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Original article
10 (
1_suppl
); S531-S538
doi:
10.1016/j.arabjc.2012.10.015

2-(5-Chlorobenzo[d]thiazol-2-ylimino)thiazolidin-4-one derivatives as an antimicrobial agent

,
 Department of Chemistry, Hemchandracharya North Gujarat University, Patan 384 265, Gujarat, India

⁎Corresponding author. Tel.: +91 2766 220932. sangitamem2000@gmail.com (S. Sharma)

Received: , Accepted: ,
© The Author(s) 2012
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

A series of 2-(5-chlorobenzo[d]thiazol-2-ylimino)-5-((3-(p-substituted phenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-ones (3a–h) were prepared from 2-(5-chlorobenzo[d]thiazol-2-ylimino)thiazolidin-4-one (1) and 1-phenyl-3-(p-substituted phenyl)-1H-pyrazole-4-carbaldehyde (2a–h). All compounds were characterized using elemental analytical (C, H, and N) and spectral (FT-IR, 1H NMR, 13C NMR and GC–MS) data. These compounds were screened for their antibacterial, antifungal and antimycobacterial activities. Antimicrobial activity was evaluated against the bacterial strains e.g., Eschericha coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), H37Rv strain of Mycobacterium tuberculosis, and the antifungal activity was observed against strains e.g., Candida albicans (MTCC 227), Aspergillus niger (MTCC 282) and Aspergillus clavatus (MTCC 1323). All the synthesized compounds were found to possess moderate to excellent activity against selected strains.

Keywords

Knoevenagel condensation reaction
Antibacterial activity
Antifungal activity
Antimycobacterial activity
1-Phenyl-3-(p-substituted phenyl)-1H-pyrazole-4-carbaldehyde
1

1 Introduction

The widespread use of antifungal and antibacterial drugs and the fast development of pathogen resistance to most of the known antibiotics is becoming a serious problem (Chu et al., 1996). So, it has become quite difficult to eradicate these microbial infections (Patterson, 2005). Heterocyclic compounds are reported to be effective against many of these pathogens up to some extent. A heterocyclic compound is one which possesses a cyclic structure with at least two different kinds of hetero atoms in the ring and the most common hetero atoms are nitrogen, oxygen, and sulfur. Heterocyclic compounds are very widely distributed in nature and are essential to life as they play a very important role in the metabolism of many living cells, e.g., amino acids, vitamins, DNA base (purines and pyrimidines) (Achson, 2009).

Benzothiazole moieties are known to be weak base heterocyclic compounds, having diverse biological activities and are of great scientific interest nowadays. They are widely studied in the areas of bioorganic and medicinal chemistry with many applications in drug discoveries. Drugs containing benzothiazole moiety are reported to possess numerable biological activities such as antimicrobial (Gupta et al., 2009; Kumbhare and Ingle, 2009; Lacova et al., 1989; Rajeeva et al., 2009; Maharan et al., 2007), anticancer (Linhong et al., 2006; Kamal et al., 2006; Kini et al., 2007; Stanton et al., 2008), anthelmintic (Sreenivasa et al., 2009), antidiabetic (Pattan et al., 2005; Hermenegilda et al., 2008), anti tuberculosis (Abdel-Rahman and Morsy, 2007; Nandy et al., 2006), antiviral (Shingare et al., 1996; Mane et al., 1996), as well as antitumor (Yoshida et al., 2005; Cedric et al., 2006). Predominantly, 4-thiazolidinones are known to possess various important biological activities such as anti-inflammatory (Ottana et al.,2005), antitubercular (Srivastava et al., 2005), antimicrobial (Mistry and Desai, 2004), anticonvulsant (Kaur et al., 2010), antiviral (Terzioglu et al., 2006), and anti-HIV (Balzarini et al., 2009). Besides these compounds, pyrazole derivatives are also associated with many biologically important activities like antimicrobial (Damljanovic et al., 2009), anti-inflammatory (Bekhit et al., 2008), antitubercular (Chovatia et al., 2007), antitumor (Joksovic et al., 2009), antiangiogenesis (Abadi et al., 2003), antiparasitic (Rathelot et al., 2002), and antiviral (Hashem et al., 2007).

Therefore, it is envisaged that chemical entities with benzothiazole, pyrazole and 4-thiazolidinone moieties would result in compounds of interesting biological activities. In view of these findings, we have attempted to incorporate all these three biologically active components together to give a confined structure like the titled compounds for evaluating their antimicrobial and anti mycobacterial activities.

2

2 Experimental

2.1

2.1 General

The melting points of the products were determined by open capillary method using Mettler Toledo FP 62 melting point apparatus (Metter Toledo-Switzerland) and were used without correction. The FT-IR spectra were recorded on a Perkin Elmer Spectrum GX FT-IR System (USA) in a KBr disk. 1H and 13C spectra were recorded on 200 and 500 MHz Bruker Avance DPX NMR spectrometer using DMSO-d6 as a solvent and TMS as an internal standard. The mass spectra were recorded on a Shimadzu QP2010 spectrometer (equipped with a direct inlet probe) operated at 70 eV. Elemental analysis was carried out on Perkin Elmer CHNS (O) analyzer (PE-2400 Series II-USA). Homogeneity of compounds was checked by analytical TLC on a silica gel GF 254 plate using ethyl acetate/methanol (10:90) as a solvent system.

2.2

2.2 Biological assay

2.2.1

2.2.1 Antibacterial activity

The newly synthesized compounds were screened for their antibacterial activity against gram positive bacteria Staphylococcus aureus (MTCC-96) and Streptococcus pyogenes (MTCC-442) and gram negative Escherichia coli (MTCC-443) and Pseudomonas aeruginosa (MTCC-1688). Thiazole inhibits protein synthesis in bacteria by binding to the complex formed between 23S rRNA and ribosomal protein L11, thereby restricting the action of GTP dependent elongation factors (Porse et al., 1998). Antibacterial activity was carried out by serial broth dilution method (Ghalem and Mohamed, 2009). The standard strains used for the antimicrobial activity was procured from the Institute of Microbial Technology, Chandigarh. The compounds (3a–h) were screened for their antibacterial activity in triplicate against E. coli, S. aureus, P. aeruginosa, and S. pyogenes at different concentrations of 1000, 500, 200, 100, 50, 25, 12.5 μg/ml as shown in (Figs. 3 and 4). The growths of bacterial cultures were monitored after 24 and 48 h. The lowest concentration, which showed no growth after spot subculture was considered as MIC for each drug. The highest dilution showing at least 99% inhibition is taken as MIC. The test mixture should contain 108 cells/ml. The standard drug used was ‘ampicillin’ for evaluating antibacterial activity and it showed 100, 100, 250, and 100 μg/ml MIC against E. coli, P. aeruginosa, S. aureus and S. pyogenes, respectively.

2.2.2

2.2.2 Antifungal activity

Same compounds were tested for antifungal activity in triplicate against Candida albicans, Aspergillus niger, and Aspergillus clavatus at various concentrations of 1000, 500, 200, and 100 μg/ml as shown in (Figs. 5 and 6). The results were recorded in the form of primary and secondary screening. The synthesized compounds were diluted at 1000 μg/ml concentration, as a stock solution. The synthesized compounds which were found to be active in this primary screening were further tested in a second set of dilution against all microorganisms. The lowest concentration, which showed no growth after spot subculture was considered as MIC for each drug. The highest dilution showing at least 99% inhibition is taken as MIC and the test mixture was found to contain 108 spores/ml. “Griseofulvin” was used as a standard drug for antifungal activity and it recorded 500, 100 and 100 μg/ml MIC for C. albicans, A. niger, and A. clavatus, respectively.

2.2.3

2.2.3 Antimycobacterial

The screening of antimycobacterial activity of novel synthesized compound was carried out in vitro against a highly virulent H37Rv strain of Mycobacterium tuberculosis. Antimycobacterial activity was performed as per the LJ Medium (conventional method). The media were incubated for four weeks. The screening was performed in triplicate at 250 μg/ml concentration of compound. “Isoniazid” was used as a standard drug for antimycobacterial activity, which showed 0.2 μg/ml MIC against H37Rv M. tuberculosis strains. The data are as shown in (Figs. 7 and 8).

2.3

2.3 General synthesis method

2.3.1

2.3.1 Synthesis of 2-(5-chlorobenzo[d]thiazol-2-ylimino)thiazolidin-4-one (1)

The titled compound was prepared according to the method reported earlier (Ameya and Nandini, 2007). Characterization data of the compounds matched well with the reported values.

To the cold glacial acetic acid (20 ml), potassium thiocyanate (0.08 mol) and 4-chloro aniline (0.01 mol) were added and mixture was placed in freezing mixture of ice with continuous mechanical stirring. Bromine (1.6 ml) was added at controlled temperature, when all the bromine was added (105 min), the solution was stirred for 2 h below room temperature and then for 10 h at room temperature, and resultant mixture was kept for overnight. Yellow precipitate so obtained was filtered out and the filtrate was neutralized with ammonia to give 2-amino-6-chloro methyl benzothiazole, which was further reacted with chloroacetyl chloride and ammonium thiocyanate to give 2-(5-chlorobenzo[d]thiazol-2-ylimino)thiazolidin-4-one. Product was filtered, washed with water and recrystallized from glacial acetic acid.

2.3.2

2.3.2 Synthesis of 1-phenyl-3-(p-substituted phenyl)-1H-pyrazole-4-carbaldehydes (2a–h)

The titled compounds were synthesized according to the method published earlier (Kira et al., 1969; Prakash et al., 2011a; Prakash et al., 2011b). Characterization data of these compounds matched well with the reported value.

p-Substituted acetophenone (10 mM) on treatment with phenyl hydrazine (10 mM) produced corresponding Schiff's bases. These were added to the chilled formylated solution of dimethyl formamide (10 ml) and phosphorous oxychloride (1.3 ml) at 0–5 °C with continuous mechanical stirring. Reaction mixture was poured to ice to get the pyrazole ring aldehyde. Product was filtered, washed with water and recrystallized from methanol.

2.3.3

2.3.3 2-(5-Chlorobenzo[d]thiazol-2-ylimino)-5-((3-(p-substituted phenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-ones (3a–h)

To a solution of 2-(5-chlorobenzo[d]thiazol-2-ylimino)thiazolidin-4-one (1) in ethanol (10 mM) and fused sodium acetate (10 mM), 1-phenyl-3-(p substituted phenyl)-1H-pyrazole-4-carbaldehyde (2a–h) (10 mM) was added. The reaction mixture was heated under reflux for 6 h. A bright yellow crystalline product was formed and the excess solvent was removed under reduced pressure. Crude product was washed with water, isolated by filtration and re-crystallized from ethanol to yield compounds (3a–h).

2.4

2.4 Physical and spectral data

2.4.1

2.4.1 2-(5-Chlorobenzo[d]thiazol-2-ylimino)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-one (3a)

Yield 76%; Yellow crystalline solid; mp 139–141 °C; IR (KBr, cm−1) ν: 3419 (NH– stretching), 3118, 3054 (Ar-H stretching, pyrazole –H stretching), 1725 (C⚌O stretching), 1579, 1499, 1440 (C⚌N, C⚌C, aromatic ring), 693 (C–S–C linkage), 1332 (C⚌S stretching); 1H NMR (DMSO-d6) δ (ppm): 8.87 (s,1H,–C⚌CH group in pyrazole ring), 8.31–7.41 (m, 15H, Ar-H, C–NH, –C⚌CH); 13C NMR (DMSO-d6) δ (ppm): 158.856, 152.616, 138.848, 131.227, 130.911, 129.755, 128.662, 127.904, 127.606, 126.934, 126.807, 126.230, 123.209, 122.230, 119.568, 116.110, 115.939; MS: m/z: 513 (M+), 276, 215,1 72, 147; Anal. Calcd for C26H16ClN5OS2 (513.0) (%): C, 60.75; H, 3.14; N, 13.62; S, 12.48. Found: C, 60.62; H, 3.28; N, 13.62; S, 12.58.

2.4.2

2.4.2 2-(5-Chlorobenzo[d]thiazol-2-ylimino)-5-((1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-one (3b)

Yield 81%; Yellow crystalline solid; mp Decomposed; IR (KBr, cm−1) ν: 3437 (NH– stretching), 3121, 3057 (Ar-H stretching, pyrazole –H stretching), 1727 (C⚌O stretching), 1579, 1421, 1438 (C⚌N, C⚌C, aromatic ring), 685 (C–S–C linkage), 1337 (C⚌S stretching); 1H NMR (DMSO-d6) δ (ppm): 8.82 (s, 1H, –C⚌CH group in pyrazole ring), 8.05–7.37 (m, 14H, Ar-H, C–NH, –C⚌CH) 2.40 (s, 3H, Ar-CH3 ring); 13C NMR (DMSO-d6) δ (ppm): 130.167, 129.030, 127.971, 127.204, 126.291, 122.899, 122.080, 119.838, 21.372; MS: m/z: 527 (M+), 290, 257, 172, 128; Anal. Calcd for C27H18ClN5OS2 (527.0) (%): C, 61.41; H, 3.44; N, 13.26; S, 12.14. Found: C, 61.72; H, 3.56; N, 13.55; S, 12.21.

2.4.3

2.4.3 2-(5-Chlorobenzo[d]thiazol-2-ylimino)-5-((3-(4-hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-one (3c)

Yield 66%; Yellow crystalline solid; mp Decomposed; IR (KBr, cm−1) ν: 3346 (NH– stretching), 3123, 3053 (Ar-H stretching, pyrazole –H stretching), 1691 (C⚌O stretching), 1576, 1480, 1436 (C⚌N, C⚌C, aromatic ring), 684 (C–S–C linkage), 1329 (C⚌S stretching); 1H NMR (DMSO-d6) δ (ppm): 8.75 (s, 1H, –C⚌CH group in pyrazole ring), 8.13–6.87 (m, 15H, Ar-H, C–NH, –C⚌CH); 13C NMR (DMSO-d6) δ (ppm): 167.091, 166.791, 163.586, 161.753, 153.003, 148.893, 138.878, 130.878, 130.132, 129.754, 128.651, 127.874, 127.562, 121.654, 119.518, 116.099, 115.928; MS: m/z: 529 (M+), 292, 264, 184, 130; Anal. Calcd for C26H16ClN5O2S2 (529.0) (%): C, 58.92; H, 3.04; N, 13.21; S, 12.10. Found: 58.37; H, 3.12; N, 13.07; S, 12.19.

2.4.4

2.4.4 2-(5-Chlorobenzo[d]thiazol-2-ylimino)-5-((3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-one (3d)

Yield 75%; Yellow crystalline solid; mp 267–269 °C; IR (KBr, cm−1) ν: 3424(NH– stretching), 3129, 3077 (Ar-H stretching, pyrazole –H stretching), 1726 (C⚌O stretching), 1579, 1401, 1437 (C⚌N, C⚌C, aromatic ring), 686 (C–S–C linkage), 1346 (C⚌S stretching); 1H NMR (DMSO-d6) δ (ppm): 8.87 (s, 1H, –C⚌CH group in pyrazole ring), 8.46–7.45 (m, 14H, Ar-H, C–NH, –C⚌CH); 13C NMR (DMSO-d6) δ (ppm): 153.922, 153.382, 151.912, 151.429, 148.638, 147.040, 144.992, 139.117, 135.348, 133.572, 151.815, 131.189, 130.239, 120.382, 124.118, 123.259, 122.193, 120.105; MS: m/z: 558 (M+), 321, 275, 209, 147; Anal. Calcd for C26H15ClN6O3S2 (558.0) (%): C, 55.86; H, 2.70; N, 15.03; S, 11.47. Found: C, 55.91; H, 2.89; N, 15.14; S, 11.53.

2.4.5

2.4.5 2-(5-Chlorobenzo[d]thiazol-2-ylimino)-5-((3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-one (3e)

Yield 59%; Yellow crystalline solid; mp Decomposed; IR (KBr, cm−1) ν: 3437 (NH– stretching), 3029 (Ar-H stretching, pyrazole –H stretching), 1728 (C⚌O stretching), 1592, 1504, 1439 (C⚌N, C⚌C, aromatic ring), 682 (C–S–C linkage), 1334 (C⚌S stretching); 1H NMR (DMSO-d6) δ (ppm): 8.86 (s, 1H, –C⚌CH group in pyrazole ring), 8.16–7.38 (m, 14H, Ar-H, C–NH, –C⚌CH); 13C NMR (DMSO-d6) δ (ppm): 162.242, 153.016, 139.322, 131.340, 130.197, 129.072, 128.406, 123.653, 122.134, 119.988; MS: m/z: 531 (M+), 294, 233, 209, 147; Anal. Calcd for C26H16ClFN5OS2 (531.0) (%): C, 58.70; H, 2.84; N, 13.16; S, 12.05. Found: C, 58.61; H, 2.67; N, 13.21; S, 12.17.

2.4.6

2.4.6 2-(5-Chlorobenzo[d]thiazol-2-ylimino)-5-((3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-one (3f)

Yield 69%; Yellow crystalline solid; mp >300 °C; IR (KBr, cm−1) ν: 3436 (NH– stretching), 3121, 3055 (Ar-H stretching, pyrazole –H stretching), 1727 (C⚌O stretching), 1592, 1527, 1439 (C⚌N, C⚌C, aromatic ring), 687 (C–S–C linkage), 1325 (C⚌S stretching); 1H NMR (DMSO-d6) δ (ppm): 8.87 (s, 1H, –C⚌CH group in pyrazole ring), 8.14–7.45 (m, 14H, Ar-H, C–NH, –C⚌CH); 13C NMR (DMSO-d6) δ (ppm): 158.291, 151.947, 138.919, 134.655, 130.090, 129.718, 128.246, 127.381, 126.869, 123.742, 123.168, 122.072, 121.685, 119.408, 115.771; MS: m/z: 591 (M+), 356, 231, 209, 172; Anal. Calcd for C26H15ClBrN5OS2 (591.0) (%): C, 52.67; H, 2.55; N, 11.81; S, 10.82. Found: C, 52.76; H, 2.63; N, 11.78; S, 10.74.

2.4.7

2.4.7 2-(5-Chlorobenzo[d]thiazol-2-ylimino)-5-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-one (3g)

Yield 72%; Yellow crystalline solid; mp >300 °C; IR (KBr, cm−1) ν: 3421 (NH– stretching), 3122, 3060 (Ar-H stretching, pyrazole –H stretching), 1727 (C⚌O stretching), 1584, 1523, 1438 (C⚌N, C⚌C, aromatic ring), 687 (C–S–C linkage), 1338 (C⚌S stretching); 1H NMR (DMSO-d6) δ (ppm): 8.88 (s, 1H, –C⚌CH group in pyrazole ring), 8.06–7.29 (m, 14H, Ar-H, C–NH, –C⚌CH); 13C NMR (DMSO-d6) δ (ppm): 168.193, 138.760, 134.929, 133.119, 129.785, 128.672, 125.720, 125.668, 122.822, 121.743, 119.642, 119.310; MS: m/z: 531 (M+−O••), 294, 283, 209, 182; Anal. Calcd for C26H15Cl2N5OS2 (547.0) (%): C, 56.94; H, 2.76; N, 12.77; S, 11.69. Found: C, 56.75; H, 2.80; N, 12.89; S, 11.79.

2.4.8

2.4.8 2-(5-Chlorobenzo[d]thiazol-2-ylimino)-5-((3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-one (3h)

Yield 79%; Yellow crystalline solid; mp 250–252 °C; IR (KBr, cm−1) ν: 3401 (NH– stretching), 3117, 3038 (Ar-H stretching, pyrazole –H stretching), 1723 (C⚌O stretching), 1585, 1524, 1438 (C⚌N, C⚌C, aromatic ring), 686 (C–S–C linkage), 1321 (C⚌S stretching); 1H NMR (DMSO-d6) δ (ppm): 8.70 (s, 1H, –C⚌CH group in pyrazole ring), 8.11–7.38 (m, 14H, Ar-H, C–NH, –C⚌CH), 4.05 (s, 3H, –OCH3 group in pyrazole ring); 13C NMR (DMSO-d6) δ (ppm): 166.436, 160.019, 153.895, 138.650, 134.125, 130.743, 130.080, 129.577, 129.381, 128.517, 127.545, 123.220, 121.652, 119.430, 115.477, 114,478, 55.290; MS: m/z: 543 (M+), 306, 263, 209, 182; Anal. Calcd for C27H18ClN5O2S2 (543.1) (%): C, 59.61; H, 3.33; N, 12.87; S, 11.79. Found: C, 59.62; H, 3.41; N, 12.97; S, 11.84.

3

3 Results and discussion

3.1

3.1 Chemistry

In present investigations, we have synthesized and characterized the novel 2-(5-chlorobenzo[d]thiazol-2-ylimino)-5-((3-(p-substituted phenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-ones (3a–h) derivatives and their antimicrobial activity was also explored. 6-Chloro-2-benzothiazolamine was synthesized by interaction of p-chloro aniline with potassium thiocyanate in the presence of bromine and further reacted with chloroacetyl chloride and ammonium thiocyanate to give 2-(5-chlorobenzo[d]thiazol-2-ylimino)thiazolidin-4-one (1) (Ameya and Nandini, 2007). The ketones on treatment with phenyl hydrazine yielded corresponding Schiff bases. The Schiff bases of ketones on treatment with dimethyl formamide and phosphorous oxychloride undergo cyclization reaction forming pyrazole derivatives and get formylated onto the pyrazole ring (2a–h) (Kira et al., 1969; Prakash et al., 2011a,b). The final compounds 2-(5-chlorobenzo[d]thiazol-2-ylimino)-5-((3-(p-substituted phenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-ones (3a–h) were synthesized by the reaction of 2-(5-chlorobenzo[d]thiazol-2-ylimino)thiazolidin-4-one with appropriate 1-phenyl-3-(p-substituted phenyl)-1H-pyrazole-4-carbaldehyde (Fig. 1). All the synthesized compounds were characterized by FT-IR, NMR and GC–MS. The IR spectra of synthesized compounds (3a–h) were assigned expected bands. The band observed around 1315–1350 cm−1 was attributed to C⚌S stretching vibration of thiazole ring. Bands at about around 1570–1600 cm−1 were attributed to C⚌N stretching vibration of pyrazole moiety. Strong bands in the region 1685–1745 cm−1 were due to –C⚌O stretching of amide group. 1H NMR and mass spectral data of compound (3a–h) are shown in Section 2. Chemical shift δ at around 8.9–8.7 ppm is due to the presence of –C⚌CH group in pyrazole ring. 13C NMR spectra show chemical shift at 21.372 is due to the presence of –CH3 and chemical shift at 55.290 is due to the presence of –OCH3 in pyrazole aldehyde. Mass-spectra data of all the synthesized compounds are in accordance with its proposed molecular weight. Proposed fragmentation pattern of compound (3d) supports the molecular weight (Fig. 2). The series of synthesized compounds were subjected to C, H, and N analyses.

Schematic representation of the synthesis of 2-(5-chlorobenzo[d]thiazol-2-ylimino)-5-((3-(p-substituted phenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-ones (3a–h).
Figure 1
Schematic representation of the synthesis of 2-(5-chlorobenzo[d]thiazol-2-ylimino)-5-((3-(p-substituted phenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidin-4-ones (3a–h).
Proposed fragmentation pattern of compound (3d).
Figure 2
Proposed fragmentation pattern of compound (3d).

3.2

3.2 Antimicrobial activity

Discovery of novel high profile antimicrobial drugs is always in demand. The process of drugs discovery requires proper scientific approach, perfect planning and technically designed effort. Antimicrobial activities of synthesized compound were performed against four different bacterial strains e.g., E. coli, P. aeruginosa, S. aureus and S. pyogenes and three different fungi e.g., C. albicans, A. niger and A. clavatus. Ampicillin, isoniazid and griseofulvin were used as positive control for bacteria, mycobacteria and fungi, respectively. A solvent control was also recorded to know the activity of the solvent.

3.2.1

3.2.1 Antibacterial activity

The results of antibacterial screening of newly synthesized compounds are presented in (Figs. 3 and 4). For the antibacterial activity, we have selected four different bacterial strains namely gram negative (E. coli, P. aeruginosa) and gram positive (S. aureus and S. pyogenes). For antibacterial activity, compound 3g (R = 4-OCH3) is considered as good active against E. coli as compared to the standard drug ampicillin, while compounds 3a (R = 4-H), 3b (R = 4-CH3), and 3f (R = 4-Br) are considered as moderately active. Compounds 3f (R = 4-Br) and 3g (R = 4-Cl) are moderately active against P. aeruginosa. Compound 3f (R = 4-Br) is considered as excellently active against S. aureus as compared to the standard drug ampicillin, while compounds 3a (R = 4-H), 3g (R = 4-Cl) and 3h (R = 4-OCH3) are considered as good active and compounds 3b (R = 4-CH3), 3d (R = 4-NO2) and 3e (R = 4-F) are considered as moderately active. Compound 3f (R = 4-Br) is considered as good active against S. pyogenes as compared to the standard drug ampicillin, while compounds 3a (R = 4-H), 3g (R = 4-Cl) and 3h (R = 4-OCH3) are considered as moderately active.

Comparative chart of antibacterial activity for compounds (3a–h).
Figure 3
Comparative chart of antibacterial activity for compounds (3a–h).
Comparative chart of antibacterial activity for compounds (1 and 2a–h).
Figure 4
Comparative chart of antibacterial activity for compounds (1 and 2a–h).

Among all the synthesized compounds, compound 3f (R = 4-Br) shows very good activity for all bacterial strains when compared to parent compound 1 and 2f except in case of E. coli (Fig. 9). However, the other synthesized compounds showed specificity for particular microbial strain and thereby revealed random distribution pattern of inhibition potential when compared to their parental compound.

3.2.2

3.2.2 Antifungal activity

Antifungal screening of data of newly synthesized compounds is as per (Figs. 5 and 6). For the antifungal activity, we have taken three different fungal strains like C. albicans, A. niger, and A. clavatus. For antifungal activity, it has been observed that compounds 3e (R = 4-F) and 3g (R = 4-Cl) are found to be excellent active against C. albicans as compared to the standard drug griseofulvin, while compounds 3d (R = 4-NO2) and 3f (R = 4-Br) are considered as very good active and compound 3c (R = 4-OH) is considered as good active. Among all the synthesized compounds, compound 3f (R = 4-Br) shows very good activity for all fungal strains compared to parent compounds 1 and 2f (Fig. 9).

Comparative chart of antifungal activity for compounds (3a–h) (∗MIC value greater than 1000 μg/ml).
Figure 5
Comparative chart of antifungal activity for compounds (3a–h) (∗MIC value greater than 1000 μg/ml).
Comparative chart of antifungal activity for compounds (1 and 2a–h) (∗MIC value greater than 1000 μg/ml).
Figure 6
Comparative chart of antifungal activity for compounds (1 and 2a–h) (∗MIC value greater than 1000 μg/ml).

3.2.3

3.2.3 Antimycobacterial activity

The results of antimycobacterial screening of the synthesized compounds are presented in (Figs. 7 and 8). For the anti tuberculosis activity, we have taken highly virulent H37RV strain of M. tuberculosis. Compounds 3a (R = 4-H) and 3e (R = 4-F) possess good antimycobacterial activity and other compounds like, 3b (R = 4-CH3), 3c (R = 4-OH), 3d (R = 4-NO2), 3f (R = 4-Br), 3g (R = 4-Cl) and 3h (R = 4-OCH3) possess poor antimycobacterial activity.

Comparative chart of antimycobacterial activity for compounds (3a–h) (∗99% Inhibition at 0.2 μg/ml concentration of isoniazid and all the compounds were screened at 250 μg/ml concentration).
Figure 7
Comparative chart of antimycobacterial activity for compounds (3a–h) (∗99% Inhibition at 0.2 μg/ml concentration of isoniazid and all the compounds were screened at 250 μg/ml concentration).
Comparative chart of antimycobacterial activity for compounds (1 and 2a–h) (∗99% Inhibition at 0.2 μg/ml concentration of isoniazid and all the compounds were screened at 250 μg/ml concentration).
Figure 8
Comparative chart of antimycobacterial activity for compounds (1 and 2a–h) (∗99% Inhibition at 0.2 μg/ml concentration of isoniazid and all the compounds were screened at 250 μg/ml concentration).
Comparative chart of antibacterial and anti fungal activity for compounds (1, 2f and 3f).
Figure 9
Comparative chart of antibacterial and anti fungal activity for compounds (1, 2f and 3f).

4

4 Conclusion

A series of 2-(5-chlorobenzo[d]thiazol-2-ylimino)-5-((3-(p-substituted phenyl)-1-phenyl-1H-pyrazol-yl)methylene)thiazolidin-4-ones (3a–h) were synthesized from 2-(5-chlorobenzo[d]thiazol-2-ylimino)thiazolidin-4-one (1) and 1-phenyl-3-(p-substituted phenyl)-1H-pyrazole-4-carbaldehydes (2a–h). Analytical and spectral data (FT-IR, 1H NMR, 13C NMR, GC–MS) of all the synthesized compounds were in good agreement with the proposed structure. Comparison of the antimicrobial results of synthesized compounds (3a–h) has revealed that the addition of pyrazole derivatives in 2-(5-chlorobenzo[d]thiazol-2-ylimino)thiazolidin-4-one (1) has improved their antimicrobial activity. Most of the compounds were found to be active against tested microorganisms. A series of 2-(5-chlorobenzo[d]thiazol-2-ylimino)-5-((3-(p-substitutedphenyl)-1-phenyl-1H-pyrazol-yl)methylene)thiazolidin-4-ones (3a–h) exhibited moderate to excellent antibacterial, antifungal and antimycobacterial activities.

Acknowledgment

Authors are thankful to the “Microcare laboratory and TRC” – Surat, Gujarat, India for carrying out microbial studies.

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Appendix A

Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2012.10.015.

Appendix A

Supplementary data

Supplementary data

Supplementary data Spectral data.


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