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Design, synthesis and biological evaluation of 5-(2-(4-(substituted benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one and 5-(2-(4-substitutedpiperazin-1-yl)acetyl)indolin-2-one analogues as novel anti-tubercular agents
⁎Corresponding author. Tel.: +91 40 6303527; fax: +91 40 66303998. kvgc@hyderabad.bits-pilani.ac.in (Kondapalli Venkata Gowri Chandra Sekhar) kvgcs@yahoo.com (Kondapalli Venkata Gowri Chandra Sekhar)
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Received: ,
Accepted: ,
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 thirty-six novel 5-(2-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one and 5-(2-(4-substitutedpiperazin-1-yl)acetyl)indolin-2-one analogues were synthesized, characterized and screened for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. These compounds exhibited minimum inhibitory concentration between 1.56 and 50 μg/mL. Among these derivatives, compounds 10c, 10d, 10j, 10o and 10v (MIC 6.25 μg/mL) displayed moderate activity, while compounds 10e, 10l, 10q, 10w,10x, 12d, 12e and 12i (MIC 3.12 μg/mL) showed good anti-tubercular activity and compounds 10f, 10k, 10p, 10r, 12f, 12j and 12k (MIC 1.56 μg/mL) exhibited excellent anti-tubercular activity. In addition, MTT assay was accomplished on the active analogues of the series against mouse macrophage (RAW 264.7) cells to evaluate the cytotoxic effect of the newly synthesized compounds and selectivity index of the compounds was determined.
Keywords
Benzisoxazole
Oxindole
Piperazine
Mycobacterium tuberculosis
Anti-tubercular agents
1 Introduction
Tuberculosis (TB) is a mortality disease caused by tubercle bacilli. TB represents one of the major public health concerns worldwide after the HIV/AIDS and it is one of the major causes of death in HIV patients. In general, tubercle bacilli attack every second individual according to the World Health Organization (WHO). When Mycobacterium tuberculosis (MTB) attacks lungs it leads to pulmonary TB and when MTB assails to any part of the body such as kidney, spine and brain it results in extra pulmonary TB. Majority of TB mortality cases are evinced in the evolving countries and more than 50% of deaths occur in Asia alone. According to WHO, in 2013 nine million people fell ill with TB including 1.5 million people with HIV among them. Worldwide, 0.51 million women died from TB in 2013 and it is top three eradicators for women. In 2013, 0.55 million children fell ill with TB and assessed 0.08 million children who were HIV-negative died from TB (WHO Global TB report, 2014a, b). The Multidrug resistant TB (MDR-TB) is a form of TB which occurs once MTB strain turns resistant to the most effective anti-TB drugs i.e. isoniazid and rifampin. In 2013, worldwide 0.45 million people developed MDR-TB and there were 0.21 million deaths resulting from MDR-TB. Extensively drug resistant TB (XDR-TB) occurs when MTB strain is resistant to at least isoniazid and rifampin in addition to being resistant to one of the fluoroquinolones, as well as resistant to at least one of the second line injectable drugs i.e. amikacin, kanamycin or capreomycin. By the end of 2013, XDR-TB was found worldwide in 100 countries. Approximately, 9% of MDR-TB cases lead to XDR-TB which is associated with higher mortality rate than MDR-TB. Totally drug resistant TB (TDR-TB) or extremely drug resistant TB (XXDR-TB) is not been clearly defined by WHO. It transpires when MTB strain becomes resistant to total first and second line anti-TB drugs. It is very uncontrollable although not always difficult to treat. Prevalence of XDR-TB and TDR-TB has increased worldwide. While in last few decades there are no novel anti-TB drugs except for bedaquiline and delamanid which are used for the treatment of pulmonary MDR-TB patients in serious or life-threatening conditions (WHO Global TB report, 2014a, b; Ashish et al., 2014). Hence, there is an urgent need to explore for novel chemophores which can cure drug resistant forms of this mortal disease with minimal side effects. Focus should also be to curtail the cost of the drugs and the treatment era.
Heterocyclic derivatives have broad spectrum of biological importance and applications. Chiefly, oxindole derivatives have known pharmacological activities such as antimicrobial (Singh et al., 2014), anticancer (Prathima et al., 2014; Natarajan et al., 2004), antioxidant (Yasuda et al., 2013), serine palmitoyl transferase inhibitor (Kiser et al., 2012; Hanada, 2004), HIV protease inhibitors (Eissenstat et al., 2012), growth hormone secretagogue (Tokunaga et al., 2005), progesterone receptor antagonists (Fensome et al., 2002), neurodepressant (Mannaioni et al., 1998), cyclin-dependent kinase inhibitor (Woodard et al., 2003; Bramson et al., 2001), tyrosine kinase inhibitor (Tourneau et al., 2007) and notably, few reports as anti-tubercular agents (Ranjith Kumar et al., 2009; Güzel et al., 2008; Karali et al., 2007; Sriram et al., 2006; Chande et al., 2005). Impressed by its wide range of pharmacological activities and our continuous investigation on novel anti-TB agents (Naidu et al., 2014) we envisaged to explore these new analogues for anti-mycobacterial activity.
The benzisoxazole analogues have all-embracing biological activities and physiochemical properties, viz. antimicrobial (Suhas et al., 2011; Priya et al., 2005), anti-HIV (Deng et al., 2009, 2006), antidiabetic (Shantharam et al., 2013), anticancer (Monish and Chul-Hoon, 2003), antipsychotic (Chen et al., 2013; Strupczewski et al., 1995), anticonvulsant (Malik et al., 2014; Uno et al., 1979), and Acetylcholinesterase inhibitors (Villalobos et al., 1994); in particular Subash et al., reported 5-tert-Butyl-N-pyrazol- 4-yl-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide derivatives with excellent anti-TB activity (Subash et al., 2008) and also our group recently published, design, synthesis and antimycobacterial activity of various 3-(4-(substitutedsulfonyl)piperazin-1-yl) benzo[d]isoxazole derivatives (Naidu et al., 2014).
The significance of aryl piperazine, and lipophilicity of chemophores play vital role in the physiochemical properties and biological activities. Attaching aryl piperazine analogues enriches the lipophilicity of compounds (Mortenson et al., 2011; Kakwani et al., 2011). Accordingly, aryl piperazine derivatives are known to exhibit wide range of pharmacological activities and physiochemical properties. Indeed, these aryl piperazine analogues display enhanced antibacterial and anti-TB activity (Patel et al., 2014; Nagesh et al., 2014; Thomas et al., 2011; Punkvang et al., 2010; Tangallapally et al., 2005).
Enthused by the pharmacological activities and significance of oxindole, benzisoxazole and aryl piperazine motifs, we sketched out a synthetic route to incorporate these three pharmacophores into a single framework. We designed and synthesized new 5-(2-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one and 5-(2-(4-substitutedpiperazin-1-yl)acetyl)indolin-2-one analogues and evaluated for their antimycobacterial activity. The strategy to achieve title compounds is portrayed in Fig. 1.
Design strategy to achieve title compounds.
2 Material and methods
2.1 General
Chemicals and solvents were procured from commercial units, viz. Aldrich India Ltd., E. Merck India Ltd. These solvents and reagents were of LR grade and if necessary purified before use. Thin-layer chromatography (TLC) was carried out on aluminium-supported silica gel plates (Merck 60 F254) with visualization of components by UV light (254 nm). Column chromatography was carried out on silica gel (Merck 100–200 mesh). 1H NMR spectra and 13C NMR spectra were recorded at 400 MHz using a Bruker AV 400 spectrometer (Bruker CO., Switzerland) in CDCl3 and DMSO-d6 solution with tetramethylsilane as the internal standard, and chemical shift values (δ) were given in ppm. Title compound reactions are accomplished in Biotage Microwave Synthesizer (model – Initiator 2.5). Melting points were determined on an electrothermal melting point apparatus (Stuart-SMP30) in open capillary tubes and are uncorrected. IR spectra were recorded with an FT-IR spectrophotometer (Jasco FTIR-4200). Solid compounds were analysed by KBr disc method and semi-solid compounds were recorded as neat samples. νmax is expressed in cm−1; Elemental analyses were analysed by Elementar Analysensysteme GmbH vario MICRO cube CHNS/O Analyzer. Mass spectra (ESI–MS) were recorded on Schimadzu MS/ESI mass spectrometer. All tested compounds’ purity was greater than 95%.
2.2 Experimental
We synthesized key intermediates, substituted 5-(2-chloroacetyl)indolin-2-ones (4a–f), from N-substituted anilines (1a–c) as per literature protocol (Howard et al., 1996; Sumpter et al., 1945). On other hand, cardinal synthon 3-(piperazin-1-yl)benzo[d]isoxazole derivatives (9a–d) were prepared from substituted 2-chlorobenzaldehyde (5a–d) according to our recently published article (Naidu et al., 2014).
2.2.1 General procedure for the synthesis of 5-(2-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one (10a–x) and 5-(2-(4-substitutedpiperazin-1-yl)acetyl)indolin-2-one (12a–l) derivatives:
To a mixture of 3-(piperazin-1-yl)benzo[d]isoxazole derivatives (9a–d) (1.0 equiv.) or 4-substitutedpiperazin (11a–b) (1.0 equiv.) analogues, oxindole derivatives (4a–f) (1.1 equiv.) and anhydrous potassium carbonate (1.2 equiv.) were added in acetonitrile and refluxed in microwave oven for 10 min. Once the reaction is complete, as indicated by TLC, the reaction mixture was allowed to rt. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic layers were collected, washed with saturated brine solution, dried over anhydrous Na2SO4 and concentrated in vacuo. The resultant crude products were purified by column chromatography (1–8% methanol in CH2Cl2) to get the title compounds in yields ranging from 60% to 94%.
2.2.1.1 5-(2-(4-(Benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one (10a)
Appearance: pale orange solid; mp = 164–165 °C; FTIR: 3366, 3174, 3037, 1726, 1681, 1522, 1500, 1446, 908. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (b, 1H), 8.08 (d, J = 9.6 Hz, 1H), 7.96 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.48 (m, 2H), 7.24 (dd, J = 8.0 Hz, 1H), 6.89 (dd, J = 8.0 Hz, 1H), 3.88 (s, 2H), 3.69 (t, 4H), 3.57 (s, 2H), 2.80 (t, 4H). 13C NMR (100 MHz, DMSO-d6) δ 190.81, 178.78, 163.31, 160.08, 148.56, 131.22, 130.45, 129.94, 127.89, 123.41, 122.97, 122.75, 115.12, 110.28, 108.44, 63.23, 52.98, 44.34, 34.12. ESI–MS: (m/z) calculated for C21H20N4O3, calculated: 376.15, found: 377.24 (M + H)+. Anal. Calcd for C21H20N4O3: (%) C 67.01, H 5.36, N 14.88. Found: C 67.12, H 5.41, N 14.94.
2.2.1.2 5-(2-(4-(Benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-3-methylindolin-2-one (10b)
Appearance: pale yellow semi solid; mp = not determined (ND); FTIR: 3385, 3156, 3061, 1721, 1699, 1550, 1502, 1451, 920. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (b, 1H), 8.04 (d, J = 9.6 Hz, 1H), 7.91 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.52 (m, 2H), 7.25 (dd, J = 8.0 Hz, 1H), 6.92 (dd, J = 8.0 Hz, 1H), 3.87 (s, 2H), 3.65 (t, 4H), 3.48 (q, 1H), 2.92 (t, 4H), 1.51 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 191.02, 178.94, 162.75, 161.12, 149.03, 132.11, 130.29, 129.88, 127.45, 124.12, 123.94, 122.67, 116.23, 111.35, 107.98, 64.01, 53.11, 43.89, 41.56, 15.78. ESI–MS: (m/z) calculated for C22H22N4O3, calculated: 390.16, found: 391.24 (M + H)+. Anal. Calcd for C22H22N4O3: (%) C 67.68, H 5.68, N 14.35. Found: C 67.76, H 5.74, N 14.42.
2.2.1.3 5-(2-(4-(Benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-methylindolin-2-one (10c)
Appearance: pale yellow solid; mp = 178–179 °C; FTIR: 3098, 3042, 1718, 1700, 1548, 1499, 1438, 918. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 9.6 Hz, 1H), 7.95 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.51 (m, 2H), 7.24 (dd, J = 8.0 Hz, 1H), 6.89 (dd, J = 8.0 Hz, 1H), 3.86 (s, 2H), 3.67 (t, 4H), 3.58 (s, 2H), 3.26 (s, 3H), 2.83 (t, 4H). 13C NMR (100 MHz, CDCl3) δ 192.01, 179.27, 162.68, 161.11, 149.84, 130.86, 130.09, 129.66, 128.22, 124.57, 123.34, 122.79, 117.14, 116.68, 110.24, 63.55, 52.61, 43.94, 36.33, 34.28. ESI–MS: (m/z) calculated for C22H22N4O3, calculated: 390.16, found: 391.26 (M + H)+. Anal. Calcd for C22H22N4O3: (%) C 67.68, H 5.68, N 14.35. Found: C 67.78, H 5.72, N 14.46.
2.2.1.4 5-(2-(4-(Benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1,3-dimethylindolin-2-one (10d)
Appearance: brown solid; mp = 114–115 °C; FTIR: 3148, 3068, 1722, 1698, 1544, 1502, 1446, 915. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 9.6 Hz, 1H), 7.94 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.49 (m, 2H), 7.23 (dd, J = 8.0 Hz, 1H), 6.95 (dd, J = 8.0 Hz, 1H), 3.92 (s, 2H), 3.68 (t, 4H), 3.52 (q, 1H), 3.27 (s, 3H), 2.88 (t, 4H), 1.48 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 191.48, 178.74, 163.08, 160.89, 149.57, 131.80, 130.22, 129.01, 128.31, 124.38, 123.12, 122.04, 118.22, 117.21, 110.99, 63.65, 53.01, 44.23, 41.28, 37.64, 16.25. ESI–MS: (m/z) calculated for C23H24N4O3, calculated: 404.18, found: 405.23 (M + H)+. Anal. Calcd for C23H24N4O3: (%) C 68.30, H 5.98, N 13.85. Found: C 68.41, H 5.92, N 13.94.
2.2.1.5 5-(2-(4-(Benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-ethylindolin-2-one (10e)
Appearance: pale yellow solid; mp = 174–175 °C; FTIR: 3154, 3068, 1720, 1688, 1549, 1500, 1451, 921. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.6 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.50 (m, 2H), 7.24 (dd, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.0 Hz, 1H), 3.90 (s, 2H), 3.66 (t, 4H), 3.54 (s, 2H), 3.31 (q, 2H), 2.92 (t, 4H), 1.31 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 190.98, 178.11, 163.75, 161.02, 148.24, 131.77, 130.45, 130.11, 128.88, 124.65, 123.13, 122.40, 117.02, 116.27, 109.44, 61.02, 52.13, 44.52, 40.56, 36.04, 13.18. ESI–MS: (m/z) calculated for C23H24N4O3, calculated: 404.18, found: 405.26 (M + H)+. Anal. Calcd for C23H24N4O3: (%) C 68.30, H 5.98, N 13.85. Found: C 68.43, H 5.94, N 13.91.
2.2.1.6 5-(2-(4-(Benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-ethyl-3-methylindolin-2-one (10f)
Appearance: orange solid; mp = 120–121 °C; FTIR: 3160, 3075, 1714, 1692, 1547, 1508, 1450, 924. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.51 (m, 2H), 7.24 (dd, J = 8.0 Hz, 1H), 6.91 (dd, J = 8.4 Hz, 1H), 3.87 (s, 2H), 3.81 (q, 2H), 3.68 (t, 4H), 3.50 (q, 1H), 2.84 (t, 4H), 1.52 (d, J = 7.6 Hz, 3H), 1.30 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 189.83, 177.84, 163.30, 160.09, 148.54, 131.12, 130.32, 129.91, 127.89, 123.40, 122.97, 122.80, 115.11, 110.18, 108.30, 59.75, 51.09, 44.34, 40.12, 34.19, 14.78, 12.55. ESI–MS: (m/z) calculated for C24H26N4O3, calculated: 418.20, found: 419.28 (M + H)+. Anal. Calcd for C24H26N4O3: (%) C 68.88, H 6.26, N 13.39. Found: C 68.94, H 6.12, N 13.42.
2.2.1.7 5-(2-(4-(4-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one (10g)
Appearance: Pale yellow semi solid; mp = ND; FTIR: 3381, 3165, 3038, 1721, 1688, 1519, 1501, 1446, 900, 780. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (b, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.72 (dd, J = 1.2 Hz, 1H), 7.68 (m, 1H), 7.49 (dd, J = 0.8 Hz, 1H), 7.28 (dd, J = 8.4 Hz, 1H), 3.91 (s, 2H), 3.72 (t, 4H), 3.48 (s, 2H), 2.81 (t, 4H). 13C NMR (100 MHz, DMSO-d6) δ 190.76, 179.08, 163.45, 161.11, 149.03, 132.33, 131.48, 130.92, 129.89, 129.47, 123.97, 122.75, 118.12, 111.35, 109.87, 63.11, 52.91, 44.13, 34.83. ESI–MS: (m/z) calculated for C21H19ClN4O3, calculated: 410.11, found: 411.18 (M + H)+. Anal. Calcd for C21H19ClN4O3: (%) C 61.39, H 4.66, N 13.64. Found: C 61.47, H 4.72, N 13.72.
2.2.1.8 5-(2-(4-(4-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-3-methylindolin-2-one (10h)
Appearance: pale yellow solid; mp = 149–150 °C; FTIR: 3368, 3164, 3030, 1718, 1679, 1518, 1508, 1451, 902, 788. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (b, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.74 (dd, J = 1.2 Hz, 1H), 7.68 (m, 1H), 7.47 (dd, J = 0.8 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 3.93 (s, 2H), 3.67 (t, 4H), 3.60 (q, 1H), 2.62 (t, 4H), 1.53 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 191.08, 179.12, 162.23, 160.92, 149.45, 132.02, 131.27, 130.66, 129.47, 129.11, 124.14, 123.23, 120.04, 112.35, 111.05, 64.01, 52.44, 43.84, 40.88, 35.12, 16.13. ESI–MS: (m/z) calculated for C22H21ClN4O3, calculated: 424.13, found: 425.22 (M + H)+. Anal. Calcd for C22H21ClN4O3: (%) C 62.19, H 4.98, N 13.19. Found: C 62.27, H 5.03, N 13.26.
2.2.1.9 5-(2-(4-(4-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-methylindolin-2-one (10i)
Appearance: pale yellow solid; mp = 191–192 °C; FTIR: 3179, 3048, 1717, 1670, 1512, 1508, 1450, 895, 792. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.71 (dd, J = 1.6 Hz, 1H), 7.58 (m, 1H), 7.46 (dd, J = 1.2 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 3.88 (s, 2H), 3.69 (t, 4H), 3.63 (s, 2H), 3.34 (s, 3H), 2.81 (t, 4H). 13C NMR (100 MHz, CDCl3) δ 190.71, 177.84, 163.03, 160.57, 150.12, 132.24, 131.11, 130.26, 129.86, 129.01, 124.38, 123.09, 119.84, 116.91, 110.12, 63.87, 52.22, 43.07, 35.19, 33.82. ESI–MS: (m/z) calculated for C22H21ClN4O3, calculated: 424.13, found: 425.25 (M + H)+. Anal. Calcd for C22H21ClN4O3: (%) C 62.19, H 4.98, N 13.19. Found: C 62.23, H 5.05, N 13.24.
2.2.1.10 5-(2-(4-(4-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1,3-dimethylindolin-2-one (10j)
Appearance: pale yellow solid; mp = 209–210 °C; FTIR: 3182, 3045, 1723, 1663, 1534, 1500, 1458, 898, 799. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.71 (dd, J = 1.2 Hz, 1H), 7.65 (m, 1H), 7.46 (dd, J = 1.6 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 3.92 (s, 2H), 3.68 (t, 4H), 3.51 (q, 1H), 3.29 (s, 3H), 2.92 (t, 4H), 1.54 (d, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 191.23, 178.18, 163.24, 159.11, 150.20, 132.21, 131.01, 130.67, 129.45, 129.23, 124.18, 123.31, 119.89, 116.78, 110.54, 63.18, 52.12, 43.11, 41.19, 35.24, 15.69. ESI–MS: (m/z) calculated for C23H23ClN4O3, calculated: 438.14, found: 439.28 (M + H)+. Anal. Calcd for C23H23ClN4O3: (%) C 62.94, H 5.28, N 12.77. Found: C 63.02, H 5.33, N 12.84.
2.2.1.11 5-(2-(4-(4-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-ethylindolin-2-one (10k)
Appearance: pale brown solid; mp = 188–189 °C; FTIR: 3180, 3048, 1720, 1651, 1534, 1498, 1461, 899, 801. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.72 (dd, J = 1.2 Hz, 1H), 7.68 (m, 1H), 7.48 (dd, J = 1.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 3.91 (s, 2H), 3.80 (q, 2H), 3.69 (s, 2H), 3.46 (t, 4H), 2.51 (t, 4H), 1.18 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 190.74, 178.79, 163.46, 160.23, 149.53, 132.04, 131.66, 130.23, 129.12, 129.00, 124.21, 123.22, 118.17, 115.78, 110.28, 63.89, 52.56, 43.09, 40.78, 36.00, 16.21. ESI–MS: (m/z) calculated for C23H23ClN4O3, calculated: 438.14, found: 439.22 (M + H)+. Anal. Calcd for C23H23ClN4O3: (%) C 62.94, H 5.28, N 12.77. Found: C 63.00, H 5.35, N 12.82.
2.2.1.12 5-(2-(4-(4-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-ethyl-3-methylindolin-2-one (10l)
Appearance: pale yellow solid; mp = 158–159 °C; FTIR: 3179, 3049, 1720, 1656, 1555, 1503, 1450, 896, 800. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.74 (dd, J = 1.6 Hz, 1H), 7.70 (m, 1H), 7.47 (dd, J = 8.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 3.98 (s, 2H), 3.82 (q, 2H), 3.76 (t, 4H), 3.61 (q, 1H), 2.94 (t, 4H), 1.52 (d, J = 7.2 Hz, 3H), 1.24 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 191.08, 178.65, 163.63, 160.37, 149.77, 132.11, 131.28, 130.45, 129.11, 129.47, 124.04, 123.25, 118.28, 116.09, 110.24, 63.17, 52.62, 43.45, 41.18, 39.79, 16.24, 14.92. ESI–MS: (m/z) calculated for C24H25ClN4O3, calculated: 452.16, found: 453.22 (M + H)+. Anal. Calcd for C24H25ClN4O3: (%) C 63.64, H 5.56, N 12.37. Found: C 63.71, H 5.59, N 12.42.
2.2.1.13 5-(2-(4-(6-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one (10m)
Appearance: pale yellow semi solid; mp = ND; FTIR: 3402, 3188, 3062, 1718, 1650, 1552, 1508, 1451, 897, 811. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (b, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 3.90 (s, 2H), 3.76 (t, 4H), 3.41 (s, 2H), 2.84 (t, 4H). 13C NMR (100 MHz, DMSO-d6) δ 190.81, 179.84, 163.12, 160.25, 149.76, 135.08, 131.75, 130.24, 129.39, 124.14, 123.88, 122.72, 118.02, 110.95, 109.27, 63.23, 52.57, 43.28, 33.89. ESI–MS: (m/z) calculated for C21H19ClN4O3, calculated: 410.11, found: 411.22 (M + H)+. Anal. Calcd for C21H19ClN4O3: (%) C 61.39, H 4.66, N 13.64. Found: C 61.45, H 4.75, N 13.69.
2.2.1.14 5-(2-(4-(6-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-3-methylindolin-2-one (10n)
Appearance: pale yellow solid; mp = 129–131 °C; FTIR: 3398, 3182, 3053, 1716, 1650, 1551, 1502, 1459, 912, 804. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (b, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 3.86 (s, 2H), 3.68 (t, 4H), 3.54 (q, 1H), 2.68 (t, 4H), 1.44 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 190.94, 179.82, 163.59, 160.01, 149.76, 136.11, 131.45, 130.07, 129.21, 124.02, 123.48, 122.63, 118.58, 111.23, 108.98, 63.44, 53.02, 43.74, 39.98, 14.12. ESI–MS: (m/z) calculated for C22H21ClN4O3, calculated: 424.13, found: 425.20 (M + H)+. Anal. Calcd for C22H21ClN4O3: (%) C 62.19, H 4.98, N 13.19. Found: C 62.26, H 5.01, N 13.24.
2.2.1.15 5-(2-(4-(6-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-methylindolin-2-one (10o)
Appearance: pale yellow solid; mp = 177–179 °C; FTIR: 3168, 3044, 1718, 1668, 1550, 1501, 1454, 906, 810. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.29 (s, 1H), 3.84 (s, 2H), 3.68 (t, 4H), 3.60 (s, 2H), 3.37 (s, 3H), 2.72 (t, 4H). 13C NMR (100 MHz, CDCl3) δ 191.35, 177.79, 163.24, 160.22, 149.88, 135.72, 130.91, 130.11, 129.23, 124.00, 123.57, 122.52, 119.40, 115.24, 112.64, 63.23, 53.11, 44.24, 34.92, 34.08. ESI–MS: (m/z) calculated for C22H21ClN4O3, calculated: 424.13, found: 425.25 (M + H)+. Anal. Calcd for C22H21ClN4O3: (%) C 62.19, H 4.98, N 13.19. Found: C 62.23, H 5.05, N 13.24.
2.2.1.16 5-(2-(4-(6-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1,3-dimethylindolin-2-one (10p)
Appearance: pale brown solid; mp = 99–101 °C; FTIR: 3167, 3048, 1721, 1650, 1548, 1500, 1452, 902, 811. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.23 (s, 1H), 3.87 (s, 2H), 3.69 (t, 4H), 3.54 (q, 1H), 3.28 (s, 3H), 2.82 (t, 4H), 1.48 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 192.08, 178.48, 163.82, 160.43, 149.89, 134.85, 130.76, 130.22, 129.34, 124.38, 123.21, 122.78, 118.35, 116.14, 111.83, 63.86, 53.24, 43.65, 40.68, 38.54, 16.18. ESI–MS: (m/z) calculated for C23H23ClN4O3, calculated: 438.14, found: 439.24 (M + H)+. Anal. Calcd for C23H23ClN4O3: (%) C 62.94, H 5.28, N 12.77. Found: C 63.07, H 5.31, N 12.86.
2.2.1.17 5-(2-(4-(6-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-ethylindolin-2-one (10q)
Appearance: pale brown solid; mp = 169–171 °C; FTIR: 3172, 3054, 1720, 1649, 1547, 1498, 1450, 900, 818. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.28 (s, 1H), 4.11 (s, 2H), 3.78 (q, 2H), 3.69 (s, 2H), 3.38 (t, 4H), 2.51 (t, 4H), 1.18 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 192.14, 178.23, 163.67, 160.52, 149.95, 135.12, 131.47, 130.04, 129.28, 124.21, 123.63, 122.09, 118.85, 116.67, 111.69, 63.45, 53.32, 43.88, 40.11, 35.23, 15.02. ESI–MS: (m/z) calculated for C23H23ClN4O3, calculated: 438.14, found: 439.26 (M + H)+. Anal. Calcd for C23H23ClN4O3: (%) C 62.94, H 5.28, N 12.77. Found: C 63.03, H 5.34, N 12.84.
2.2.1.18 5-(2-(4-(6-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-ethyl-3-methylindolin-2-one (10r)
Appearance: pale brown solid; mp = 122–123 °C; FTIR: 3170, 3060, 1724, 1651, 1555, 1499, 1452, 909, 812. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.31 (s, 1H), 3.92 (s, 2H), 3.81 (q, 2H), 3.79 (t, 4H), 3.57 (q, 1H), 2.85 (t, 4H), 1.25 (d, J = 6.0 Hz, 3H), 1.24 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 191.74, 178.65, 163.23, 160.11, 149.84, 135.31, 131.68, 130.35, 129.69, 124.11, 123.64, 122.54, 118.63, 116.98, 111.84, 63.40, 53.12, 44.08, 40.74, 39.82, 16.45, 14.87. ESI–MS: (m/z) calculated for C24H25ClN4O3, calculated: 452.16, found: 453.24 (M + H)+. Anal. Calcd for C24H25ClN4O3: (%) C 63.64, H 5.56, N 12.37. Found: C 63.70, H 5.62, N 12.46.
2.2.1.19 5-(2-(4-(7-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one (10s)
Appearance: pale yellow semi solid; mp = ND; FTIR: 3398, 3168, 3058, 1721, 1652, 1550, 1498, 1455, 902, 818. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (b, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.30 (m, 1H), 3.88 (s, 2H), 3.76 (t, 4H), 3.50 (s, 2H), 2.65 (t, 4H). 13C NMR (100 MHz, DMSO-d6) δ 191.97, 179.82, 161.12, 159.45, 148.92, 131.75, 130.46, 129.34, 127.88, 123.45, 122.29, 122.46, 119.92, 116.28, 109.48, 63.21, 52.98, 44.34, 34.36. ESI–MS: (m/z) calculated for C21H19ClN4O3, calculated: 410.11, found: 411.22 (M + H)+. Anal. Calcd for C21H19ClN4O3: (%) C 61.39, H 4.66, N 13.64. Found: C 61.45, H 4.71, N 13.74.
2.2.1.20 5-(2-(4-(7-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-3-methylindolin-2-one (10t)
Appearance: pale yellow solid; mp = 168–170 °C; FTIR: 3405, 3172, 3063, 1720, 1658, 1557, 1500, 1464, 908, 821. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (b, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.32 (m, 1H), 3.91 (s, 2H), 3.70 (t, 4H), 3.68 (q, 1H), 2.65 (t, 4H), 1.25 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 191.82, 179.85, 161.31, 159.87, 148.90, 131.98, 130.33, 129.28, 127.58, 124.42, 123.39, 122.17, 120.31, 117.20, 109.76, 63.34, 52.79, 44.02, 40.81, 15.74. ESI–MS: (m/z) calculated for C22H21ClN4O3, calculated: 424.13, found: 425.21 (M + H)+. Anal. Calcd for C22H21ClN4O3: (%) C 62.19, H 4.98, N 13.19. Found: C 62.26, H 5.05, N 13.24.
2.2.1.21 5-(2-(4-(7-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-methylindolin-2-one (10u)
Appearance: creamy off white solid; mp = 203–204 °C; FTIR: 3170, 3068, 1722, 1654, 1555, 1504, 1468, 902, 820. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.41 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 3.89 (s, 2H), 3.72 (t, 4H), 3.60 (s, 2H), 3.36 (s, 3H), 2.57 (t, 4H). 13C NMR (100 MHz, CDCl3) δ 190.99, 178.24, 161.64, 159.22, 148.45, 131.75, 130.92, 129.36, 127.72, 124.81, 123.44, 122.66, 120.57, 116.96, 116.18, 63.14, 52.64, 43.80, 35.36, 34.78. ESI–MS: (m/z) calculated for C22H21ClN4O3, calculated: 424.13, found: 425.24 (M + H)+. Anal. Calcd for C22H21ClN4O3: (%) C 62.19, H 4.98, N 13.19. Found: C 62.27, H 5.02, N 13.22.
2.2.1.22 5-(2-(4-(7-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1,3-dimethylindolin-2-one (10v)
Appearance: pale yellow solid; mp = 208–209 °C; FTIR: 3180, 3072, 1717, 1664, 1560, 1511, 1465, 900, 818. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.41 (m, 1H), 7.33 (s, 1H), 3.92 (s, 2H), 3.69 (t, 4H), 3.52 (q, 1H), 3.34 (s, 3H), 2.65 (t, 4H), 1.24 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 191.42, 179.08, 162.22, 159.35, 149.81, 132.22, 130.07, 129.71, 127.88, 124.65, 123.23, 122.31, 120.68, 116.98, 115.97, 63.63, 52.89, 43.87, 40.86, 34.25, 15.78. ESI–MS: (m/z) calculated for C23H23ClN4O3, calculated: 438.14, found: 439.25 (M + H)+. Anal. Calcd for C23H23ClN4O3: (%) C 62.94, H 5.28, N 12.77. Found: C 63.06, H 5.31, N 12.82.
2.2.1.23 5-(2-(4-(7-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-ethylindolin-2-one (10w)
Appearance: yellow solid; mp = 163–164 °C; FTIR: 3181, 3070, 1718, 1662, 1567, 1512, 1468, 904, 819. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.769 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.40 (m, 1H), 7.33 (d, J = 7.6 Hz, 1H), 3.88 (s, 2H), 3.80 (q, 2H), 3.64 (s, 2H), 3.63 (t, 4H), 2.52 (t, 4H), 1.22 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 190.88, 179.73, 162.09, 159.21, 149.72, 132.31, 130.64, 129.45, 127.36, 124.38, 123.59, 122.44, 120.02, 116.77, 115.84, 63.48, 52.99, 43.82, 41.15, 36.13, 16.23. ESI–MS: (m/z) calculated for C23H23ClN4O3, calculated: 438.14, found: 439.28 (M + H)+. Anal. Calcd for C23H23ClN4O3: (%) C 62.94, H 5.28, N 12.77. Found: C 63.02, H 5.36, N 12.84.
2.2.1.24 5-(2-(4-(7-Chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)-1-ethyl-3-methylindolin-2-one (10x)
Appearance: pale yellow solid; mp = 149–151 °C; FTIR: 3178, 3068, 1715, 1660, 1562, 1508, 1462, 908, 816. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 1H), 7.92 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.40 (m, 1H), 7.36 (s, 1H), 3.92 (s, 2H), 3.79 (q, 2H), 3.70 (t, 4H), 3.62 (q, 1H), 2.67 (t, 4H), 1.51 (d, J = 6.8 Hz, 3H), 1.32 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 191.23, 179.68, 162.31, 159.45, 149.63, 132.84, 130.79, 129.23, 127.48, 124.21, 123.68, 122.24, 120.11, 116.89, 115.72, 63.79, 53.18, 43.78, 40.89, 39.88, 16.21, 15.45. ESI–MS: (m/z) calculated for C24H25ClN4O3, calculated: 452.16, found: 453.28 (M + H)+. Anal. Calcd for C24H25ClN4O3: (%) C 63.64, H 5.56, N 12.37. Found: C 63.72, H 5.62, N 12.44.
2.2.1.25 5-(2-(4-(4-Nitrophenyl)piperazin-1-yl)acetyl)indolin-2-one (12a)
Appearance: yellow semi solid; mp = ND; FTIR: 3412, 3098, 3005, 1712, 1599, 1545, 1492, 1456, 1324, 995, 824. 1H NMR (400 MHz, CDCl3) δ 8.93 (b, 1H), 8.59 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 3.80 (s, 2H), 3.72 (t, 4H), 3.51 (s, 2H), 2.65 (t, 4H). 13C NMR (100 MHz, CDCl3) δ 194.81, 174.78, 159.42, 148.22, 140.04, 137.54, 130.10, 129.64, 124.75, 124.53, 113.45, 108.08, 64.87, 53.45, 45.12, 34.08. ESI–MS: (m/z) calculated for C20H20N4O4, calculated: 380.14, found: 381.22 (M + H)+. Anal. Calcd for C20H20N4O4: (%) C 63.15, H 5.30, N 14.73. Found: C 63.23, H 5.39, N 14.82.
2.2.1.26 3-Methyl-5-(2-(4-(4-nitrophenyl)piperazin-1-yl)acetyl)indolin-2-one (12b)
Appearance: yellow semi solid; mp = ND; FTIR: 3418, 3128, 3015, 1714, 1610, 1548, 1498, 1454, 1322, 990, 821. 1H NMR (400 MHz, CDCl3) δ 8.91 (b, 1H), 8.48 (d, J = 9.2 Hz, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.22 (d, J = 8.8 Hz, 2H), 3.80 (s, 2H), 3.72 (t, 4H), 3.64 (q, 1H), 2.62 (t, 4H), 1.30 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 194.02, 179.96, 158.03, 147.94, 139.67, 137.08, 130.34, 129.07, 125.12, 124.64, 114.45, 109.21, 65.01, 54.11, 46.07, 42.45, 18.19. ESI–MS: (m/z) calculated for C21H22N4O4, calculated: 394.16, found: 395.24 (M + H)+. Anal. Calcd for C21H22N4O4: (%) C 63.95, H 5.62, N 14.20. Found: C 63.86, H 5.68, N 14.26.
2.2.1.27 1-methyl-5-(2-(4-(4-nitrophenyl)piperazin-1-yl)acetyl)indolin-2-one (12c)
Appearance: brown solid; mp = 209–211 °C; FTIR: 3124, 3018, 1718, 1613, 1557, 1499, 1450, 1328, 985, 820. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 3.84 (s, 2H), 3.69 (t, 4H), 3.61 (s, 2H), 3.34 (s, 3H), 2.65 (t, 4H). 13C NMR (100 MHz, CDCl3) δ 195.38, 176.01, 158.44, 148.17, 140.14, 137.58, 130.45, 129.88, 124.17, 123.58, 118.05, 114.38, 66.02, 55.15, 45.19, 36.05, 34.78. ESI–MS: (m/z) calculated for C21H22N4O4, calculated: 394.16, found: 395.28 (M + H)+. Anal. Calcd for C21H22N4O4: (%) C 63.95, H 5.62, N 14.20. Found: C 63.84, H 5.69, N 14.25.
2.2.1.28 1,3-Dimethyl-5-(2-(4-(4-nitrophenyl)piperazin-1-yl)acetyl)indolin-2-one (12d)
Appearance: brown solid; mp = 183–184 °C; FTIR: 3140, 3012, 1721, 1610, 1555, 1500, 1452, 1329, 978, 822. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 9.2 Hz, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 3.88 (s, 2H), 3.64 (t, 4H), 3.54 (q, 1H), 3.30 (s, 3H), 2.62 (t, 4H), 1.31 (d, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 194.14, 175.26, 157.80, 148.41, 140.68, 139.77, 131.48, 130.29, 124.44, 124.01, 121.00, 118.4, 65.58, 54.92, 44.88, 40.12, 34.55, 16.28. ESI–MS: (m/z) calculated for C22H24N4O4, calculated: 408.17, found: 409.24 (M + H)+. Anal. Calcd for C22H24N4O4: (%) C 64.69, H 5.92, N 13.72. Found: C 64.78, H 5.99, N 13.80.
2.2.1.29 1-Ethyl-5-(2-(4-(4-nitrophenyl)piperazin-1-yl)acetyl)indolin-2-one (12e)
Appearance: brown solid; mp = 171–173 °C; FTIR: 3138, 3011, 1720, 1628, 1562, 1504, 1450, 1321, 982, 823. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 3.74 (s, 2H), 3.68 (q, 2H), 3.61 (t, 4H), 3.40 (s, 2H), 2.69 (t, 4H), 1.20 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 195.08, 174.84, 159.41, 148.00, 140.79, 137.54, 130.50, 129.63, 124.72, 124.49, 119.43, 115.88, 64.74, 53.87, 45.90, 36.08, 34.87, 13.79. ESI–MS: (m/z) calculated for C22H24N4O4, calculated: 408.17, found: 409.28 (M + H)+. Anal. Calcd for C22H24N4O4: (%) C 64.69, H 5.92, N 13.72. Found: C 64.79, H 5.97, N 13.82.
2.2.1.30 1-Ethyl-3-methyl-5-(2-(4-(4-nitrophenyl)piperazin-1-yl)acetyl)indolin-2-one (12f)
Appearance: pale brown solid; mp = 154–156 °C; FTIR: 3145, 3009, 1724, 1625, 1560, 1509, 1452, 1324, 988, 826. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 3.81 (s, 2H), 3.74 (q, 2H), 3.65 (t, 4H), 3.51 (q, 1H), 2.72 (t, 4H), 1.29 (t, 3H), 1.21 (d, J = 6.4 Hz, 3H),. 13C NMR (100 MHz, CDCl3) δ 195.12, 178.01, 158.56, 148.24, 141.03, 138.22, 130.78, 129.95, 125.83, 124.72, 121.08, 116.64, 65.02, 53.45, 45.18, 39.87, 38.04, 16.85, 14.82. ESI–MS: (m/z) calculated for C23H26N4O4, calculated: 422.19, found: 423.26 (M + H)+. Anal. Calcd for C23H26N4O4: (%) C 65.39, H 6.20, N 13.26. Found: C 65.51, H 6.27, N 13.34.
2.2.1.31 5-(2-(4-(Pyridin-2-yl)piperazin-1-yl)acetyl)indolin-2-one (12g)
Appearance: dark brown semi solid; mp = ND; FTIR: 3421, 3099, 3012, 1720, 1622, 1508, 1450, 1314, 990, 822. 1H NMR (400 MHz, CDCl3) δ 8.82 (b, 1H), 8.15 (d, J = 3.6 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.63 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.96 (m, 1H), 3.81 (s, 2H), 3.73 (t, 4H), 3.49 (s, 2H), 2.64 (t, 4H). 13C NMR (100 MHz, CDCl3) δ 193.88, 173.78, 159.02, 148.84, 147.90, 138.06, 130.28, 129.84, 125.11, 124.52, 120.00, 110.74, 108.14, 64.84, 54.09, 45.27, 35.12. ESI–MS: (m/z) calculated for C19H20N4O2, calculated: 336.15, found: 337.08 (M + H)+. Anal. Calcd for C19H20N4O2: (%) C 67.84, H 5.99, N 16.66. Found: C 67.91, H 6.07, N 16.74.
2.2.1.32 3-Methyl-5-(2-(4-(pyridin-2-yl)piperazin-1-yl)acetyl)indolin-2-one (12h)
Appearance: brown solid; mp = 173–174 °C; FTIR: 3424, 3095, 3011, 1722, 1630, 1515, 1454, 1318, 991, 824. 1H NMR (400 MHz, CDCl3) δ 8.90 (b, 1H), 8.18 (d, J = 4.0 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.61 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.98 (m, 1H), 3.83 (s, 2H), 3.72 (t, 4H), 3.69 (q, 1H), 2.60 (t, 4H), 1.31 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 194.75, 173.99, 159.38, 148.91, 147.92, 137.62, 130.41, 129.60, 124.71, 124.50, 119.22, 111.54, 107.89, 64.09, 53.44, 45.06, 41.08, 14.67. ESI–MS: (m/z) calculated for C20H22N4O2, calculated: 350.17, found: 351.24 (M + H)+. Anal. Calcd for C20H22N4O2: (%) C 68.55, H 6.33, N 15.99. Found: C 68.61, H 6.39, N 16.08.
2.2.1.33 1-Methyl-5-(2-(4-(pyridin-2-yl)piperazin-1-yl)acetyl)indolin-2-one (12i)
Appearance: dark brown solid; mp = 188–189 °C; FTIR: 3099, 3002, 1719, 1638, 1518, 1451, 1315, 985, 821. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 4.0 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.51 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.81 (m, 1H), 3.82 (s, 2H), 3.70 (t, 4H), 3.59 (s, 2H), 3.32 (s, 3H), 2.56 (t, 4H). 13C NMR (100 MHz, CDCl3) δ 194.24, 174.67, 159.44, 148.80, 147.87, 137.59, 130.73, 129.22, 125.42, 124.09, 118.15, 110.87, 108.14, 64.53, 53.35, 44.88, 37.22, 33.14. ESI–MS: (m/z) calculated for C20H22N4O2, calculated: 350.17, found: 351.25 (M + H)+. Anal. Calcd for C20H22N4O2: (%) C 68.55, H 6.33, N 15.99. Found: C 68.63, H 6.37, N 16.06.
2.2.1.34 1,3-Dimethyl-5-(2-(4-(pyridin-2-yl)piperazin-1-yl)acetyl)indolin-2-one (12j)
Appearance: dark brown solid; mp = 154–155 °C; FTIR: 3105, 3010, 1721, 1642, 1524, 1450, 1314, 988, 820. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.94 (s, 1H), 7.63 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.88 (m, 1H), 3.86 (s, 2H), 3.68 (t, 4H), 3.59 (q, 1H), 3.31 (s, 3H), 2.63 (t, 4H), 1.34 (d, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 194.69, 174.11, 159.35, 148.90, 147.94, 138.01, 130.38, 129.72, 124.58, 124.44, 115.82, 108.12, 107.91, 64.50, 53.40, 45.95, 36.04, 35.76, 17.08. ESI–MS: (m/z) calculated for C21H24N4O2, calculated: 364.18, found: 365.26 (M + H)+. Anal. Calcd for C21H24N4O2: (%) C 69.21, H 6.64, N 15.37. Found: C 69.32, H 6.69, N 15.44.
2.2.1.35 1-Ethyl-5-(2-(4-(pyridin-2-yl)piperazin-1-yl)acetyl)indolin-2-one (12k)
Appearance: dark brown solid; mp = 133–134 °C; FTIR: 3112, 3011, 1720, 1640, 1528, 1452, 1318, 992, 824. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 3.2 Hz, 1H), 8.07 (d, J = 7.2 Hz, 1H), 7.95 (s, 1H), 7.50 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.63 (m, 1H), 3.82 (s, 2H), 3.79 (q, 2H), 3.63 (t, 4H), 3.49 (s, 2H), 2.72 (t, 4H), 1.30 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 194.81, 174.84, 159.43, 148.83, 147.90, 137.50, 130.41, 129.60, 124.71, 124.52, 113.43, 107.66, 107.11, 64.44, 53.34, 45.07, 35.48, 34.87, 12.72. ESI–MS: (m/z) calculated for C21H24N4O2, calculated: 364.18, found: 365.22 (M + H)+. Anal. Calcd for C21H24N4O2: (%) C 69.21, H 6.64, N 15.37. Found: C 69.34, H 6.68, N 15.46.
2.2.1.36 1-Ethyl-3-methyl-5-(2-(4-(pyridin-2-yl)piperazin-1-yl)acetyl)indolin-2-one (12l)
Appearance: brown solid; mp = 128–130 °C; FTIR: 3114, 3008, 1718, 1644, 1527, 1455, 1322, 990, 823. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 3.6 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), 7.52 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.68 (m, 1H), 3.87 (s, 2H), 3.78 (q, 2H), 3.66 (t, 4H), 3.54 (q, 1H), 2.76 (t, 4H), 1.51 (t, 3H), 1.33 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 194.84, 175.02, 159.22 149.23, 147.94, 137.72, 131.22, 129.82, 124.74, 124.66, 114.48, 108.89, 107.76, 65.12, 53.88, 45.21, 39.84, 35.90, 13.34, 13.08. ESI–MS: (m/z) calculated for C22H26N4O2, calculated: 378.20, found: 379.32 (M + H)+. Anal. Calcd for C22H26N4O2: (%) C 69.82, H 6.92, N 14.80. Found: C 69.91, H 6.99, N 14.93.
2.3 Microplate Alamar Blue Assay (MABA)
The anti-TB activities of title analogues 10a–x and 12a–l were evaluated against MTB H37Rv (ATCC 27294) strain using MABA (Franzblau et al., 1998; Collins et al., 1997). Isoniazid, rifampin and pyrazinamide are used as positive controls. Compound stock solutions were prepared in DMSO at a concentration 100 mg/mL, and the final test concentrations ranged from 50 to 0.78 μg/mL. Twofold serial dilutions of compounds were prepared in Middlebrook 7H9GC medium in a volume of 100 mL in 96-well microplates. TB culture (100 mL inoculum of 2 × 105 CFU/mL) was added, yielding a final testing volume of 200 mL. The plates were incubated at 37 °C. On the seventh day of incubation 25 μL of 10% Tween 80 and 25 mL of Alamar Blue (Accumed International, Westlake, Ohio) were added to the wells of test plate. After incubation at 37 °C for 24 h, colours of all wells were recorded. A blue colour in the well was interpreted as no growth, and a pink colour was scored as growth. The MICs were defined as the lowest concentration which prevented a colour change from blue to pink.
2.4 Cytotoxicity assay
Furthermore, most active anti-TB compounds (⩽6.25 μg/mL) were analysed for Cytotoxicity in RAW 264.7 cell line at concentration of 50 μg/mL. Selectivity index of the compounds was also determined. After 72 h of exposure, viability was evaluated on the basis of cellular conversion of 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) into a formazan product using the Promega Cell Titer 96 non-radioactive cell proliferation assay. MTT, a yellow tetrazole, is reduced to purple formazan in living cells which is further quantified spectrophotometrically (Gerlier et al., 1986).
3 Results and discussion
3.1 Chemistry
In the present report, we synthesized 5-(2-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one and 5-(2-(4-(pyridin-2-yl)piperazin-1-yl)acetyl)indolin-2-one derivatives as depicted in Scheme 1. The N-substituted aniline (1a–c) on treatment with 2-chloroacetyl chloride/2-chloropropanoyl chloride and N(C2H5)3 in Dichloro methane (DCM) at 0 °C – rt for 1 h yielded 2-chloro-N-substituted-N-phenyl amide derivatives (2a–f). Further cyclization with AlCl3 under solvent free conditions at 130 °C for 4 h afforded substituted indolin-2-one derivatives (3a–f). Substituted 5-(2-chloroacetyl)indolin-2-ones (4a–f) were synthesized by reacting 2-chloroacetyl chloride with anhydrous AlCl3 in CH2Cl2 at rt for 4 h. Substituted 2-chlorobenzaldehyde (5a–d) on treatment with NH2OH·HCl and CH3COONa in EtOH and H2O at 0 °C – rt for 1 h yielded oxime derivatives (6a–d). Further chlorination with N-chlorosuccinimide in CCl4 at 0 °C – rt for 45 min afforded substituted 2-chloro-N-hydroxybenzimidoyl chloride derivatives (7a–d). Substituted (2-chlorophenyl) (piperazin-1-yl)methanone oximes (8a–d) were synthesized by reacting 7a–d with anhydrous piperazine and N(C2H5)3 in CH2Cl2 at rt. 9a–d was synthesized from 8a–d by reacting with 30% KOH in aqueous dioxane at 120 °C.
General synthetic route to achieve the title compounds. Reagents and conditions: (i) Chloroacetyl chloride/2-chloropropanoyl chloride (1.1 equiv.), N(C2H5)3 (2.0 equiv.), DCM, 0 °C – rt, 1 h; (ii) AlCl3 (3.0 equiv.), 130 °C, 4 h; (iii) Chloroacetyl chloride (1.5 equiv.), AlCl3 (3.0 equiv.), DCM, rt, 4 h; (iv) NH2OH⋅HCl (1.2 equiv.), CH3COONa (2.0 equiv.), EtOH, H2O, °C-rt, 1 h; (v) N-Chlorosuccinimide (1.2 equiv.), CCl4, 0 °C – rt, 45 min; (vi) Piperazine (8.0 equiv.), N(C2H5)3 (2.0 equiv.), CH2Cl2, rt, 2 h; (vii) 30% KOH (3.0 equiv.), Dioxane, 120 °C, 4 h, (65–90%); (viii and ix) K2CO3 (1.2 equiv.), acetonitrile, μW, 80 °C, 8 min.
Final compounds, 10a–x and 12a–l were synthesized by refluxing a mixture of 3-(piperazin-1-yl)benzo[d]isoxazole derivatives (9a–d) or 4-substitutedpiperazins (11a and b) with oxindole derivatives (4a–f) and anhydrous potassium carbonate using acetonitrile in microwave oven for 8 min. All the synthesized compounds were confirmed by 1H NMR, 13C NMR, IR, LCMS and Elemental analyses. In general, the 1H NMR showed singlets and multiplets in aliphatic region 1.12–4.45, multiplets in the range 3.22–3.68 ppm due to piperazine (-CH2-) protons, aromatic protons of substituted oxindole group and benzisoxazole appeared at 6.48–9.42 ppm and amine group at 9.10–10.45. 13C NMR showed carbonyl group at 172–196, aromatic carbons in the range of 107–168 ppm and piperazine carbons in the range of 42–68 ppm. Absence of NH stretching peak at ∼3228 cm−1 in the title compounds, 10a–x and 12a–l, confirms the formation of products.
3.2 Antimycobacterial activity
All the synthesized analogues are tested for anti-TB activity against MTB H37Rv (ATCC 27294) strain by MABA with compound concentration ranging from 50 to 0.78 μg/mL. Isoniazid, Rifampin and Pyrazinamide were used as the positive drug standards. The in vitro antimycobacterial results of title compounds are tabulated in Table 1 as MIC and the activity ranged between 1.56 and 50 μg/mL. The compounds 10c, 10d, 10j, 10o and 10v displayed moderate activity (MIC 6.25 μg/mL), whereas chemo synthetics 10e, 10l, 10q, 10w,10x, 12d, 12e and 12i showed good anti-TB activity (MIC 3.12 μg/mL) and few analogues 10f, 10k, 10p, 10r, 12f, 12j and 12k exhibited excellent anti-TB activity (MIC 1.56 μg/mL). Compounds with MIC ⩽ 6.25 μg/mL were subjected to cytotoxicity studies.
Entry
R1
R2
R3
X
% Yield
MIC (μg/mL) against MTB H37Rv
10a
H
H
–
H
63
50
10b
H
CH3
–
H
60
25
10c
CH3
H
–
H
84
6.25
10d
CH3
CH3
–
H
79
6.25
10e
C2H5
H
–
H
91
3.12
10f
C2H5
CH3
–
H
83
1.56
10g
H
H
–
4-Cl
60
25
10h
H
CH3
–
4-Cl
62
25
10i
CH3
H
–
4-Cl
81
12.5
10j
CH3
CH3
–
4-Cl
90
6.25
10k
C2H5
H
–
4-Cl
88
1.56
10l
C2H5
CH3
–
4-Cl
82
3.12
10m
H
H
–
6-Cl
65
>50
10n
H
CH3
–
6-Cl
60
12.5
10o
CH3
H
–
6-Cl
94
6.25
10p
CH3
CH3
–
6-Cl
89
1.56
10q
C2H5
H
–
6-Cl
81
3.12
10r
C2H5
CH3
–
6-Cl
80
1.56
10s
H
H
–
7-Cl
67
>50
10t
H
CH3
–
7-Cl
63
50
10u
CH3
H
–
7-Cl
92
12.5
10v
CH3
CH3
–
7-Cl
86
6.25
10w
C2H5
H
7-Cl
84
3.12
10x
C2H5
CH3
–
7-Cl
90
3.12
12a
H
H
4-NO2Ph
–
61
25
12b
H
CH3
4-NO2Ph
–
65
50
12c
CH3
H
4-NO2Ph
–
78
12.5
12d
CH3
CH3
4-NO2Ph
–
85
3.12
12e
C2H5
H
4-NO2Ph
–
88
3.12
12f
C2H5
CH3
4-NO2Ph
–
81
1.56
12g
H
H
2-Pyridyl
–
60
25
12h
H
CH3
2-Pyridyl
–
62
25
12i
CH3
H
2-Pyridyl
–
78
3.12
12j
CH3
CH3
2-Pyridyl
–
84
1.56
12k
C2H5
H
2-Pyridyl
–
80
1.56
12l
C2H5
CH3
2-Pyridyl
–
91
3.12
INH
–
–
–
–
–
0.1
RFA
–
–
–
–
–
0.2
PZA
–
–
–
–
–
6.25
Among the analogues, compounds 10f, 10k, 10p, 10r, 12f, 12j and 12k emerged as the most auspicious entrants by inhibiting 99% growth of MTB H37Rv strain at concentration of 1.56 μg/mL. Electronic effects of substituent play a vital role in exhibiting anti-TB activity. SAR studies for Oxindole benzisoxazole derivatives (10a–x) and Oxindole piperazine analogues (12a–l) are described based on activity of compound 10a. Presence of electron donating methyl or ethyl groups at 1st position on oxindole, greatly enhanced the anti-TB activity by 4–32 fold with MIC 12.5–1.56 μg/mL. However, unsubstitution at 1st position of oxindole resulted in one fold increase in activity (10b, 10g, 10h, 10n, 12a, 12g and 12h) or retention of anti-TB activity (10t and 12b) or decrease in anti-TB activity (10m and 10s). Presence of chlorine at 4th, 6th and 7th position of benzisoxazole moiety or its absence, did not impact the activity. In totality, we observe that piperazine analogues (12a–l) were more active than the benzisoxazole analogues (10a–x).
3.3 Cytotoxicity
The compounds with MIC ⩽ 6.25 μg/mL were subjected to Promega Cell Titer 96 non-radioactive cell proliferation assay to analyse the selectivity profile against mouse macrophage (RAW264.7) cell lines. The IC50 values and selectivity index (SI) values (Kamal et al., 2013) are tabulated in Table 2. We notice that most active compounds 10f, 10k, 10p, 10r, 12f, 12j and 12k with MIC 1.56 μg/mL, have SI ⩾ 34 indicating the appropriation of the chemophores in further drug development.
S. no.
Compound
MIC (μg/mL) in MTB H37Rv
% Cell inhibition at 50 μg/mL
IC50 approximation
aSI value
1
10c
6.25
35.62
70.18
11.22
2
10d
6.25
22.80
109.64
17.54
3
10e
3.12
38.42
65.07
20.85
4
10f
1.56
36.46
68.56
43.95
5
10j
6.25
38.10
65.61
10.49
6
10k
1.56
35.62
70.18
44.99
7
10l
3.12
40.40
61.88
19.83
8
10o
6.25
42.80
58.41
9.34
9
10p
1.56
46.43
53.84
34.51
10
10q
3.12
31.76
78.71
25.22
11
10r
1.56
44.60
56.05
35.93
12
10v
6.25
28.92
86.44
13.83
13
10w
3.12
30.16
82.89
26.56
14
10x
3.12
22.16
112.81
36.15
15
12d
3.12
35.62
70.18
22.49
16
12e
3.12
40.40
61.88
19.83
17
12f
1.56
30.72
81.38
52.16
18
12i
3.12
19.16
130.48
41.82
19
12j
1.56
22.12
113.01
72.44
20
12k
1.56
26.52
94.26
60.42
4 Conclusion
In conclusion, a series of 5-(2-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one and 5-(2-(4-(pyridin-2-yl)piperazin-1-yl)acetyl)indolin-2-one analogues were synthesized in moderate to excellent yields. Out of 36 derivatives synthesized 7 analogues (10f, 10k, 10p, 10r, 12f, 12j and 12k) unveiled excellent anti-TB activity with MIC 1.56 μg/mL. The most active compounds exhibited good selectivity profile. This outcome indicates that novel chemophores are not toxic and might be considered for further structural modification. The observed potency of these compounds against MTB encourages further optimization of the hybrid of oxindole, piperazine and benzo[d]isoxazoles to produce essential pharmacophoric features that might lead to the promising candidate in developing anti-tubercular agents.
Acknowledgements
We acknowledge the financial assistance provided by Department of Science & Technology (No. SB/S1/OC-60/2013), New Delhi, India. We also gratefully acknowledge the assistance provided by Antimycobacterial Research Laboratory, Department of Pharmacy, BITS Pilani Hyderabad Campus in carrying out the anti-TB screening. KMN is thankful to BITS Pilani, Hyderabad Campus, for award of institute fellowship.
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