научная статья по теме ONE-POT THREE-COMPONENT MICROWAVE-ASSISTED SYNTHESIS OF NOVEL THIAZOLIDINONE DERIVATIVES CONTAINING THIENO[D]PYRIMIDINE-4-ONE MOIETY AS POTENTIAL ANTIMICROBIAL AGENTS Химия

ONE-POT THREE-COMPONENT MICROWAVE-ASSISTED SYNTHESIS OF NOVEL THIAZOLIDINONE DERIVATIVES CONTAINING THIENO[^]PYRIMIDINE-4-ONE MOIETY AS POTENTIAL ANTIMICROBIAL AGENTS

© 2015 I. H. El Azab*, **, 1 and Sh. H. Abdel-Hafez*, ***

*Chemistry Department, Faculty of Science, Taif University, Al-Haweiah, Taif, 21974 Saudi Arabia **Chemistry Department, Faculty of Science, Aswan University, Aswan, 81528Egypt ***Chemistry Department, Faculty of Applied Science, Assiut University, Assiut, Egypt

New 2-methyl-5-(4-oxo-2-(substituted phenyl)thiazolidin-3-yl)thieno[3,4-d]-pyrimidin-4-one, 5-(2,7-diphe-nyl-5-thioxo-5,6,7,7a-tetrahydrothiazolo[4,5-d]pyrimidin-3(2H)-yl)-2-methylthieno[3,4-d]pyrimidin-4(3H)-one, and 2-methyl-5-(5-phenyl-thiazolo[5,4-d]isoxazol-6(5H)-yl)thieno[3,4-d]pyrimidin-4(3H)-one have been prepared under microwave-assisted and conventional conditions. The new compounds were screened for their in vitro antimicrobial activity against two gram-positive bacteria (Bacillus subtilis NCIM-2063 and Staphylococcus aureus NCIM-2901), one gram-negative bacteria (Escherichia coli NCIM-2256), and three fungal strains (Candida albicans NCIM-3471, Aspergillus flavus NCIM-539, and Aspergillus niger NCIM-1196) and showed promising biological activity.

Keywords: 4-thiazolidinone derivatives, microwave-assisted synthesis, antimicrobial activity, cytotoxicity.

DOI: 10.7868/S0132342315030021

INTRODUCTION

4-Thiazolidinone ring system has diverse chemother-apeutic potentials including hypnotic activity [1, 2], antitubercular [3], anticonvulsant [4, 5], antibacterial [6, 7], anticancer [8, 9], antihistaminic [10, 11], antifungal [12], anti-inflammatory [13], antiviral [14], and cardiovascular effects [15]. Microwave technique has been used to accelerate chemical reactions in the laboratories [16] as it is a convenient way toward the goal of green/sustainable chemistry, and is strongly recommended for use in recent organic preparations due to its advantages over conventional methods [16—19]. Herein, we report an attempt to use the microwave assistance to prepare new thiazolidine derivatives comparing to the conventional method and to investigate the biological activity of these new compounds on some selected bacteria and fungi.

RESULTS AND DISCUSSION

Chemistry

Irradiation of a mixture of equimolar amounts of 5-amino-2-methylthieno[3,4-rf|-pyrimidin-4(3^)-one (I) with benzaldehyde (IIa) and thioglycolic acid in DMF in presence of 3—4 drops of glacial acetic acid using micro-

1 Corresponding author (phone: +2097480446; fax: +2097480450; e-mail: ihelmy2003@yahoo.com; i.helmy@tu.edu.sa).

wave has afforded compound (IIIa) as shown in Scheme 1. Formation of (IIIa) proceeds via initial condensation reaction of the amino group in (I) with aldehydic group of (II) to afford the corresponding SchifFs base. A nucleo-philic attack by thiol function of thioglycolic acid on the double bond of SchifFs base led to formation of new thiazolidine derivatives (IIIa—j) via two successive intermediates with elimination of water as shown in the figure. IR spectrum of compound (IIIa) showed bands at 1681-1708 cm-1 and 3156-3480 cm-1 assigned for carbonyl and imino groups, respectively. The mass spectrum revealed a molecular ion peak at m/z at 343 (M+, 56%) corresponding to a molecular formula C16H13N3O2S2. Also, the 1H NMR spectrum showed four singlet signals at 5 2.71, 6.12, 6.42, and 9.12 ppm assigned for methyl, methine of thiazolidine, methine of thiophene, and NH groups, respectively, and multiplets at 5 6.71-7.54 ppm due to aromatic protons.

Upon repetition of the reactions under thermal conditions the yields were lower and the time of completion of the reaction wass longer than with microwave assistance, which is a known advantage of the microwave technique in organic synthesis.

Reactivity of the 4-thiazolidinone derivative (IIIa) as a key intermediate for the synthesis offused thiazolo[4,5-d]pyrimidine derivative has been investigated. The one-pot three-component condensation reaction of 2-meth-

X JH2

+

(I)

CHO

R + HS

(IIa—j)

O

Method A

OH

O N-

Method b" HN гЛ

Л,/8

(IIIa—j)

II, III R II, III R

a H f 2,4-Methoxy

b 4-Hydroxy g 2-Chloro

c 2-Nitro h 4-Chloro

d 4-Nitro i 4-CN

e 4-Methoxy j 4-F

Scheme 1. Synthesis of 2-methyl-5-(4-oxo-2-(substituted phenyl)thiazolidin-3-yl)thieno[3,4-rf]pyrimi-din-4-one (IIIa—j). Method A. Microwave-assisted synthesis: AcOH, DMF as a solvent, 110°C, 8—10 min. Method B. Conventional synthesis: AcOH, DMF as a solvent, reflux 4—6 h.

yl-5-(4-oxo-2-phenylthiazolidin-3-yl)thieno[3,4-d]py-rimidin-4(3#)-one (Ilia) with benzaldehyde (Ila) and thiourea proceeded smoothly in DMF containing 34 drops of glacial acetic acid via microwave assistance, as well as the conventional synthesis, to give 5-(2,7-diphe-nyl-5-thioxo-5,6,7,7a-tetrahydrothiazolo[4,5-d]pyrimi-din-3(2^-yl)-2-methyltWeno[3,4-^pyrimidin-4(3#)-one (IV) in excellent yield (Scheme 2, Table 1). The structure of newly synthesized compound was elucidated by combined use ofIR, 1H NMR, 13C NMR, mass spectral data, and elemental analysis. Its IR spectrum showed peaks at 1380, 1681-1708 and 3156-3480 cm-1 assigned for C=S, C=O, and NH stretching, respectively. The 1H NMR spectrum showed the presence of

four singlet signals at 5 2.71, 5.47, 6.42, and 9.41 ppm due to the methyl, thiazole-H2, thiophene-H5, and —NH-C=O of pyrimidine ring, respectively, three doublets centered around 3.41, 4.21, and 4.23 ppm attributed to thiazole-H5, pyrimidine-H6, and -NH-C=S of py-rimidine ring, respectively, and multiplets at 7.03-7.51 due to aromatic protons. The mass spectrum of (IV) showed a molecular ion peak at m/z 489 (55%), corresponding to a molecular formula C24H19N5OS3.

The reaction of thiazolidinone (Ilia) with dimeth-ylformamide-dimethylacetal (DMF-DMA) and hy-droxylamine as potential precursors for thiazolo[5,4-J]isoxazole was also investigated. The one-pot three-component condensation reaction of 2-methyl-5-

H

HN ^ ( O©H mi8ration

Ar

A + O

Ar O

a = HN jl*

Me N

O.

^ /НГ>

N-^-^OH

Ar A ■

-H2O

§0

S —OH HO

Ar

, A

oO

S ^ HO J S N^ HN—(

Ar Ar

Mechanistic pathway of substituted phenyl thiazolidinones (IIIa—j).

(IV)

Scheme 2. Synthesis of 5-(2,7-diphenyl-5-thioxo-5,6,7,7a-tetrahydrothiazolo[4,5-d]pyrimidin-3(2H)-yl)-2-methylthieno[3,4-d]pyrimidin-4(3H)-one (IV).

Method A. Microwave-assisted synthesis: AcOH, DMF as a solvent, 110°C, 9 min. Method B. Conventional synthesis: dry EtOH, conc. hydrochloric acid as a solvent, reflux 6 h.

(4-oxo-2-phenylthiazohdin-3-yl)tWeno[3,4-d]pyrimi-din-4(3#)-one (IIIa) with dimethylformamide-dime-thylacetal and hydroxylamine in DMF containing 34 drops of glacial acetic acid via microwave assisted, as well as the conventional synthesis, to give 2-methyl-5-(5-phenylthiazolo[5,4-d]isoxazol-6(5#)-yl)thieno[3,4-d]pyrimidin-4(3#)-one (V) (Scheme 3). The spectral data of the isolated product was in complete agreement with structure (V). Its IR spectrum showed absorption bands at 3156-3480 and 1681-1708 cm-1 corresponding to NH and two C=O functions, respectively. Its 1H NMR spectrum (DMSO-d6) showed four sharp singlet signals at 6 2.71, 4.95, 6.42, and 8.14 ppm and one broad singlet signal at 6 9.41 ppm characteristic of methyl, thiazole-H2, thiophene-H5, isoxazole-H3, and NH protons, respectively, and a multiplet signal at

8 7.28—7.80 ppm region distinctive for aromatic protons. The mass spectrum showed a molecular ion peak at m/z 367 (35%), corresponding to a molecular formula C14H12N4O2S2.

Antimicrobial Activity

All the synthesized compounds (IIIa—j), (IV), and (V) were screened for their in vitro antimicrobial activity against two gram-positive bacteria (Bacillus subtilis NCIM-2063 and Staphylococcus aureus NCIM-2901) one gram-negative bacteria (Escherichia coli NCIM-2256), and three fungal strains (Candida albicans NCIM-3471 Aspergillus flavus NCIM-539, and Aspergillus niger NCIM-1196). The antibacterial activity of the compounds was monitored by observing their minimum inhibitory concentration (MIC, ^g/mL) as

Table 1. Synthesis of 2-methyl-5-(4-oxo-2-(substituted phenyl)thiazolidin-3-yl)thieno[3,4-d]pyrimidin-4-ones (IIIa—j), (VI), and (V)

Comps. Aldehydes Time Yield, % Melting point, °C

microwave, min conventional, h microwave conventional

(IIIa) Benzaldehyde 8 4 95 85 115-117

(IIIb) 4-Hydroxybenzaldehyde 10 5 97 80 175-177

(IIIc) 2-Nitrobenzaldehyde 10 5 98 87 138-140

(IIId) 4-Nitrobenzaldehyde 8 5 95 78 186-188

(IIIe) 4-Methoxybenzaldehyde 9 4 98 80 252-254

(IIIf) 2, 4-Dimethoxybenzaldehyde 8 6 94 70 151-153

(IIIg) 2-Chlorobenzaldehyde 8 5 96 89 255-257

(IIIh) 4-Chlorobenzaldehyde 9 4 98 75 275-277

(IIIi) 4-Formylbenzonitrile 10 4 98 70 310-312

(IIIj) 4-Fluorobenzaldehyde 9 5 96 85 264-266

(IV) 9 6 97 60 239-241

(V) 10 8 96 65 258-260

(V)

Scheme 3. Synthesis of 2-methyl-5-(5-phenylthiazolo[5,4-d]isoxazol-6(5#)-yl)thieno[3,4-d]pyrimidin-4(3#)-one (V).

Method A. Microwave-assisted synthesis: AcOH, DMF as a solvent, 110°C, 10 min.

Method B. Conventional synthesis: dry xylene containing anhydrous K2CO3 as a solvent, reflux 8 h.

previously described [20, 21] by broth dilution method with ciprofloxacin and ampicillin as control drugs. Flu-conazole and miconazole were used as control drugs for antifungal activity investigation. Methanol was used as solvent control for both antibacterial and antifungal testing.

Antimicrobial activity (MIC value) of the synthesized compound (IIIa—j), (IV), and (V) is shown in Table 2. The synthesized compounds (IIIb), (IIIe), (IIIf), and (V) are the most potent ones against B. subtilis, S. aureus, and E. coli, exhibiting MIC value of15 ^g/mL. This value is about 80% of the value produced with standard antibiotic ampicilline and 28% of that of ciprofloxacin.

Concerning the effect of the synthesized compounds on the tested fungi, the compound (IIIe) was the most potent and declared MIC value of 5 ^g/mL in case of C. albicans and A. flavus. Sur

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