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Original article
12 (
8
); 2091-2097
doi:
10.1016/j.arabjc.2015.01.007

Synthesis and biological evaluation of some novel pyrazole, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives bearing an aryl sulfonate moiety as antimicrobial and anti-inflammatory agents

, ,
 Department of Chemistry, Dnyanopasak College, Parbhani 431401, MS, India

⁎Corresponding author. Fax: +91 2452 242466. babasahebkendre@gmail.com (Babasaheb V. Kendre),

Received: , Accepted: ,
© The Author(s) 2019
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

Abstract

A new series of pyrazole, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives were prepared by the multi-component cyclo-condensation reaction of 1-phenyl-3-(2-(tosyloxy)phenyl)propane-1,3-dione, N,N-dimethylformamide dimethyl acetal and hydrazine or hydroxylamine hydrochloride or 2-aminothiophenol or 2-aminophenol or benzene-1,2-diamine using μwave technique in aqueous media. All the synthesized compounds were evaluated for their anti-bacterial and antifungal activities. Some of the selected compounds were also screened for their anti-inflammatory activity.

Keywords

Pyrazole
Isoxazole
Benzothiazepine
Benzoxazepine
Benzodiazepine
Anti-inflammatory
1

1 Introduction

The efficient and rapid synthesis of biologically active molecules has stimulated synthetic chemists to explore and develop novel strategies which could be certainly useful to the academia and industry. In the past decade the diversity-oriented synthesis and versatile concepts of multi-component processes have extensively motivated the synthetic scientific community (Ugi et al., 2000; Dömling, 2006; Zhu and Bienaymé, 2005). The synthesis of pyrazole and isoxazole derivatives has been the subject of consistent interest because of the widespread applications of such heterocycles in pharmaceutical as well as agrochemical industry (Liu et al., 2010; Liu and Chi, 2013; Kasiotis et al., 2014). Pyrazoles and isoxazoles are well known for their anti-inflammatory activity (Bekhit et al., 2009; Selvam et al., 2005). Numerous compounds containing pyrazole and isoxazole moieties have been shown to exhibit anticancer, integrin αvβ3 receptor antagonists, antimicrobial, molluscicidal, glycine agonists, 20-hydroxyeicosatetraeonic acid (20-HETE) synthase inhibitory, histone deacetylase 3 and 8 (HDAC3 and HDAC8) gene inhibitory, and antioxidant activities (Balbi et al., 2011; Penning et al., 2006; Chauhan et al., 2012; Sharshira and Hamada, 2012; el-Shehry et al., 2010; Drummond et al., 1989; Nakamura et al., 2003; Neelarapu et al., 2011; Padmaja et al., 2009). Furthermore, 1,5-benzoxazepine derivatives have been recognized as novel microtubule-targeting agents (Nathwani et al., 2010). Some substituted benzoxazepine and benzothiazepine were found to exhibit antipsychotic and anticonvulsant activity (Kaur et al., 2012). Moreover, there are some reports for benzothiazepine and benzodiazepine derivatives as anti-inflammatory agents (Gokhan-Kelekc et al., 2007; Panda et al., 2009; Mhaske et al., 2014; Nawrocka et al., 2001; Torres et al., 2000). Several benzothiazepine derivatives have been reported to have potential calcium channel blocker activity (Kaneko, 1994). Benzodiazepines were found to show sentrin-specific protease 1 (SENP1) and p53-mouse double minute 2 (p53-MDM2) inhibitory activities (Qiao et al., 2011; Zhuang et al., 2011). On the other hand, the heterocyclic compounds containing aryl sulfonate moiety are known to exhibit marked antimicrobial activity (Habib et al., 1995). In addition, they are possessed of potential papillomavirus microbicidal, anti-human immunodeficiency virus-1, antineoplastic and anticancer activity (Christensen et al., 2001; Rusconi et al., 1996; Hanna et al., 1991; Betts et al., 2006).

These observations have encouraged us to synthesize some new pyrazole, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives containing aryl sulfonate moiety via the cyclo-condensation reaction in aqueous medium under microwave irradiation conditions by an efficient and general one pot-three component procedure in the hope to evaluate their potential antimicrobial and anti-inflammatory activities.

2

2 Results and discussion

2.1

2.1 Chemistry

The synthesis of pyrazole, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives was carried out by using a more versatile and efficient synthetic route as outlined in Scheme 1. A key step to establish the optimal reaction conditions for the multi-component reaction is the condensation reaction of 1-phenyl-3-(2-(tosyloxy) phenyl) propane-1,3-dione, N,N-dimethylformamide dimethyl acetal and hydrazine hydrate. To accomplish this, we employed similar conditions to those used by Molteni, for the synthesis of pyrazoles from cyclic 1,3-diketone, N,N-dimethylformamide dimethyl acetal and hydrazine hydrate in water at 110 °C temperature under microwave irradiation (Molteni et al., 2002). In continuation of our investigations on the applications of microwave irradiation in organic synthesis (Kendre et al., 2012a, 2012b, 2013), firstly we investigated the synthesis of pyrazoles via the condensation of 1-phenyl-3-(2-(tosyloxy) phenyl) propane-1,3-dione, hydrazine hydrate and N,N-dimethylformamide dimethyl acetal under reflux conditions in water in the absence of catalyst but reaction did not proceed even on prolonged heating. However, the same reaction under conventional condition in the presence of catalytic amount of acetic acid (2–3 drops) gave 40% yield of pyrazole 3a. Similarly, for other derivatives also the conventional heating gave 30–40% yields and time period required for the completion of reaction was 18–20 h. Therefore, we moved our strategy toward the microwave assisted synthesis using same substrates in the presence of catalytic amount of acetic acid (3–4 drops) in water (3–4 mL), maintaining the temperature in the range of 120–140 °C to give pyrazole 3a in 90% yield as a major product in short reaction time. The same condensation reaction was investigated for optimization of the reaction conditions.

Synthesis of pyrazoles, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives.
Scheme 1 Synthesis of pyrazoles, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives.

Thus, the challenge for catalyst optimization that we faced was by using the different amounts of catalyst at 140 °C temperature for the time period of 9–10 min and results are entered in Table 1. The smooth transformation of reactants to product was observed when the amount of catalyst employed was 3 drops at 140 °C temperature to give 90% yield (Entry 3, Table 1). However, the yield remains unchanged when the amount of catalyst was further increased from 3 to 4 and 5 drops.

Table 1 Catalyst optimization for the synthesis of 3a.
Entry Catalyst Time (min) T (°C) Yield (%)a
1 1 Drop 09 140 50.0
2 2 Drops 10 140 80.0
3 3 Drops 10 140 90.0
4 4 Drops 09 140 90.0
5 5 Drops 10 140 90.0
a Isolated yield.

To optimize the reaction temperature, the condensation of 1-phenyl-3-(2-(tosyloxy) phenyl) propane-1,3-dione with hydrazine hydrate and N,N-dimethylformamide dimethyl acetal in water was carried out under microwave irradiation in the presence of catalytic amount of acetic acid (3 drops) at different temperatures ranging from 100 to 150 °C, with an increment of 10 °C temperature each time, the satisfactory yield (90%) of 3a was obtained at 140 °C temperature (Entry 5, Table 2), whereas the yield remains unchanged when the temperature was further increased to 150 °C (Entry 6, Table 2).

The reaction was carried out at different temperatures and at various molar ratios of substrates in the presence of water and acetic acid. The best condition offered for the reaction was 1:1:1 mol ratio of 1-phenyl-3-(2-(tosyloxy) phenyl) propane-1,3-dione, hydrazine hydrate and N,N-dimethylformamide dimethyl acetal in water 3–4 mL at 140 °C temperature in the presence of 3 drops of acetic acid for 9–10 min. The applicability of the present method to a large scale process was examined with 1,3-diketone (15 mmol), phenylhydrazine hydrochloride (15 mmol) and N,N-dimethylformamide dimethyl acetal (15 mmol) in water under microwave irradiation conditions by using acetic acid to give pyrazole 3b in 87% yield. We believe that the current method is simple, efficient and less time consuming for the synthesis of pyrazoles.

The condensation of 1-phenyl-3-(2-(tosyloxy) phenyl) propane-1,3-dione with N,N-dimethylformamide dimethyl acetal and hydroxyl amine hydrochloride in water produces isoxazole 4 in 88% yield under microwave irradiation conditions at 115 °C temperature. Similarly, the synthesis of benzoxazepine, benzothiazepine and benzodiazepine was performed using microwave irradiation technique in short reaction time by condensing 1,3-diketone with N,N-dimethylformamide dimethyl acetal and 2-aminophenol or 2-aminothiophenol or benzene-1,2-diamine in the presence of acetic acid in water.

2.2

2.2 Microwave heating technique

All the reactions were carried out using μwave irradiations in 9–10 min., whereas same reactions under conventional condition gave poor yields and time period required for the completion of reaction was comparatively longer. Therefore, the microwave assisted synthesis offers clean and cheaper alternative path to that of conventional heating, demonstrating that the microwave irradiation facilitates the polarization of molecules causing reaction to occur in shorter reaction times in excellent yield (Polshettiwar and Varma, 2010; Kappe, 2004). In addition, the role of water as solvent in microwave assisted organic synthesis is increased dramatically due to polarity of water which increases heating efficiency causing reaction to occur rapidly. The use of microwave irradiation in present investigation gave 77–90% yields of product, whereas low yields were obtained by conventional method.

3

3 Study of antimicrobial activity

The antibacterial activity of the test samples was determined by agar cup plate method (Indian Pharmacopoeia, 1996; British Pharmacopoeia, 2005) using ampicillin (100 μg/mL) as standard drug and four pathogens such as Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. A sterile borer was used to prepare cups of 10 mm diameter in the agar media spread with the microorganisms. 0.1 mL of inoculums was spread on the agar plate by spread plate technique. Accurately measured (0.1 mL) solution of each synthesized compound and standard samples were added to the cups with a micropipette. All the plates were kept in a refrigerator at 2–8 °C for a period of two hours for effective diffusion of test compounds and standards. Later, they were incubated at 37 °C for 24 h. The presence of definite zones of inhibition around the cup indicated antibacterial activity. The solvent control was run simultaneously to assess the activity of dimethyl sulphoxide (DMSO), which was used as a solvent for extracts. The diameter of the zone of inhibition was measured and recorded.

The antifungal activity of synthesized compounds was determined by using Aspergillus niger, Aspergillus flavus, and Fusarium oxysporium pathogens. Dimethyl sulphoxide was used as control and dextrose agar as culture medium for antifungal activity. Norcadine (100 μg/mL) was used as standard drug for the comparison and determination of their antifungal activities. This method is based on diffusion of antifungal component from reservoir hole to the surrounding inoculated Sabouraud dextrose agar medium, so that the growth of fungus is inhibited as zone around the hole. Using flamed sterile borer the medium was bored and the prepared extracts of three concentrations were taken and 0.1 mL each extract was added in each bore. This procedure was carried out for the both fungi. The surface of Sabouraud’s agar plate was dried out at 35 °C. The above operation was carried out in aseptic condition and 0.1 mL test solution was added to the respective bore and 0.1 mL norcadine was taken as standard reference. A control having only dimethyl sulphoxide was maintained in each plate. The plates were incubated at 35 °C for 48 h. In the end values of zones of inhibition were recorded in mm.

3.1

3.1 Conclusion of antimicrobial activity

All the synthesized compounds in a series 3–5 were screened for their antimicrobial activities using ampicillin and norcadine as standard drugs by the agar cup plate method as reported in Indian and British Pharmacopoeia. The results of survey, Table 3, indicate that all the tested compounds are active against bacterial and fungal strains. However, the compounds 3b and 3c are potent against both Gram-positive and Gram-negative bacteria. This increased potency may be due to the presence of pyrazole ring with aryl sulfonate moiety and the introduction of Ph and (NO2)2Ph groups into position 2 of pyrazole ring in these compounds. The compounds 4, 5a and 5c are equipotent and somewhat less active to that of 3b and 3c against bacteria. Unfortunately, compound 3a is moderately active against both bacterial and fungal strains even though the molecule contains pyrazole ring. The compound 5b exhibits increased potency against fungal strains this may be because of the presence of thiazepine ring and aryl sulfonate moiety. The compound 3c was found to be ineffective against fungi fusarium oxysporium with zero zone of inhibition. The zone of inhibition was also zero for the compounds 5a and 5c against fungi aspergillus flavus.

Table 3 Anti-microbial activity of pyrazole, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives (MCRs).
Entry Zone of inhibition in mm Zone of inhibition in mm
Bacteria Fungi
EC BS PA SA FO AF AN
3a 10 12 12 14 08 10 12
3b 14 18 20 16 13 12 13
3c 17 20 22 18 00 08 12
4 10 16 21 10 15 20 10
5a 15 12 10 19 19 00 10
5b 14 18 16 12 18 18 22
5c 10 15 18 20 15 00 14
Ampicillin 21 24 22 24 NT NT NT
Norcadine NT NT NT NT 27 20 25

EC = E. coli, BS = B. Subtilis, PA = P. aeruginosa, SA = S. aureus, FO = F. oxysporium, AF = A. flavus and AN = A. niger; Concentration: 100 μg mL−1; Control: Dimethyl sulfoxide (DMSO).

3.2

3.2 Study of anti-inflammatory activity

The normal control, indomethacin and test compounds were administered to the rats 30 min before the injection of 0.1 mL of 1% carrageenan suspension in normal saline. The test drugs 50 mg/kg and the standard drug 10 mg/kg were dosed to the animals. The animals were divided into seven groups containing six animals in each group. Each group of the adult Wistar albino rats is divided into three sub groups marked as H (weights 25 g each for male and female), B (weights 30 g each for male and female) and T (weights 50 g each for male and female) respectively and they were used for the study. The animals were kept overnight on fasting. The anti-inflammatory activity study was carried by using Winter et al. method (Winter et al., 1962). The experimental procedures were carried out under the guidelines of Institutional Animal Ethics Committee (IAEC) at National Toxicology Centre, Pune. A No. 26 gauge needle was used to inject the carrageenan suspension into the subplanar region of the right hind paw. Immediately thereafter the edema volume of the injected paws was measured plethysmographically by water displacement method. For comparison purpose the volume of edema at various prefixed time intervals 1 h, 2 h, 4 h and 6 h was measured. The difference between paw volumes of the treated animals was measured and the mean edema volume was calculated. Percentage reduction in edema volume was calculated by using the formula, % reduction = 100 × V0 − Vt/V0. Where, V0 = volume of the paw of control at time ‘t’. Vt = volume of the paw of drug treated at time ‘t’. From the obtained data, the mean edema volume and percentage reduction in edema were calculated. The SD and SEM were calculated by using ANOVA, Dunnet’s ‘t’ test.

3.3

3.3 Conclusion of anti-inflammatory activity

Anti-inflammatory activity data (Table 2) reveal that, most of the tested compounds are found to exhibit good anti-inflammatory effects on the edema paw volumes of treated animals. It is worth mentioning that the minor changes in molecular structure of the pyrazole due to introduction of Ph and (NO2)2Ph groups profoundly influence the activity. Among the tested compounds, only 3a and 3c have showed significant reduction in edema volume when compared to the standard drug indomethacin. This may be due to the presence of pyrazole ring, phenyl ring with –NO2 substituent and aryl sulfonate moiety in a molecule. The derivative 5b also showed good anti-inflammatory activity and this may be due to the presence of benzothiazepine ring. In contrast to pyrazole derivatives the remaining compounds of a series, 4 and 5a were found to be equipotent and moderately active (see Table 4).

Table 2 Temperature optimization for the synthesis of 3a.
Entry Catalyst Time (min) T (°C) Yield (%)a
1 3 Drops 09 100 Trace
2 3 Drops 09 110 20.0
3 3 Drops 09 120 50.0
4 3 Drops 10 130 80.0
5 3 Drops 09 140 90.0
6 3 Drops 10 150 90.0
a Isolated yield
Table 4 Anti-inflammatory activity of pyrazole, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives (MCRs).
Group(n) Substance Dose mg/kg Difference in paw edema value after
1 h 2 h 4 h 6 h
Mean ± SEM % REV Mean ± SEM % REV Mean ± SEM % REV Mean ± SEM % REV
1 Control 0.1 mL 4.94 – 4.63a – 4.93 – 4.73 –
0.219 0.210 0.446 0.262
2 Indomethacin 10 4.56a 7.69 4.16 10.15 4.29 12.98 3.96a 16.27
0.256 0.171 0.231 0.182
3 3a 50 4.74 4.04 4.36b 5.83 4.48b 9.12 4.10 13.31
0.034 0.162 0.311 0.210
4 3c 50 4.78b 3.23 4.39b 5.46 4.50b 8.72 4.15a 12.26
0.404 0.310 0.310 0.223
5 4 50 4.82b 2.42 4.46b 3.67 4.60b 6.69 4.29a 9.30
0.224 0.321 0.312 0.142
6 5a 50 4.80b 2.83 4.40a 4.96 4.58c 7.14 4.28b 9.51
0.211 0.414 0.402 0.256
7 5b 50 4.81b 3.63 4.42b 4.53 4.59c 7.34 4.22b 10.78
0.130 0.114 0.514 0.254

n: Six albino rats in each group; REV: Reduction in edema volume; ± SEM: The standard error of the mean; Standard: Indomethacin drug; Significance level:

a p < 0.05.
b p < 0.01.
c p < 0.001 compared with respective control.

4

4 Experimental

4.1

4.1 Measurements

All the chemicals used were of analytical grade. Melting points were taken in open capillaries and are uncorrected. Purity of compounds was monitored on silica gel-G coated TLC plates. IR spectra were recorded in KBr disk on a shimadzu 650, FTIR spectrophotometer. 1H NMR and 13C NMR spectra were recorded in CDCl3 using a Bruker Avance DPX instrument (1H NMR 200 MHz, 13C NMR 50 MHz). All chemical shifts were reported as δ (ppm) values. Elemental analyses were performed on a Carlo Erba-1108 analyzer. Microwave-assisted reactions were carried out by using Cata Scientific Microwave System (2450 MHz, India).

4.2

4.2 Synthesis

4.2.1

4.2.1 Synthesis of N-substituted 2-(4-Benzoyl-1H-pyrazol-5-yl)phenyl 4-methylbenzene sulfonates 3a–c

A mixture of hydrazine hydrate or phenyl hydrazine (0.01 mol), 1,3-diketone 1 (0.01 mol) and N,N-dimethylformamide dimethyl acetal 2 (0.01 mol) in freshly distilled water (3–4 mL) and acetic acid (2–3 drops) was stirred well and subjected to the microwave irradiation at 130–140 °C temperature for 9–10 min. The progress of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled, dissolved in ethyl acetate, the organic layer was separated, dried by using sodium sulfate and the solid left after the evaporation of solvent was crystallized from ethanol.

4.2.1.1
4.2.1.1 2-(4-Benzoyl-1H-pyrazol-5-yl) phenyl 4-methylbenzene sulfonate 3a

White crystals, Yield 90%, m. p. 120–123 °C; IR (KBr, cm−1): νmax 3081, 2955, 1674, 3445, 1638–1467, 1340. 1H NMR (200 MHz, CDCl3): δ 12.97 (s, 1H), 7.97–7.78 (m, J = 8.7 Hz, 5H), 7.75–7.53 (m, J = 8.4 Hz, 4H), 7.50 (s, 1H), 7.41–7.21 (m, J = 8.9 Hz, 4H), 2.39 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 183.7, 149.4, 147.1, 143.9, 134.9, 132.8, 132.7, 131.5, 130.7, 130.4(2xCH), 129.8, 128.4, 128.0, 127.5, 127.3, 125.6(2xCH), 124.0, 116.1, 114.4, 105.3, 21.7. Elemental analysis: C23H18N2O4S: Calcd: C, 66.01; H, 4.34; N, 6.69; Found; C, 66.11; H, 4.19; N, 6.40.

4.2.1.2
4.2.1.2 2-(4-Benzoyl-1-phenyl-1H-pyrazol-5-yl)phenyl 4-methylbenzene sulfonate 3b

White crystals, Yield 87%, m. p. 132–135 °C; IR (KBr, cm−1): νmax 3085, 2977, 1694, 16348–1465, 1320. 1H NMR (200 MHz, CDCl3): δ 7.91–7.78 (m, J = 8.7 Hz, 4H), 7.76–7.48 (m, J = 8.4 Hz, 5H), 7.42–7.30 (m, J = 8.6 Hz, 5H), 7.27–7.10 (m, J = 7.9 Hz, 4H), 6.55 (s, 1H), 2.29 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 184.7, 147.0, 142.4, 140.3, 138.7, 134.9, 132.8, 132.7, 131.8, 131.5, 130.8, 130.3, 130.2, 129.8, 128.9, 128.7(2xCH), 128.0, 127.7, 127.5, 127.3, 125.8, 124.4, 124.1(2xCH), 120.5, 118.4, 117.4, 21.7. Elemental analysis: C29H22N2O4S: Calcd; C, 70.43; H, 4.48; N, 5.66; Found: C, 70.24; H, 4.44; N, 5.51.

4.2.1.3
4.2.1.3 2-(4-Benzoyl-1-(2,4-dinitro)-phenyl-1H-pyrazol-5-yl)phenyl 4-methylbenzene sulfonate 3c

White crystals, Yield 77.5%, m. p. 204–207 °C; IR (KBr, cm−1): νmax 3087, 2983, 1690, 1652–1470, 1327. 1H NMR (200 MHz, CDCl3): δ 9.46 (s, 1H), 8.84 (s, 1H), 7.83–7.60 (m, J = 8.7 Hz, 5H), 7.52–7.35 (m, J = 8.4 Hz, 5H), 7.18 (s, 1H), 7.01–6.80 (m, J = 7.8 Hz, 4H), 2.32 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 185.1, 147.2, 144.0, 139.7, 137.5, 134.4, 132.6, 132.3, 131.7, 131.5, 130.7, 130.5, 130.3, 129.5, 128.6, 128.5, 128.1(2xCH), 127.6, 127.2, 125.7, 123.5, 120.7, 120.4 (2xCH), 119.3, 118.5, 115.3, 21.7. Elemental analysis: C29H20N4O8S: Calcd; C, 59.59; H, 3.45; N, 9.58; Found: C, 59.60; H, 3.44; N, 9.58.

4.2.2

4.2.2 Synthesis of 2-(4-Benzoyl-1H-isoxazol-5-yl) phenyl 4-methylbenzene sulfonate 4

A mixture of hydroxyl amine hydrochloride (0.01 mol), 1,3-diketone 1 (0.01 mol) and N,N-dimethylformamide dimethyl acetal 2 (0.01 mol) in distilled water (4 mL) was stirred well in the presence of 3–4 drops of acetic acid and subjected to the microwave irradiation at 115 °C temperature for 9–10 min. The progress of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled, dissolved in ethyl acetate, the organic layer was separated, dried by using sodium sulfate and the solid left after the evaporation of solvent was crystallized from ethanol.

4.2.2.1
4.2.2.1 2-(4-Benzoyl-1H-isoxazol-5-yl) phenyl 4-methylbenzene sulfonate

White crystals, Yield 88%, m. p. 115–117 °C; IR (KBr, cm-1): νmax 3089, 2975, 1690, 1648–1470, 1331.1H NMR (200 MHz, CDCl3): δ 7.91–7.76 (m, J = 7.4 Hz, 4H), 7.71–7.40 (m, J = 7.5 Hz, 5H), 7.37 (s, 1H), 7.32–7.10 (m, J = 8.2 Hz, 4H), 2.36 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 183.8, 170.4, 159.4, 147.0, 145.9, 134.9, 132.7, 132.4 (2xCH), 131.8, 130.8 (2xCH), 130.2, 129.8, 128.8, 128.6, 127.5, 127.3 (2xCH), 124.3, 117.4, 98.4, 21.6. Elemental analysis: C23H17NO5S Calcd: C, 65.86; H, 4.09; N, 3.34; Found: C, 65.81; H, 4.07; N, 3.30.

4.2.3

4.2.3 Synthesis of benzoxazepine and benzothiazepine and benzodiazepine 4-methylbenzene sulfonates 5a–c

A mixture of 2-aminothiophenol or 2-aminophenol or benzene-1,2-diamine (0.01 mol), 1, 3-diketone 1 (0.01 mol) and N,N-dimethylformamide dimethyl acetal 2 (0.01 mol) in distilled water (3–4 mL) and acetic acid (4–5 drops) was stirred well and subjected to the microwave irradiation at 130–140 °C temperature for 9–10 min. The progress of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled, dissolved in ethyl acetate, the organic layer was separated, dried by using sodium sulfate and the solid left after the evaporation of solvent was crystallized from ethanol.

4.2.3.1
4.2.3.1 2-(-3-Benzoylbenzo[b] [1, 4] oxazepin-2-yl)phenyl 4-methylbenzene sulfonate 5a

White crystals, Yield 80%, m. p. 108–110 °C; IR (KBr, cm−1): νmax 3069, 2961, 1682, 1648–1492, 1338. 1H NMR (200 MHz, CDCl3): δ 7.89–7.52 (m, J = 8.2 Hz, 4H), 7.41–7.23 (m, J = 8.2 Hz, 5H), 7.12–6.91 (m, 4H), 6.80–6.73 (m, J = 7.4 Hz, 4H), 2.37 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 182.8, 168.0, 159.8, 148.5, 147.0 (2xCH), 143.9, 137.2, 133.8, 133.4 (2xCH), 132.8, 131.7 (2xCH), 130.6, 130.0 (2xCH), 129.4, 128.6, 126.9, 126.5 (2xCH), 124.3, 120.8, 117.0, 116.3 (2xCH), 91.5, 21.7. Elemental analysis: C29H21NO5S: Calcd: C, 70.29; H, 4.27; N, 2.83; Found: C, 70.27; H, 4.26; N, 2.81.

4.2.3.2
4.2.3.2 2-(-3-Benzoylbenzo[b] [1, 4] thiazepin-2-yl)phenyl 4-methylbenzene sulfonate 5b

White crystals, Yield 85%, m. p. 101–104 °C; IR (KBr, cm−1): νmax 3077, 2965, 1684, 1658–1487, 1344. 1H NMR (200 MHz, CDCl3): δ 7.89–7.52 (m, J = 8.2 Hz, 4H), 7.41–7.23 (m, J = 8.4 Hz, 5H), 7.12–6.91 (m, J = 7.6 Hz, 4H), 6.84–6.74 (m, J = 7.4 Hz, 4H), 2.37 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 183.8, 168.0, 158.8, 148.7, 147.0 (2xCH), 145.9, 136.9, 132.8 (2xCH), 132.7, 131.8, 131.7 (2xCH), 130.8, 130.2, 129.8, 128.8 (2xCH), 127.9, 127.5 (2xCH), 124.4, 119.8, 118.3, 115.3 (2xCH), 98.4, 21.7. Elemental analysis: C29H21NO4S2: Calcd: C, 68.08; H, 4.14; N, 2.74; Found: C, 68.17; H, 4.24; N, 2.80.

4.2.3.3
4.2.3.3 2-(-3-Benzoylbenzo[b] [1, 4] diazepin-2-yl)phenyl 4-methylbenzene sulfonate 5c

White crystals, Yield 82%, m. p. 93–95 °C; IR (KBr, cm−1): νmax 3085, 2968, 1687, 1660–1490, 1340. 1H NMR (200 MHz, CDCl3): δ 7.82–7.50 (4H, J = 8.4 Hz, m), 7.40–7.21 (m, J = 8.4 Hz, 5H), 7.10–6.87 (m, J = 7.6 Hz, 4H), 6.81–6.70 (m, J = 6.4 Hz, 4H), 4.75 (s, 1H), 2.35 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 183.8, 163.5, 157.0, 155.3, 148.7, 147.0, 145.9 (2xCH), 137.4, 132.7, 132.5 (2xCH), 131.8, 131.5, 131.4 (2xCH), 130.2, 129.1, 128.0 (2xCH), 127.6, 127.5 (2xCH), 125.4, 120.8, 118.5, 115.6, 98.4, 21.7. Elemental analysis: C29H22N2O4S: Calcd: C, 70.43; H, 4.48; N, 5.66; Found: C, 70.37; H, 4.44; N, 5.70.

5

5 Conclusion

In summary, we have developed an improved and environmentally friendly procedure for the synthesis of pyrazoles, isoxazole, benzoxazepine and benzothiazepine in aqueous media. This methodology offers several advantages such as excellent yield, rapid synthesis, mild reaction conditions and use of eco-friendly solvent media. All the compounds 3a–c, 4 and 5a–c were screened for their antimicrobial activities using ampicillin and norcadine as standard drugs. The comparative activity data for these derivatives showed good antibacterial activity for 3b and 3c and antifungal activity for 5b. Among the tested compounds for anti-inflammatory activity, the pyrazole derivatives 3a and 3b have showed strong activity.

Acknowledgments

We are thankful to Dr. P.L. More, Principal, Dnyanopasak College, Parbhani and Dr. R.K. Ippar, Principal, Vaidyanath College, Parli-Vaijnath for encouragement and laboratory facilities. Authors are also thankful to Dr. K.G. Apte, National Toxicology Centre, Pune, for providing anti-inflammatory activity evaluation data.

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