1H, indole C2-H), 7.60 (d, J = 7.8 Hz, 2H, 2H phenyl), 7.51 (bs, 1H, 1H phenyl), 7.46 (t, J = 7.8 Hz, 1H, 1H phenyl), 7.37–7.26 (m, 4H, C4-H, C5-H, C6-H and 1H phenyl), 5.43 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, CDCl3): δ = 184.7 (CHO), 138.6 (indole C2), 137.5 (Cquat), 135.4 (Cquat), 129.2 (2 CH), 128.5 (CH), 127.3 (2 CH), 125.6 (Cquat), 124.3 (CH), 123.1 (CH), 122.2 (CH), 118.6 (Cquat), 110.5 (indole C7), 51.0 (CH2) ppm.
1-(3-Chlorobenzyl)-1H-indole-3-carbaldehyde (3d): White solid, 93%, 2.50 g. mp 79–81 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.99 (s, 1H, CHO), 8.36–8.31 (m, 1H, indole C7-H), 7.72 (s, 1H, indole C2-H), 7.36–7.25 (m, 5H, indole C4-H, C5-H, C6-H, 2H phenyl), 7.17 (bs, 1H, 1H phenyl), 7.04–7.00 (m, 1H, 1H phenyl), 5.32 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, CDCl3): δ = 184.8 (CHO), 138.6 (indole C2), 137.5 (Cquat), 137.4 (Cquat), 135.1 (Cquat), 130.5 (CH), 128.7 (CH), 127.3 (CH), 125.5 (Cquat), 125.3 (CH), 124.5 (CH), 123.3 (CH), 122.3 (CH), 118.7 (Cquat), 110.4 (indole C7), 50.4 (CH2) ppm.
2-((3-Formyl-1H-indol-1-yl)methyl)benzonitrile (3e): White solid, 94%, 2.44 g. mp 133–135 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.99 (s, 1H, CHO), 8.45 (s, 1H, indole C2-H), 8.18 (d, J = 8 Hz, 1H, indole C4-H), 7.97 (d, 1H, J = 8 Hz, 1H, indole C7-H), 7.67 (1H, td, J = 1.4 Hz, J = 7.7 Hz, Ar-H), 7.60–7.52 (m, 2H, Ar-H), 7.35–7.25 (m, 2H, Ar-H), 7.07 (1H, d, J = 7.58 Hz, Ar-H), 5.83 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, CDCl3): δ = 185.0 (CHO), 141.2 (indole C2), 140.0 (Cquat), 137.1 (Cquat), 133.8 (CH), 133.5 (CH), 128.7 (CH), 127.8 (CH), 124.7 (CH), 123.9 (CH), 122.8 (CH), 121.2 (CH), 117.7 (Cquat), 117.2 (Cquat), 111.1 (Cquat), 110.4 (CH), 48.2 (CH2) ppm.

3.2.2. General Procedure for the Synthesis of Thiosemicarbazones (5ae) (35)

To a solution of 4-chlorophenylthiosemicarbazide 4 (0.605 g, 3 mmol, 1 equiv) in ethanol (33 mL) were added the 1-substituted-1H-indole-3-carbaldehyde (6.3 mmol, 1.05 equiv) and acetic acid (0.50 mL). The mixture was stirred and heated under reflux for 3 h. The reaction was stopped and cooled to room temperature. After, the solid was filtered and recrystallized from ethanol-DMF (3:1) to give compounds 5ae.
(E)-2-((1-Benzyl-1H-indol-3-yl)methylene)-N-(4-chlorophenyl)hydrazine-1-carbothioamide (5a): Beige solid, 93%, 0.97 g. mp 203–205 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 11.68 (bs, 1H, NH), 9.68 (bs, 1H, NH), 8.41 (s, 1H, indole C2-H), 8.26 (d, 1H, J = 7.3 Hz, Ar-H), 8.10 (s, 1H, CH=N), 7.68 (d, 2H, J = 8.7 Hz, Ar-H), 7.52 (d, 1H, J = 7.6 Hz, Ar-H), 7.42 (d, 2H, J = 8.7 Hz, Ar-H), 7.36–7.14 (m, 7H, Ar-H), 5.47 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 174.5 (CS), 141.0 (CH), 138.3 (Cquat), 137.4 (Cquat), 136.9 (Cquat), 134.3 (CH), 128.9 (Cquat), 128.6 (2CH), 127.9 (2CH), 127.6 (CH), 127.1 (2CH), 126.9 (2CH), 124.7 (Cquat), 122.9 (CH), 122.2 (CH), 121.1 (CH), 110.7 (CH), 110.6 (Cquat), 49.4 (CH2) ppm. HRMS (ESI): calcd. for C23H20ClN4S [M + H]+ 419.10972; found 419.10981.
(E)-N-(4-Chlorophenyl)-2-((1-(4-fluorobenzyl)-1H-indol-3-yl)methylene)hydrazine-1-carbothioamide (5b): Beige solid, 92%, 0.97 g. mp 211–213 °C. 1H-NMR (300 MHz, Acetone-d6): δ = 10.5 (bs, 1H, NH), 9.62 (bs, 1H, NH), 8.51 (s, 1H, indole C2-H), 8.28 (dd, 1H, J = 7.1 Hz, J = 1.3 Hz, Ar-H), 7.96 (s, 1H, CH=N), 7.90–7.83 (m, 2H, Ar-H), 7.51 (d, 1H, J = 7.4 Hz, Ar-H), 7.40 (d, 2H, J = 8.8 Hz, Ar-H), 7.37–7.31 (m, 2H, Ar-H), 7.29–7.18 (m, 2H, Ar-H), 7.11 (t, 2H, J = 8.8 Hz, Ar-H), 5.53 (s, 2H, PhCH2) ppm. 19F-NMR (282 MHz, DMSO-d6): δ = −116.3 ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 174.5 (CS), 161.5 (d, J = 244 Hz, Cquat), 140.9 (CH), 138.3 (Cquat), 136.8 (Cquat), 134.2 (CH), 133.6 (d, J = 3.1 Hz, Cquat), 129.3 (d, J = 3.2 Hz, 2CH), 128.9 (Cquat), 127.9 (2CH), 126.8 (2CH), 124.8 (Cquat), 122.9 (CH), 122.3 (CH), 121.1 (CH), 115.4 (d, J = 21.6 Hz, 2CH), 110.7 (Cquat), 110.6 (CH), 48.6 (CH2) ppm. HRMS (ESI): calcd. for C23H19ClFN4S [M + H]+ 437.10030; found 437.10029.
(E)-N-(4-Chlorophenyl)-2-((1-(3-(trifluoromethyl)benzyl)-1H-indol-3-yl)methylene)hydrazine-1-carbothioamide (5c): White solid, 89%, 1.00 g. mp 224–226 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 11.68 (bs, 1H, NH), 9.69 (bs, 1H, NH), 8.42 (s, 1H, indole C2-H), 8.28 (d, 1H, J = 7.1 Hz, Ar-H), 8.12 (s, 1H, CH=N), 7.67 (d, 2H, J = 8.7 Hz, Ar-H), 7.54 (d, 1H, J = 7.7 Hz, Ar-H), 7.42 (d, 2H, J = 8.7 Hz, Ar-H), 7.38–7.32 (m, 3H, Ar-H), 7.27–7.15 (m, 3H, Ar-H), 5.49 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 174.6 (CS), 140.9 (CH), 138.9 (Cquat), 138.3 (Cquat), 136.8 (Cquat), 134.3 (CH), 131.2 (CH), 129.8 (CH), 129.3 (q, J = 31.7 Hz, Cquat), 128.9 (Cquat), 127.9 (2CH), 126.9 (2CH), 124.7 (Cquat), 124.4 (q, J = 3.6 Hz, CH), 124.0 (q, J = 272 Hz, Cquat), 123.7 (q, J = 3.8 Hz, CH), 123.1 (CH), 122.4 (CH), 121.2 (CH), 110.9 (Cquat), 110.5 (CH), 48.7 (CH2) ppm. HRMS (ESI): calcd. for C24H19ClF3N4S [M + H]+ 487.09710; found 487.09720.
(E)-2-((1-(3-Chlorobenzyl)-1H-indol-3-yl)methylene)-N-(4-chlorophenyl)hydrazine-1-carbothioamide (5d): Beige solid, 93%, 0.97 g. mp 203–205 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 11.68 (bs, 1H, NH), 9.68 (bs, 1H, NH), 8.41 (s, 1H, indole C2-H), 8.26 (d, 1H, J = 7.3 Hz, Ar-H), 8.10 (s, 1H, CH=N), 7.68 (d, 2H, J = 8.7 Hz, Ar-H), 7.52 (d, 1H, J = 7.6 Hz, Ar-H), 7.42 (d, 2H, J = 8.7 Hz, Ar-H), 7.36–7.14 (m, 7H, Ar-H), 5.47 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 174.6 (CS), 140.9 (CH), 139.9 (Cquat), 138.3 (Cquat), 136.8 (Cquat), 134.3 (CH), 133.2 (Cquat), 130.6 (CH), 128.9 (Cquat), 127.9 (2CH), 127.6 (CH), 127.0 (CH), 126.9 (2CH), 125.8 (CH), 124.7 (Cquat), 123.1 (CH), 122.3 (CH), 121.2 (CH), 110.8 (Cquat), 110.6 (CH), 48.7 (CH2) ppm. HRMS (ESI): calcd. for C23H19Cl2N4S [M + H]+ 453.07075; found 453.07083.
(E)-N-(4-Chlorophenyl)-2-((1-(2-cyanobenzyl)-1H-indol-3-yl)methylene)hydrazine-1-carbothioamide (5e): Beige solid, 89%, 1.00 g. mp 229–231 °C. 1H-NMR (300 MHz, Acetone-d6): δ = 10.56 (bs, 1H, NH), 9.64 (bs, 1H, NH), 8.53 (s, 1H, indole C2-H), 8.31 (d, 1H, J = 7.2 Hz, Ar-H), 7.99 (s, 1H, CH=N), 7.90–7.82 (m, 3H, Ar-H), 7.63 (td, 1H, J = 7.6 Hz, J = 1.4 Hz, Ar-H), 7.58–7.50 (m, 2H, Ar-H), 7.40 (d, 2H, J = 8.8 Hz, Ar-H), 7.32–7.22 (m, 2H, Ar-H), 7.09–7.04 (m, 1H, Ar-H), 5.78 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, CHCl3): δ = 174.7 (CS), 140.8 (CH), 140.7 (Cquat), 138.3 (Cquat), 137.0 (Cquat), 134.5 (CH), 133.8 (CH), 133.4 (CH), 128.9 (Cquat), 128.6 (CH), 127.9 (2CH), 127.6 (CH), 126.9 (2CH), 124.7 (Cquat), 123.3 (CH), 122.5 (CH), 121.4 (CH), 117.2 (Cquat), 111.2 (Cquat), 110.4 (CH), 110.3 (Cquat), 47.8 (CH2) ppm. HRMS (ESI): calcd. for C24H19ClN4S [M + H]+ 444.10497; found 444.10489.

3.2.3. General Procedure for the Synthesis of Thiazolidin-4-ones (7ae)

A mixture of compound 5ae (1.5 mmol, 1 eq), ethyl 2-bromoacetate 6 (0.24 mL, 1.5 mmol), and anhydrous sodium acetate (0.37 g, 4.5 mmol, 3 eq) in ethanol (30 mL) was stirred at 80 °C for 6 h. The reaction mixture was cooled at room temperature, poured into ice cold water, and the solid was filtered, washed with water, and recrystallized from a mixture of ethanol-DMF (3:1).
2-(2-((1-Benzyl-1H-indol-3-yl)methylene)hydrazono)-3-(4-chlorophenyl)thiazolidin-4-one (7a): Yellow solid, 94%, 0.43 g. mp 250–252 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.45 (s, 1H, indole C2-H), 8.43–8.40 (m, 1H, Ar-H), 7.85 (s, 1H, CH=N), 7.56 (d, 2H, J = 8.9 Hz, Ar-H), 7.52–7.46 (m, 3H, Ar-H), 7.36–7.22 (m, 7H, Ar-H), 5.52 (s, 2H, PhCH2), 4.06 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 172.2 (CO), 161.8, 153.9, 137.9, 137.7, 135.3, 134.6, 133.6, 130.6, 129.5, 129.1, 127.6, 125.8, 123.4, 122.7, 121.6, 111.3, 50.0 (CH2), 32.7 (CH2) ppm. HRMS (ESI): calcd. for C25H20ClN4OS [M + H]+ 459.10463; found 459.10475.
2-(2-((1-(4-Fluorobenzyl)-1H-indol-3-yl)methylene)hydrazono)-3-(4-chlorophenyl)thiazolidin-4-one (7b): Brown solid, 94%, 0.42 g. mp 242–244 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.45 (s, 1H, indole C2-H), 8.27–8.24 (m, 1H, Ar-H), 7.96 (s, 1H, CH=N), 7.61 (d, 2H, J = 8.9 Hz, Ar-H), 7.57–7.46 (m, 1H, Ar-H), 7.46 (d, 2H, J = 8.7 Hz, Ar-H), 7.33–7.28 (m, 2H, Ar-H), 7.25–7.21 (m, 2H, Ar-H), 7.15 (t, 2H, J = 8.9 Hz, Ar-H), 5.46 (s, 2H, PhCH2), 4.08 (s, 2H, CH2) ppm. 19F-NMR (282 MHz, DMSO-d6): δ = −114.9 ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 171.9 (CO), 161.7 (Cquat), 161.5 (d, J = 243 Hz, Cquat), 153.3, 136.9, 134.8, 134.0, 133.5 (d, J = 3.2 Hz, Cquat), 133.1, 130.2, 129.3 (d, J = 8.3 Hz), 129.1, 125.2, 123.0, 122.3, 121.3, 115.4 (d, J = 21.5 Hz), 111.6, 110.8, 48.6 (CH2), 32.7 (CH2) ppm. HRMS (ESI): calcd. for C25H19ClFN4OS [M + H]+ 477.09521; found 477.09528.
2-(2-((1-(3-(Trifluoromethyl)benzyl)-1H-indol-3-yl)methylene)hydrazono)-3-(4-chlorophenyl)thiazolidin-4-one (7c): Beige solid, 91%, 0.48 g. mp 230–232 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.46 (s, 1H, indole C2-H), 8.29–8.26 (m, 1H, Ar-H), 8.02 (s, 1H, CH=N), 7.66–7.58 (m, 4H, Ar-H), 7.56–7.53 (m, 3H, Ar-H), 7.47 (d, 2H, J = 8.7 Hz, Ar-H), 7.28–7.20 (m, 2H, Ar-H), 5.60 (s, 2H, PhCH2). 4.09 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 171.8 (CO), 161.8, 153.3, 138.9, 136.9, 134.9, 134.0, 133.1, 131.1, 130.2, 129.8, 129.7 (q, J = 31 Hz), 129,1, 125.2, 124.4 (q, J = 3.7 Hz), 124.0 (q, J = 272 Hz), 123.7 (q, J = 4 Hz), 123.1, 122.3, 121.4, 111.8, 110.7, 48.7 (CH2), 32.3 (CH2) ppm. HRMS (ESI): calcd. for C26H19ClF3N4OS [M + H]+ 527.09202; found 527.09212.
2-(2-((1-(3-Chlorobenzyl)-1H-indol-3-yl)methylene)hydrazono)-3-(4-chlorophenyl)thiazolidin-4-one (7d): Yellow solid, 90%, 0.44 g. mp 252–254 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.45 (s, 1H, indole C2-H), 8.27–8.24 (m, 1H, Ar-H), 7.96 (s, 1H, CH=N), 7.60 (d, 2H, J = 8.8 Hz, Ar-H), 7.56–7.51 (m, 1H, Ar-H), 7.47 (d, 2H, J = 8.7 Hz, Ar-H), 7.33–7.20 (m, 6H, Ar-H), 5.47 (s, 2H, PhCH2), 4.09 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 171.9 (CO), 161.7, 153.4, 137.4, 137.1, 135.0, 134.1, 133.1, 130.2, 129.1, 128.8 (2CH), 127.6, 127.1 (2CH), 125.2, 123.0, 122.3, 121.3, 111.5, 110.9, 49.4 (CH2), 32.3 (CH2) ppm. HRMS (ESI): calcd. for C25H19Cl2N4OS [M + H]+ 493.06566; found 493.06574.
2-(2-((1-(2-Cyanobenzyl)-1H-indol-3-yl)methylene)hydrazono)-3-(4-chlorophenyl)thiazolidin-4-one (7e): Beige solid, 85%, 0.41 g. mp 253–255 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.46 (s, 1H, indole C2-H), 8.31–8.28 (s, 1H, Ar-H), 7.93 (s, 1H, CH=N), 7.91–7.90 (m, 1H, Ar-H), 7.62–7.58 (m, 3H, Ar-H), 7.52–7.45 (m, 4H, Ar-H), 7.25–7.22 (m, 1H, Ar-H), 5.72 (s, 2H, PhCH2), 4.09 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 171.8 (CO), 161.9 (Cquat), 153.3 (CH), 140.6 (Cquat), 137.2 (Cquat), 135.1 (CH), 134.0 (Cquat), 133.7 (CH), 133.4 (CH), 133.1 (Cquat), 130.2 (2CH), 129.1 (2CH), 128,5 (CH), 127.7 (CH), 125.1 (Cquat), 123.2 (CH), 122.4 (CH), 121.5 (CH), 117.2 (Cquat), 112.0 (Cquat), 110.6 (CH), 110.3 (Cquat), 47.8 (CH2), 32.3 (CH2) ppm. HRMS (ESI): calcd. for C26H19ClN5OS [M + H]+ 484.09988; found 484.09994.

3.2.4. General Procedure for the Synthesis of Thioxothiazolinones (10ae)

We mixed 2-thioxothiazolidin-4-one 9 (0.2 g, 1.5 mmol, 1 equiv) and indole-3-carbaldehyde (3ae) (1.65 mmol, 1.1 equiv) in a two-neck round-bottom flask, with a sufficient quantity of ethanol for the dissolution of the starting reagents. The reaction mixture was heated at reflux at 80 °C, and 10 mol% of piperidine was added. The reaction was followed by TLC and at the end of the reaction, the reaction was stopped, and the mixture was cooled to room temperature. The final product was filtered and washed with distilled water to remove traces of piperidine.
(Z)-5-((1-Benzyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one (10a): Yellow solid, 85%, 0.45 g. mp 243–245 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 13.58 (s, 1H, NH), 8.11 (s, 1H), 7.97 (dd, 1H, J = 7.0 Hz, J = 1.6 Hz, Ar-H), 7.91 (s, 1H), 7.57 (dd, 1H, J = 7.0 Hz, J = 1.5 Hz, Ar-H), 7.36–7.20 (m, 7H, Ar-H), 5.60 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 194.6 (CS), 169.1 (CO), 136.9 (Cquat), 136.1 (Cquat), 132.7 (CH), 128.7 (2CH), 127.7 (CH), 127.5 (Cquat), 127.3 (2CH), 123.8 (CH), 123.4 (CH), 121.7 (CH), 118.8 (Cquat), 118.5 (CH), 111.4 (CH), 110.5 (Cquat), 49.8 (CH2) ppm. HRMS (ESI): calcd. for C19H15N2OS2 [M + H]+ 351.06258; found 351.06264.
(Z)-5-((1-(4-Fluorobenzyl)-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one (10b): Yellow solid, 74%, 0.41 g. mp 219–221°C. 1H-NMR (300 MHz, DMSO-d6): δ = 13.58 (s, 1H, NH), 8.12 (s, 1H), 7.96 (dd, 1H, J = 7.0 Hz, J = 1.4 Hz, Ar-H), 7.91 (s, 1H), 7.59 (dd, 1H, J = 7.3 Hz, J = 1.1 Hz, Ar-H), 7.43–7.36 (m, 2H, Ar-H), 7.29–7.14 (m, 4H, Ar-H) 5.58 (s, 2H, PhCH2) ppm. 19F-NMR (282 MHz, DMSO-d6): δ = −114.8 ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 194.6 (CS), 169.1 (CO), 161.9 (d, J = 243 Hz, Cquat), 136.5 (Cquat), 133.1 (d, J = 3.1 Hz, Cquat), 132.6 (CH), 129.5 (d, J = 8.3 Hz, CH), 127.6 (Cquat), 123.8 (CH), 123.5 (CH), 121.8 (CH), 118.8 (CH), 118.6 (Cquat), 115.4 (d, J = 21.5 Hz, CH), 113.4 (CH), 110.6 (Cquat), 49.0 (CH2) ppm. HRMS (ESI): calcd. for C19H14FN2OS2 [M + H]+ 369.05316; found 369.05319.
(Z)-2-Thioxo-5-((1-(3-(trifluoromethyl)benzyl)-1H-indol-3-yl)methylene)thiazolidin-4-one (10c): Yellow solid, 85%, 0.50 g. mp 208–210 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.08 (s, 1H), 7.91–7.87 (m, 1H, Ar-H), 7.87 (s, 1H), 7.73 (bs, 1H, Ar-H), 7.64 (d, 1H, J = 7.8 Hz, Ar-H), 7.59–7.53 (m, 2H, Ar-H), 7.46 (d, 1H, J = 7.6 Hz, Ar-H), 7.28–7.17 (m, 2H, Ar-H), 5.69 (s, 2H, PhCH2) ppm. 19F-NMR (282 MHz, DMSO-d6): δ = −61.1 ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 179.6 (CS), 172.4 (CO), 138.9 (Cquat), 136.1 (Cquat), 131.0 (CH), 130.3 (CH), 129.8 (CH), 129.2 (q, J = 31.7 Hz, Cquat), 127.5 (Cquat), 124.3 (q, J = 3.8 Hz, CH), 124.0 (q, J = 272 Hz, Cquat), 123.7 (q, J = 3.8 Hz, CH), 123.5 (Cquat), 123.1 (CH), 121.1 (CH), 120.7 (CH), 118.7 (CH), 111.0 (Cquat), 110.9 (CH), 48.9 (CH2) ppm. HRMS (ESI): calcd. for C20H14ClF3N2OS2 [M + H]+ 419.04996; found 419.05003.
(Z)-5-((1-(3-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one (10d): Yellow solid, 73%, 0.42 g. mp 265–267 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 13.6 (bs, 1H, NH), 8.13 (s, 1H), 7.97 (d, J = 7.7 Hz, Ar-H), 7.90 (s, 1H), 7.58 (d, 1H, J = 7.8 Hz, Ar-H), 7.41–7.22 (m, 5H, Ar-H), 5.61 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 179.6 (CS), 161.1 (CO), 140.0, 136.5, 133.7, 133.0, 131.2, 131.1, 128.3, 128.2, 127.6, 126.4, 124.0, 122.3, 119.4, 111.8, 111.3, 49.6 (CH2) ppm. HRMS (ESI): calcd. for C19H14ClN2OS2 [M + H]+ 385.02361; found 385.02372.
(Z)-2-((3-((4-Oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indol-1-yl)methyl)benzonitrile e (10e): Yellow solid, 73%, 0.42 g. mp 244–246 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.04 (s, 1H), 7.95–7.91 (d, J = 7.7 Hz, Ar-H), 7.88 (s, 1H), 7.60 (td, 1H, J = 7.7 Hz, J = 1.4 Hz, Ar-H), 7.51–7.46 (m, 2H, Ar-H), 7.28–7.20 (m, 2H, Ar-H), 6.84 (d, J = 7.7 Hz, Ar-H), 5.83 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 179.6 (CS), 172.3 (CO), 140.8 (Cquat), 136.3 (Cquat), 133.8 (CH), 133.4 (CH), 130.8 (CH), 128.4 (CH), 127.4 (Cquat), 127.2 (CH), 123.7 (Cquat), 123.3 (CH), 121.3 (CH), 120.6 (CH), 118.8 (CH), 117.3 (Cquat), 111.2 (Cquat), 110.8 (CH), 110.1 (Cquat), 48.7 (CH2) ppm. HRMS (ESI): calcd. for C20H14N3OS2 [M + H]+ 376.05783; found 376.05788.

4. Conclusions

In summary, we have developed an effective new protocol for the preparation of indole substituted at position 1 and 3 for the series A. Knoevenagel-type condensation affords a new series of thiosemicarbazones or thioxothiazolinones with excellent yields according to the procedures described in [35]. The cyclization of thiosemicarbazones with ethyl bromoacetate furnished a new series of thiazolidinones also with a good yield. In vitro studies of the antimicrobial activity of all these molecules on various pathogenic bacteria (Staphylococcus aureus and Pseudomonas aeruginosa) are in progress in our laboratory.

Supplementary Materials

The following are available online. 1H- & 13C-NMR for compounds 3ae, 4a, 5ae, 7ae, and 10ae.

Author Contributions

Conceptualization, A.B. and A.D.; data curation, N.R. and A.B.; formal analysis, N.R., J.T. and A.B.; investigation, A.B.; methodology, N.R. and S.K.; project administration, A.B.; validation, A.D.; resources, J.T.; writing—original draft preparation, J.T. and A.B.; writing—review and editing, J.T. and A.B.; visualization, J.T. and A.B.; supervision, J.T. All authors discussed the results and commented on the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

We acknowledge Frédéric Montigny (Analysis Department, Tours University) for HRMS analysis. We acknowledge the Algeria Minister of Higher Education and Scientific Research for the financial support.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Singh, P.; Verma, P.; Yadav, B.; Komath, S.S. Synthesis and evaluation of indole-based new scaffolds for antimicrobial activities-identification of promising candidate. Bioorg. Med. Chem. Lett. 2011, 21, 3367–3372. [Google Scholar] [CrossRef] [PubMed]
  2. Minvielle, M.J.; Eguren, K.; Melander, C. Highly active modulators of indole signaling alter pathogenic behaviors in gram-negative and gram-positive bacteria. Chem. Eur. J. 2013, 19, 17595–17602. [Google Scholar] [CrossRef] [PubMed]
  3. Zhang, M.Z.; Mulholland, N.; Beattie, D.; Irwin, D.; Gu, Y.C.; Chen, Q.; Yang, G.F.; Clough, J. Synthesis and antifungal activity of 3-(1,3,4-oxadiazol-5-yl)-indoles and 3-(1,3,4-oxadiazol-5-yl)methyl-indoles. Eur. J. Med. Chem. 2013, 63, 22–32. [Google Scholar] [CrossRef]
  4. Mandour, A.H.; El-Sawy, E.R.; Shaker, K.H.; Mustafa, M.A. Synthesis, anti-inflammatory, analgesic and anticonvulsant activities of 1,8-dihydro-1-aryl-8-alkyl pyrazolo(3,4-b)indoles. Acta Pharm. 2010, 60, 73–88. [Google Scholar] [CrossRef] [Green Version]
  5. Guerra, A.S.; Malta, D.J.; Laranjeira, L.P.; Maia, M.B.; Colaco, N.C.; de Lima Mdo, C.; Galdino, S.L.; Pitta Ida, R.; Goncalves-Silva, T. Anti-inflammatory and antinociceptive activities of indole-imidazolidine derivatives. Int. Immunopharmacol. 2011, 11, 1816–1822. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Ozdemir, A.; Altintop, M.D.; Turan-Zitouni, G.; Ciftci, G.A.; Ertorun, I.; Alatasc, O.; Kaplancikli, Z.A. Synthesis and evaluation of new indole-based chalcones as potential antiinflammatory agents. Eur. J. Med. Chem. 2015, 89, 304–309. [Google Scholar] [CrossRef]
  7. Gitto, R.; Luca, L.D.; Ferro, S.; Citraro, R.; Sarro, G.D.; Costa, L.; Ciranna, L.; Chimirri, A. Development of 3-substituted-1H-indole derivatives as NR2B/NMDA receptor antagonists. Bioorg. Med. Chem. 2009, 17, 1640–1647. [Google Scholar] [CrossRef]
  8. Huang, S.-M.; Hsu, P.-C.; Chen, M.-Y.; Li, W.-S.; More, S.V.; Lu, K.-T.; Wang, Y.-C. The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse. Int. J. Cancer 2012, 131, 722–732. [Google Scholar] [CrossRef]
  9. Ahn, S.; Hwang, D.J.; Barrett, C.M.; Yang, J.; Duke, C.B., III; Miller, D.D.; Dalton, J.T. A novel bis-indole destabilizes microtubules and displays potent in vitro and in vivo antitumor activity in prostate cancer. Cancer Chemoth. Pharmacol. 2011, 67, 293–304. [Google Scholar] [CrossRef]
  10. Schuck, D.C.; Jordao, A.K.; Nakabashi, M.; Cunha, A.C.; Ferreira, V.F.; Garcia, C.R.S. Synthetic indole and melatonin derivatives exhibit antimalarial activity on the cell cycle of the human malaria parasite Plasmodium falciparum. Eur. J. Med. Chem. 2014, 78, 375–382. [Google Scholar] [CrossRef]
  11. Nagalakshmi, G.; Maity, T.K.; Maiti, B.C. Synthesis, characterization and antiviral evaluation of some novel 2-[(substitutedphenyl/heteroaryl)imino]-3-phenyl-1,3-thiazolidin-4-ones. Der Pharm. Lett. 2013, 5, 177–188. [Google Scholar]
  12. Patil, A.P.; Patel, T.K.; Patil, A.R.; Patil, C.S.; Patil, S.T.; Pawar, P. Chemistry and biological activity of 4-thiazolidinone. World J. Pharm. Pharm. Sci. 2015, 4, 1780–1791. [Google Scholar]
  13. Wang, S.; Zhao, Y.; Zhang, G.; Lv, Y.; Zhang, N.; Gong, P. Design, synthesis and biological evaluation of novel 4-thiazolidinones containing indolin-2-one moiety as potential antitumor agent. Eur. J. Med. Chem. 2011, 46, 3509–3518. [Google Scholar] [CrossRef]
  14. Monte, C.D.; Carradori, S.; Bizzarri, B.; Bolasco, A.; Caprara, F.; Mollica, A.; Rivanera, D.; Mari, E.; Zicari, A.; Akdemir, A. Anti-Candida activity and cytotoxicity of a large library of new N-substituted-1,3-thiazolidin-4-one derivatives. Eur. J. Med. Chem. 2016, 107, 82–96. [Google Scholar] [CrossRef] [PubMed]
  15. Abo-Ashour, M.F.; Eldehna, W.M.; George, R.F.; Abdel-Aziz, M.M.; Elaasser, M.M.; Gawad, N.M.A.; Gupta, A.; Bhakta, S.; Abou-Seri, S.M. Novel indole thiazolidinone conjugates: Design, synthesis and whole-cell phenotypic evaluation as a novel class of antimicrobial agents. Eur. J. Med. Chem. 2018, 160, 49–60. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Ottana, R.; Maccari, R.; Giglio, M.; Del Corso, A.; Cappiello, M.; Mura, U.; Cosconati, S.; Marinelli, L.; Novellino, E.; Sartini, S.; et al. Identification of 5-arylidene-4 thiazolidinone derivatives endowed with dual activity as aldose reductase inhibitors and antioxidant agents for the treatment of diabetic complications. Eur. J. Med. Chem. 2011, 46, 2797–2806. [Google Scholar] [CrossRef] [PubMed]
  17. Aly, A.A.; Ishak, E.A.; El Malah, T.; Brown, A.B.; Elayat, W.M. Synthesis of potentially antioxidant and antibacterial biologically active thiazolidines. J. Heterocycl. Chem. 2015, 52, 1758–1764. [Google Scholar] [CrossRef]
  18. Rawal, R.K.; Tripathi, R.; Katti, S.B.; Pannecouque, C.; de Clercq, E. Design, synthesis, and evaluation of 2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents. Bioorg. Med. Chem. 2007, 15, 1725–1731. [Google Scholar] [CrossRef] [PubMed]
  19. Masic, L.P.; Tomasic, T. Rhodanine as a privileged scaffold in drug discovery. Curr. Med. Chem. 2009, 16, 1596–1629. [Google Scholar]
  20. Nitsche, C.; Klein, C.D. Aqueous microwave-assisted one-pot synthesis of N-substituted rhodanines. Tetrahedron Lett. 2012, 53, 5197–5201. [Google Scholar] [CrossRef]
  21. Yarovenko, V.N.; Nikitina, A.S.; Zavarzin, I.V.; Krayushkin, M.M.; Kovalenko, L.V. A convenient synthesis of N-substituted 2-thioxo-1,3-thiazolidin-4-ones. Synthesis 2006, 8, 1246–1248. [Google Scholar] [CrossRef]
  22. Velezheva, V.; Brennan, P.; Ivanov, P.; Kornienko, A.; Lyubimov, S.; Kazarian, K.; Nikonenko, B.; Majorov, K.; Apt, A. Synthesis and antituberculosis activity of indole-pyridine derived hydrazides, hydrazide-hydrazones, and thiosemicarbazones. Bioorg. Med. Chem. 2016, 26, 978–985. [Google Scholar] [CrossRef]
  23. Bacher, G.; Nickel, B.; Emig, P.; Vanhoefer, U.; Seeber, S.; Shandra, A.; Klenner, T.; Beckers, T. D-24851, a novel stnthetic microytubule inhibitor, exerts curative antitumoral activity in vivo, shows efficacy towrd multidrug-resistant tumor celles and lacks neurotoxicity. Cancer Res. 2001, 61, 392–399. [Google Scholar]
  24. Benmohammed, A.; Khoumeri, O.; Djafri, A.; Terme, T.; Vanelle, P. Synthesis of novel highly functionalized 4-thiazolidinone derivatives from 4-phenyl-3-thiosemicarbazones. Molecules 2014, 19, 3068–3083. [Google Scholar] [CrossRef] [Green Version]
  25. Ma, J.; Bao, G.; Wang, L.; Li, W.; Xu, B.; Du, B.; Lv, J.; Zhai, X.; Gong, P. Synthesis, biological evaluation and preliminary mechanism study of novel benzothiazole derivatives bearing indole-based moiety as potent antitumor agents. Eur. J. Med. Chem. 2015, 96, 173–186. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Sing, W.T.; Lee, C.L.; Yeo, S.L.; Lim, S.P.; Sim, M.M. Arylalkylidene rhodanine with bulky and hydrophobic functional group as selective HCV NS3 protease inhibitor. Bioorg. Med. Chem. Lett. 2001, 11, 91–94. [Google Scholar] [CrossRef]
  27. Radi, M.; Botta, L.; Casaluce, G.; Bernardini, M.; Botta, M. Practical One-Pot Two-Step Protocol for the Microwave-Assisted Synthesis of Highly Functionalized Rhodanine Derivatives. J. Comb. Chem. 2010, 12, 200–205. [Google Scholar] [CrossRef]
  28. Kumar, B.R.P.; Soni, M.; Kumar, S.S.; Singh, K.; Patil, M.; Baig, R.B.N.; Adhikary, L. Synthesis, glucose uptake activity and structure–activity relationships of some novel glitazones incorporated with glycine, aromatic and alicyclic amine moieties via two carbon acyl linker. Eur. J. Med. Chem. 2011, 46, 835–844. [Google Scholar] [CrossRef]
  29. Kumar, B.R.P.; Nanjan, M.J. Novel glitazones: Design, synthesis, glucose uptake and structure–activity relationships. Bioorg. Med. Chem. Lett. 2010, 20, 1953–1956. [Google Scholar] [CrossRef] [PubMed]
  30. Kumar, B.R.P.; Nanjan, M.J. QSAR Study on Thiazolidine-2,4-dione Derivatives for Antihyperglycemic Activity. Indian J. Pharm. Sci. 2008, 70, 565–571. [Google Scholar]
  31. Kumar, B.R.P.; Desai, B.J.; Vergheese, J.; Praveen, T.K.; Suresh, B.; Nanjan, M.J. CoMFA Study on Thiazolidine-2,4-diones for their Antihyperglycemic Activity. Lett. Drug Des. Discov. 2008, 5, 79–87. [Google Scholar]
  32. Kumar, B.R.P.; Karvekar, M.D.; Adhikary, L.; Nanjan, M.J.; Suresh, B. Microwave induced synthesis of the thiazolidine-2,4-dione motif and the efficient solvent free-solid phase parallel syntheses of 5-benzylidene-thiazolidine-2,4-dione and 5-benzylidene-2-thioxo-thiazolidine-4-one compounds. J. Heterocycl. Chem. 2006, 45, 897–903. [Google Scholar] [CrossRef]
  33. Kumar, B.R.P.; Praveen, T.K.; Nanjan, M.J.; Karvekar, M.D.; Suresh, B. Serum glucose and triglyceride lowering activity of some novel glitazones against dexamethasone-induced hyperlipidemia and insulin resistance. Indian J. Pharmacol. 2007, 39, 299–302. [Google Scholar]
  34. Armarego, W.L.F.; Chai, C.L.L. Purification of Laboratory Chemicals, 7th ed.; Butterworth-Heinemann: Oxford, UK, 2013. [Google Scholar]
  35. Benmohammed, A.; Rebika, N.; Sehanine, Y.; Louail, A.E.; Khoumeri, O.; Kadiri, M.; Djafri, A.; Terme, T.; Vanelle, P. Synthesis and antimicrobial activities of new thiosemicarbazones and thiazolidinones in indole series. Monatsh. Chem. 2021, 152, 977–986. [Google Scholar] [CrossRef]
Figure 1. Selected biologically active compounds bearing indole-based moiety.
Figure 1. Selected biologically active compounds bearing indole-based moiety.
Molbank 2021 m1284 g001
Scheme 1. Preparation of A, B, or C series.
Scheme 1. Preparation of A, B, or C series.
Molbank 2021 m1284 sch001
Scheme 2. Preparation of N-benzylindole-3-carboaldehyde derivatives 3ae.
Scheme 2. Preparation of N-benzylindole-3-carboaldehyde derivatives 3ae.
Molbank 2021 m1284 sch002
Scheme 3. Preparation of thiosemicarbazones 5ae.
Scheme 3. Preparation of thiosemicarbazones 5ae.
Molbank 2021 m1284 sch003
Scheme 4. Preparation of thiazolidin-4-one derivatives 7ae.
Scheme 4. Preparation of thiazolidin-4-one derivatives 7ae.
Molbank 2021 m1284 sch004
Scheme 5. Preparation of thioxothiazolinones 10ae.
Scheme 5. Preparation of thioxothiazolinones 10ae.
Molbank 2021 m1284 sch005
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Rekiba, N.; Benmohammed, A.; Khanoussi, S.; Djafri, A.; Thibonnet, J. Synthesis and Characterization of Novel Thiazolidinones and Thioxothiazolidinones Derived from Substituted Indole. Molbank 2021, 2021, M1284. https://doi.org/10.3390/M1284

AMA Style

Rekiba N, Benmohammed A, Khanoussi S, Djafri A, Thibonnet J. Synthesis and Characterization of Novel Thiazolidinones and Thioxothiazolidinones Derived from Substituted Indole. Molbank. 2021; 2021(4):M1284. https://doi.org/10.3390/M1284

Chicago/Turabian Style

Rekiba, Nawel, Abdelmadjid Benmohammed, Sofiane Khanoussi, Ayada Djafri, and Jérôme Thibonnet. 2021. "Synthesis and Characterization of Novel Thiazolidinones and Thioxothiazolidinones Derived from Substituted Indole" Molbank 2021, no. 4: M1284. https://doi.org/10.3390/M1284

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop