Design, synthesis and antimicrobial activities of novel ferrocenyl and organic chalcone based sulfones and bis-sulfones

Naseem Ahmed; Naveen Kumar Konduru; Mohammad Owais

doi:10.1016/j.arabjc.2014.12.008

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Original article

12 (

); 1879-1894

doi:

10.1016/j.arabjc.2014.12.008

Design, synthesis and antimicrobial activities of novel ferrocenyl and organic chalcone based sulfones and bis-sulfones

Naseem Ahmed^{^a,⁎}, Naveen Kumar Konduru^{^a}, Mohammad Owais^{^b}

a Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India

b Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, India

⁎Corresponding author. Tel./fax: +91 1332 285745. nasemfcy@iitr.ac.in (Naseem Ahmed)

Received: 2014-4-5, Accepted: 2014-12-27, Published: 2019-12-01

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 variety of different novel functionalized ferrocenyl chalcone and organic chalcone based sulfones and bis-sulfones were synthesized in excellent yield under mild reaction condition. The antimicrobial activities as bactericide and fungicide were evaluated for all the synthesized compounds and structure–activity relationships were established. Many compounds exhibited high and broad-range bactericidal activity. Among them, organic chalcone based on nitro-substituted 4c and chloro-substituted 6c, ferrocenyl chalcone based trimethoxy-substituted 20c and dimethyl-substituted 24c molecules displayed the best and broad-range bactericidal activity. Product 24c also exhibited the highest antifungal activity against most of the fungi tested. In fact some compounds are more potent and some are comparable with standard drugs.

Keywords

Ferrocenyl & organic chalcone sulfides

Sulfones

Bis-sulfones

Thia-Michael addition reaction

m-CPBA

Bactericidal & fungicidal activities

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1 Introduction

Despite advances in the multimodal management of a wide spectrum of human microbial infections, it remains life-threatening along with the drug-resistant bacterial and fungal strains globally, highlighting the need for the development of new drugs. Interestingly, nature has proven to be one of the best sources of molecules that can help in the prevention and the treatment (Belofsky et al., 2004; Lin and Lee, 2012). Therefore, the search for the novel natural molecules, semi-synthetic and synthetic molecules that display fast-acting and broad-spectrum antimicrobial activity against bacteria and fungi is of great interest for the scientific community and the pharmaceutical industry (Ceylan et al., 2011; Karaman et al., 2012).

Chalcones, a sub-class of flavonoids are widely distributed as secondary metabolites in plant kingdom. They are reported for various biological activities such as antimicrobial, anti-inflammatory, anti-malarial, anti-leishmanial, antioxidant and antitubercular (Ahmed et al., 2014; Prasad et al., 2008; Wu et al., 2002; Lin et al., 2002 ). Substitutions on chalcone moieties have shown enhanced biological activities. For example, pyrimidinyl substitution on chalcone displayed high antitumor property (Jin et al., 2013), quinolone substitution on chalcone exhibited great antimalarial activity (Li et al., 1995), and thiophenol addition on chalcone showed potent anti-breast cancer property (Kumar et al., 2011).

Similarly, the sulfide and sulfone substituted organic molecules are found useful precursors in organic synthesis and the biologically relevant compounds (Alba et al., 2010; Simpkins, 1993; Patai et al., 1988; Backvall et al., 1998; Carreno, 1995; Frenanez and Khiar, 2003 ). The sulfonyl group has electron withdrawing property and hence stabilizes carbanion intermediates during the reaction (Najera and Sansano, 1998) and have shown radical stabilizer (Paquette, 2001) and cationic synthon properties during the reactions (Chinchilla and Najera, 1997). In biology, the polar nature of sulfonyl group enhanced lipophilicity (Buehrdel et al., 2009), and hence the antimicrobial activity of the molecule (Caron et al., 1997). For example, Penicillin G, methicillin, ampicillin, piperacillin and sulfanilamide antimicrobial drugs have sulfide and sulfone moieties (Saga and Yamaguchi, 2009). Moreover, compounds possessing a para-substituted –SO₂Me group on the phenyl ring have shown inhibition of COX-activity (Talley, 1999). Compounds such as 1,3-diphenylprop-2-yn-1-one (2) and etoricoxib (4) exhibit selective COX-2 (cyclooxygenase-2) inhibitory activity (Rao et al., 2005). Rofecoxib (1), a non-steroidal anti-inflammatory drug (NSAID) is used in the treatment of arthritis and other similar conditions causing chronic or acute pain. Sulindac sulfone (3) is used in the treatment of tumor and HCA-7 cells which led to inhibition of prostaglandin E₂ production (Fig. 1) (Williams et al., 1999).

Natural and biologically active sulfone derivatives.

The sulfur containing ferrocenyl compounds have displayed important biological and pharmaceutical activities such as antitumor, antimalarial, anti-microbial and DNA cleaving properties (Ilic et al., 2012; Fourie et al., 2011). These compounds remained a frontier research area (Arrayas et al., 2006) in the development of novel materials (Patra et al., 2011), catalysts for asymmetric conversion of aldehydes to epoxides (Miniere et al., 2004). The synthesis of novel organic sulfones is mainly reported via oxidation of sulfides, which is typically achieved using stoichiometric or catalytic amounts of inorganic reagents (Choudary et al., 2002; Zali et al., 2008; Kirihara et al., 2009 ). However, these reactions are slow due to rapid decomposition of reactants and thus gave low yield. Therefore, an extensive study has been undertaken to develop new catalysts for these oxidations (Shaabani and Rezayan, 2007; Rahimi et al., 2009). Recently, we reported some organic chalcone based sulfone synthesis where oxidation of sulfide to sulfone has been optimized with m-CPBA (meta-Chloroperbenzoic acid) in terms of molar ratio and reaction conditions (Konduru et al., 2013). Our previous antimicrobial results (Konduru et al., 2013) encouraged to synthesize the new class of sulfones and their evaluation for antimicrobial activity. Following the reported method (Konduru et al., 2013), a variety of novel ferrocenyl chalcone based sulfones (17–24c), organic chalcone based sulfones (1–4c, 5–8c, 13–16c) and bis-sulfones (9–12c) were synthesized and evaluated for their antimicrobial properties.

2 Materials and methods

2.1

2.1 General

All the required chemicals were purchased from Merck and Aldrich Chemical Company. Pre-coated aluminum sheets (silica gel 60 F₂₅₄, Merck) were used for thin-layer chromatography (TLC) and spots were visualized under UV light. High-resolution mass spectra (HRMS) were recorded using Bruker EI and ES-TOF mass spectrometers. Elemental analysis was performed by using Perkin-Elmer 2400 series CHNS/O analyzer. IR spectra were recorded with KBr on Thermo Nicolet FT-IR spectrophotometer. ¹H NMR and ¹³C NMR spectra were recorded respectively on Bruker Spectrospin DPX 500 MHz and Bruker Spectrospin DPX 125 MHz spectrometer using CDCl₃ as a solvent and trimethylsilane (TMS) as an internal standard. Splitting patterns are designated as follows; s, singlet; d, doublet; and m, multiplet. Chemical shift values are given in ppm.

2.2

2.2 General procedure for synthesis of compounds (1–8c)

To a stirred solution of chalcone sulfide (1 mmol) in dichloromethane was added m-CPBA (2.2 mmol, 379.5 mg) at 0 °C portion wise for 15 min and the reaction mixture stirred at this temperature for 30 min, then warmed to room temperature and stirred for appropriate time in Table 1. TLC monitoring, the reaction was diluted with dichloromethane (8 mL) and washed with 5% aqueous K₂CO₃ (3 × 8 mL) and 5% NaHCO₃ (10 mL) solution for removing excess m-CPBA. Then, the aqueous layer extracted with dichloromethane (3 × 10 mL), the combined organic layers dried over anhydrous Na₂SO₄ and solvent evaporated in vacuo. Pure sulfone was obtained by recrystallization from methanol.

2.2.1

2.2.1 1-(2-Hydroxyphenyl)-3-(4-methylphenyl)-3-(phenylsufonyl)propan-1-one (1c)

Yield 90%; white solid; mp 155–157 °C; ¹H NMR (CDCl_3, 500 MHz) δ 11.61 (s, br, D₂0 exchangeable, 1H), 7.93–7.83 (m, 2H), 7.64–7.47 (m, 4H), 7.26–7.23 (m, 2H), 7.06–7.02 (m, 3H), 6.95–6.92 (m, 2H), 4.90 (dd, J = 9.5 Hz, 3.5 Hz, 1H), 4.13 (dd, J = 16 Hz, 3.5 Hz, 1H), 3.97–3.92 (m, 1H), 2.30 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 198.63, 161.38, 139.83, 136.25, 135.48, 132.02, 129.92, 129.64, 129.27, 128.81, 128.29, 127.93, 127.63, 126.21, 116.22, 62.94, 37.22, 21.28. IR (KBr): 3438, 3067, 2997, 2952, 1707, 1543, 1315, 1154, 761 cm⁻¹. HR-MS (ESIMS) for C₂₂H₂₁O₄S (M + H)⁺ Anal. calcd. 381.1161; found 381.1169. CHNS: Anal. calcd. for C₂₂H₂₀O₄S; C, 69.45; H, 5.30; S, 8.43. Found: C, 69.55; H, 5.21; S, 8.29.

2.2.2

2.2.2 1-(2-Hydroxyphenyl)-3-(4-chlorophenyl)-3-(phenylsufonyl)propan-1-one (2c)

Yield 95%; white solid; mp 165–167 °C; ¹H NMR (CDCl_3, 500 MHz) δ 11.63 (s, br, D₂0 exchangeable, 1H), 7.96 (d, J = 8 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.60–7.57 (m, 3H), 7.43–7.4 (m, 3H), 7.16 (dd, J = 13 Hz, 8 Hz, 3H), 6.96–6.93 (m, 2H), 4.89 (dd, J = 18 Hz, 3 Hz, 1H), 4.16 (dd, J = 18 Hz, 3 Hz, 1H), 3.94–3.89 (m, 1H). ¹³C NMR (CDCl₃, 125 MHz): 199.24, 160.54, 138.74, 136.14, 133.14, 131.35, 130.14, 129.81, 129.07, 128.64, 128.05, 127.99, 127.43, 125.74, 115.98, 64.43, 37.22. IR (KBr): 3438, 3067, 2997, 2952, 1707, 1543, 1154, 761 cm⁻¹. HR-MS (ESIMS) for C₂₁H₁₈ClO₄S (M + H)⁺. Anal. calcd. 401.0614; found 401.0625. CHNS: Anal. calcd. for C₂₁H₁₇ClO₄S; C, 62.92; H, 4.27; S, 8.00. Found: C, 62.86; H, 4.21; S, 7.84.

2.2.3

2.2.3 1-(2-Hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)-3-(phenylsufonyl)propan-1-one (3c)

Yield 91%; white solid; mp 121–122 °C; ¹H NMR (CDCl_3, 500 MHz) δ 12.10 (s, br, D₂0 exchangeable, 1H), 7.70 (dd, J = 8 Hz, 1.5 Hz, 1H), 7.42–7.38 (m, 2H), 7.26–7.23 (m, 3H), 6.95 (d, J = 8.5 Hz, 1H), 6.9 (t, J = 7.5 Hz, 1H), 6.6 (s, 2H), 5.0 (dd, J = 16 Hz, 3 Hz, 1H), 3.8 (s, 3H), 3.78 (s, 6H), 3.7 (m, 1H), 3.68 (m, 1H). ¹³C NMR (CDCl₃, 125 MHz):200.01, 161.64, 151.43, 139.84, 136.76, 135.47, 134.28, 131.54, 130.58, 129.67, 128.53, 122.58, 116.29, 105.94, 65.47, 56.64, 56.13, 38.24. IR (KBr): 3412, 3019, 2967, 1701, 1355, 1206. HR-MS (ESIMS) for C₂₄H₂₅O₇S (M + H)⁺ Anal. calcd 457.1321; found 457.1336. CHNS: Anal. calcd. for C₂₄H₂₄O₇S; C, 63.14; H, 5.30; S, 7.02. Found: C, 63.29; H, 5.26; S, 7.34.

2.2.4

2.2.4 1-(2-Hydroxyphenyl)-3-(3-nitrophenyl)-3-(phenylsufonyl)propan-1-one (4c)

Yield 92%; white solid; mp 121–123 °C; ¹H NMR (CDCl_3, 500 MHz) δ 12.10 (s, br, D₂0 exchangeable, 1H), 8.2 (s, 1H), 7.66–7.43 (m, 6H), 7.4–7.01 (m, 4H), 6.72 (d, J = 8 Hz, 1H), 5.05 (m, 1H), 3.82–3.78 (m, 1H), 3.76–3.72 (m, 1H). ¹³C NMR (CDCl₃, 125 MHz): 200.11, 160.54, 149.84, 140.24, 138.76, 135.64, 133.84, 132.24, 130.54, 129.21, 129.01, 128.75, 128.60, 128.10, 122.68, 119.64, 116.58, 63.54, 36.95. IR (KBr): 3412, 3019, 2967, 1701, 1355, 1206. HR-MS (ESIMS) for C₂₁H₁₇NNaO₆S (M + Na)⁺ Anal. calcd 434.0674; found 434.0665. CHNS: Anal. calcd. for C₂₁H₁₇NO₆S; C, 61.30; H, 4.16; N, 3.40; S, 7.79. Found: C, 61.18; H, 4.09; N, 3.43; S, 7.88.

2.2.5

2.2.5 1-(2-Aminophenyl)-3-(4-methylphenyl)-3-(phenylsufonyl)propan-1-one (5c)

Yield 94%; white solid; mp 152–153 °C; ¹H NMR (CDCl_3, 500 MHz) δ 7.82 (d, J = 8 Hz, 1H), 7.44–7.30 (m, 1H), 6.52 (d, J = 8 Hz, 1H), 6.5 (s, br, D₂0 exchangeable, 2H), 5.04–498 (m, 1H), 3.72–3.69 (m, 1H), 3.68 (m, 1H), 2.3 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 199.01, 150.67, 138.55, 137.01, 134.58, 132.51, 13.02, 130.73, 129.35, 129.26, 129.04, 127.88, 125.46, 117.54, 115.84, 65.24, 37.96, 21.32. IR (KBr): 3416, 3318, 3175, 2985, 2872, 1679, 1647, 1176, 748. HR-MS (ESIMS) for C₂₂H₂₂NO₃S (M + H)⁺ Anal. calcd 380.1320; found 380.1327. CHNS: Anal. calcd. for C₂₂H₂₁NO₃S; C, 69.63; H, 5.58; N, 3.69; S, 8.45. Found: C, 69.76; H, 5.44; N, 3.76; S, 8.25.

2.2.6

2.2.6 1-(2-Aminophenyl)-3-(4-chlorophenyl)-3-(phenylsufonyl)propan-1-one (6c)

Yield 95%; white solid; mp 163–165 °C; ¹H NMR (CDCl_3, 500 MHz) δ 7.84 (dd, J = 8 Hz, 1H), 7.66–7.3 (m, 11 Hz), 6.69–6.17 (m, 1H), 6.3 (s, br, D₂0 exchangeable, 2H), 4.95–4.86 (m, 1H), 3.68–3.64 (m, 2H). ¹³C NMR (CDCl₃, 125 MHz):198.46, 150.73, 140.43, 135.31, 134.27, 132.98, 130.99, 130.72, 129.27, 129.18, 127.87, 127.28, 117.69, 115.95, 68.65, 40.46. IR (KBr): 3415, 3317, 3015, 2984, 1686, 1175, 1267, 741. HR-MS (ESIMS) for C₂₁H₁₉ClNO₃S (M + H)⁺ Anal. Calcd 400.0774; found 400.0770. CHNS: Anal. calcd. for C₂₁H₁₈ClNO₃S; C, 63.07; H, 4.54; N, 3.50; S, 8.02. Found: C, 63.24; H, 4.49; N, 3.30; S, 8.31.

2.2.7

2.2.7 1-(2-Aminophenyl)-3-phenyl-3-(phenylsulfonyl)propan-1-one (7c)

Yield 93%; white solid; mp 135–136 °C; ¹H NMR (CDCl_3, 500 MHz) δ 7.65 (d, J = 8 Hz, 1H), 7.45–7.40 (m, 3H), 7.33–7.18 (m, 8H), 6.58–6.5 (m, 1H), 6.40 (s, br, D₂0 exchangeable, 2H), 4.97 (m, 1H), 3.59–3.56 (m, 1H). ¹³C NMR (CDCl₃, 125 MHz): ¹³C NMR (CDCl₃, 125 MHz): 198.36, 150.27, 140.98, 135.99, 134.73, 132.46, 130.31, 130.65, 129.95, 129.28, 127.87, 127.18, 117.69, 115.27, 68.72, 40.43. IR (KBr): 3418, 3328, 3075, 2978, 2872, 1679, 1648, 1206, 756. HR-MS (ESIMS) for C₂₁H₁₉NNaO₃S (M + Na)⁺ Anal. Calcd 388.0983; found 388.0994. CHNS: Anal. calcd. for C₂₁H₁₉NO₃S; C, 69.02; H, 5.24; N, 3.83; S, 8.77. Found: C, 69.16; H, 5.22; N, 3.85; S, 8.65.

2.2.8

2.2.8 1-(2-Aminophenyl)-3-(3-nitrophenyl)-3-(phenylsufonyl)propan-1-one (8c)

Yield 91%; white solid; mp 220–222 °C; ¹H NMR (CDCl_3, 500 MHz) δ 8.02 (s, 1H), 7.79–7.71 (m, 4H), 7.67–7.51 (m, 3H), 7.45–7.42 (m, 2H), 6.69–6.59 (m, 2H), 6.12 (s, br, D₂0 exchangeable, 2H), 5.0 (m, 1H), 4.13 (m, 1H), 3.9 (m, 1H). ¹³C NMR (CDCl₃, 125 MHz): 200.11, 150.64, 149.32, 140.15, 139.67, 135.21, 135.02, 134.54, 134.22, 130.21, 129.52, 129.10, 128.67, 124.88, 119.81, 119.00, 116.54, 63.41, 38.01. IR (KBr): 3416, 3308, 3070, 2925, 2852, 1724, 1647, 1612, 1533, 1141, 746. HR-MS (ESIMS) for C₂₁H₁₉N₂O₅S (M + H)⁺ Anal. Calcd 411.1015; found 411.1032. CHNS: Anal. calcd. for C₂₁H₁₈N₂O₅S; C, 61.45; H, 4.42; N, 6.83; S, 7.81. Found: C, 61.59; H, 4.39; N, 6.88; S, 7.70.

2.3

2.3 General procedure for synthesis of compounds (9–12c)

To a stirred solution of chalcone sulfide (1 mmol) in dichloromethane was added m-CPBA (4.5 mmol, 776.5 mg) at 0 °C portion wise for 25 min and the reaction mixture stirred at this temperature for 30 min then warmed to room temperature and stirred appropriate time in Table 2. TLC monitoring, the reaction was diluted with dichloromethane (8 mL) and washed with 5% aqueous K₂CO₃ (3 × 8 mL) and NaHCO₃ (10 mL) solution for removing excess m-CPBA. Then, the aqueous layer extracted with dichloromethane (3 × 10 mL), the combined organic layers dried over anhydrous Na₂SO₄ and solvent evaporated in vacuo. Pure sulfone was obtained by recrystallization from methanol.

2.3.1

2.3.1 1-[4-(methylsulfonyl)phenyl]-3(4-chlorophenyl)-3-(phenylsulfonyl)propan-1-one (9c)

Yield 95%; white solid; mp 124–126 °C; ¹H NMR (CDCl_3, 500 MHz) δ 7.86 (d, J = 8.5 Hz, 2H), 7.54 (dd, J = 8 Hz, 2 Hz, 3H), 7.42–7.38 (m, 3H), 7.28–7.22 (m, 5H), 4.99 (dd, J = 8.5 Hz, 6 Hz, 1H), 3.63–3.61 (m, 1H), 3.59–3.56 (m, 1H), 3.01 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 195.66, 146.49, 139.88, 133.73, 132.98, 132.84, 129.18, 128.97, 128.60, 128.47, 127.82, 124.98, 99.99, 63.84, 44.25, 37.68. IR (KBr): 3131, 2979, 2921, 1653, 1589, 1401, 1303, 1057, 740. HR-MS (ESIMS) for C₂₂H₁₉ClNaO₅S₂ (M + Na)⁺ Anal. Calcd 485.0260; found 485.0257. CHNS: Anal. calcd. for C22H19ClO5S2; C, 57.07; H, 4.14; S, 13.85. Found: C, 57.25; H, 4.11; S, 13.67.

2.3.2

2.3.2 1-[4-(methylsulfonyl)phenyl]-3(3-nitrophenyl)-3-(phenylsulfonyl)propan-1-one (10c)

Yield 96%; white solid; mp 152–153 °C; ¹H NMR (CDCl_3, 500 MHz) δ 8.18 (s, 1H), 8.10 (d, J = 8 Hz, 1H), 7.9–7.85 (m, 2H), 7.68 (dd, J = 15 Hz, 4 Hz, 2H), 7.55–7.51 (m, 4H), 7.28–7.23 (m, 3H), 4.98 (dd, J = 17.5 Hz, 4.5 Hz, 1H), 3.56–3.53 (m, 1H), 3.45–3.42 (m, 1H), 3.01 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 195.15, 146.87, 143.76, 134.31, 133.46, 132.83, 132.50, 130.73, 129.26, 128.47, 128.32, 127.17, 125.00, 122.64, 99.99, 63.54, 44.65, 38.52. IR (KBr): 3418, 3328, 3075, 2978, 2872, 1679, 1648, 1206 cm⁻¹. HR-MS (ESIMS) for C₂₂H₁₉NNaO₃S₂ (M + Na)⁺ Anal. Calcd 432.0704; found 432.0698. CHNS: Anal. calcd. for C₂₂H₁₉NO₇S₂; C, 55.80; H, 4.04; N, 2.96; S, 13.54. Found: C, 55.56; H, 4.12; N, 3.00; S, 13.78.

2.3.3

2.3.3 1-[4-(methylsulfonyl)phenyl]-3(4-methylphenyl)-3-(phenylsulfonyl)propan-1-one (11c)

Yield 91%; white solid; mp 162–163 °C; ¹H NMR (CDCl_3, 500 MHz) δ 8.12 (dd, J = 8.5 Hz, 2 Hz, 1H), 8.06–8.02 (m, 2H), 7.97 (dd, J = 8.5 Hz, 1 Hz, 2H), 7.75–7.72(m, 3H), 7.42–7.39 (m, 2H), 7.03 (q, 3H), 4.88 (dd, J = 9.5 Hz, 4 Hz, 1H), 4.40–4.30 (m, 1H), 4.18 (dd, J = 18 Hz, 4 Hz, 1H), 3.89–3.83 (m, 1H), 3.10 (s, 3H), 2.27 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 196.13, 146.16, 138.11, 137.04, 132.94, 132.52, 130.74, 129.20, 129.04, 28.88, 128.52, 127.65, 127.41, 127.17, 124.92, 63.51, 44.34, 38.00, 21.14. IR (KBr): 3064, 2942, 2831, 1663, 1584, 1342, 1111, 781 cm⁻¹. HR-MS (ESIMS) for C₂₃H₂₂NaO₅S₂ (M + Na)⁺ Anal. Calcd 465.0806; found 465.0811. CHNS: Anal. calcd. for C₂₃H₂₂O₅S₂; C, 62.42; H, 5.01; S, 14.49. Found: C, 62.34; H, 5.11; S, 14.22.

2.3.4

2.3.4 1-(4-(methylsulfonyl)phenyl)-3-phenyl-3-(phenylsulfonyl)propan-1-one (12c)

Yield 92%; white solid; mp 143–144 °C; ¹H NMR (CDCl_3, 500 MHz) δ8.10 (dd, J = 8 Hz, 1.5 Hz, 1H), 8.05–8.03 (m, 2H), 7.95 (dd, J = 8 Hz, 1.5 Hz, 2H), 7.62–7.59 (m, 3H), 7.41–7.38 (m, 2H), 7.0–6.56 (m, 3H), 4.96 (dd, J = 8.5 Hz, 3 Hz, 1H), 4.34–4.30 (m, 1H), 4.20–4.18 (m, 1H), 3.90–3.88 (m, 1H), 3.05 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 195.82, 147.32, 141.83, 131.92, 130.74, 130.02, 129.21, 128.69, 127.63, 127.14, 126.26, 124.74, 122.53, 65.52, 38.53, 44.65. IR (KBr): 3054, 2929, 2851, 1660, 1599, 1302, 1146, 756. HR-MS (ESIMS) for C₂₂H₂₀NaO₅S₂ (M + Na)⁺ Anal. Calcd 451.0650; found 451.0661. CHNS: Anal. calcd. for C₂₂H₂₀O₅S₂; C, 61.66; H, 4.70; S, 14.97. Found: C, 61.75; H, 4.68; S, 14.78.

2.4

2.4 General procedure for synthesis of chalcone based sulfones (13–16c)

To a stirred solution of chalcone sulfide (1 mmol) in dichloromethane was added m-CPBA (2.2 mmol, 379.5 mg) at 0 °C portion wise for 15 min and the reaction mixture stirred at this temperature for 30 min then warmed to room temperature and stirred for appropriate time in Table 3. TLC monitoring, the reaction was diluted with dichloromethane (8 mL) and washed with 5% aqueous K₂CO₃ (3 × 8 mL) and 5% NaHCO₃ (10 mL) solution for removing excess m-CPBA. Then, the aqueous layer extracted with dichloromethane (3 × 10 mL), the combined organic layers dried over anhydrous Na₂SO₄ and solvent evaporated in vacuo. Pure sulfone was obtained by recrystallization from methanol.

2.4.1

2.4.1 (E)-3-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (13c)

Yield 96%; White solid; mp 199–200 °C; ¹H NMR (CDCl₃, 500 MHz) δ 8.09 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 15.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.41–7.34 (m, 3H), 3.03 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 189.13, 145.15, 143.81, 142.30, 137.15, 132.78, 129.81, 129.41, 129.26, 127.83, 121.76, 44.36. IR (KBr): 3021, 2926, 1726, 1298, 1143. HR-MS (ESIMS) for C₁₆H₁₃ClO₃NaS (M + Na)⁺ Anal. Calcd 343.0172; found 343.0152. CHNS: Anal. calcd. for C₁₆H₁₃ClO₃S; C, 59.91; H, 4.08; S, 10.00. Found: C, 59.86; H, 4.11; S, 10.21.

2.4.2

2.4.2 (E)-3-(3-nitrophenyl)-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (14c)

Yield 95%; White solid; mp 243–244 °C; ¹H NMR (CDCl_3, 500 MHz) δ 8.55 (s, 1H), 8.31–8.29 (m, 1H), 8.21–8.2 (dd, J = 6.5 Hz, 2 Hz, 2H), 8.13 (dd, J = 7 Hz, 2 Hz, 2H), 7.95–7.9 (m, 2H), 7.67–7.6 (m, 2H), 3.12 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz):189.65, 149.58, 146.83, 139.46, 138.53, 136.84, 134.93, 134.23, 132.02, 129.60, 122.84, 121.04, 44.75. IR (KBr): 3011, 2985, 1698, 1534, 1443, 1268. HR-MS (ESIMS) for C₁₆H₁₄NO₅S (M + H)⁺ Anal. Calcd 332.0593; found 332.0600. CHNS: Anal. calcd. for C₁₆H₁₃NO₅S; C, 58.00; H, 3.95; N, 4.23; S, 9.68. Found: C, 57.91; H, 3.91; N, 4.22; S, 9.60.

2.4.3

2.4.3 (E)-3-(4-methylphenyl)-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (15c)

Yield 96%; White solid; mp 160–162 °C; ¹H NMR (CDCl_3, 500 MHz) δ 8.07 (d, J = 3.5 Hz, 2H), 8.0 (d, J = 3.5 Hz, 2H), 7.74 (d, J = 15.5 Hz, 1H), 7.48 (d, J = 5 Hz, 2H), 7.36 (d, J = 16 Hz, 1H), 7.21–7.16 (m, 2H), 3.13 (s, 3H), 2.21 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 189.50, 146.81, 143.51, 142.66, 141.88, 131.55, 129.81, 129.19, 128.70, 127.70, 120.36, 44.33, 21.56. IR (KBr): 3017, 2921, 1660, 1597. HR-MS (ESIMS) for C₁₇H₁₇O₃S (M + H)⁺ Anal. Calcd 301.0898; found 301.0904. CHNS: Anal. calcd. for C₁₇H₁₆O₃S; C, 67.98; H, 5.37; S, 10.68. Found: C, 67.87; H, 5.43; S, 10.82.

2.4.4

2.4.4 (E)-3-phenyl-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (16c)

Yield 98%; White solid; mp 168–170 °C; ¹H NMR (CDCl_3, 500 MHz) δ 8.08 (d, J = 8 Hz, 2H), 7.80 (d, J = 8 Hz, 2H), 7.75 (d, J = 16 Hz, 1H), 7.41–7.36 (m, 4H), 3.03 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 188.12, 145.76, 143.54, 142.45, 141.62, 134.15, 130.42, 129.49, 128.27, 126.41, 120.36, 45.10. IR (KBr): 3024, 2921, 1633, 1307, 1149. HR-MS (ESIMS) for C₁₆H₁₄NaO₃S (M + Na)⁺ Anal. calcd 309.0561; found 309.0554. CHNS: Anal. calcd. for C16H14O3S; C, 67.11; H, 4.93; S, 11.20. Found: C, 67.23; H, 4.89; S, 11.34.

2.5

2.5 General procedure for synthesis of compounds (17c–24c)

In a flame dried round bottom flask was added ferrocenyl chalcone sulfide (1 mmol) and dissolved in dry dichloromethane under N₂ gas for 6 min. Then, m-CPBA (2.2 mmol, 379.5 mg) in dichloromethane was added at 0 °C drop wise for 15 min and the reaction mixture stirred at this temperature for 30 min. then warmed to room temperature and stirred for appropriate time in Table 4. TLC monitoring, the reaction was diluted with dichloromethane (8 mL) and washed with 5% aqueous K₂CO₃ (3 × 8 mL) and 5% NaHCO₃ (10 mL) solution for removing excess m-CPBA. Then, the aqueous layer extracted with dichloromethane (3 × 10 mL), the combined organic layers dried over anhydrous Na₂SO₄ and solvent evaporated in vacuo. Pure ferrocenyl sulfone was obtained by recrystallization from methanol.

2.5.1

2.5.1 1-(4-Chlorophenyl)-3-ferrocenyl-3-phenylsulfonylpropan-1-one (17c)

Yield 92%; orange red solid; mp 147–148 °C; ¹H NMR (CDCl_3, 500 MHz) δ 7.81 (d, J = 9 Hz, 2H), 7.45 (dd, J = 9 Hz, 2.5 Hz, 2H), 7.32–7.30 (m, 2H), 7.25–7.20 (m, 3H), 4.98 (t, J = 6.5 Hz, 1H), 4.19–4.10 (m, 4H), 4.09 (s, 5H), 3.85–3.84 (m, 1H), 3.58 (dd, 18 Hz, 4 Hz, 1H), ¹³C NMR (CDCl₃, 125 MHz): 197.25, 138.14, 135.41, 134.24, 133.84, 131.54, 130.68, 129.38, 128.56, 81.21, 71.12, 70.15, 68.8, 67.9, 67.7, 66.9, 37.81. IR (KBr): 3021, 2954, 1702, 1463, 1401, 1298, 1108, 1156. HR-MS (ESIMS) for C₂₅H₂₂ClFeO₃S (M + H)⁺ Anal. Calcd 493.0328; found 493.0321. CHNS: Anal. calcd. for C₂₅H₂₁ClFeO₃S; C, 60.93; H, 4.30; S, 6.51. Found: C, 60.85; H, 4.29; S, 6.43.

2.5.2

2.5.2 1-(4-Methylphenyl)-3-ferrocenyl-3-phenylsulfonylpropan-1-one (18c)

Yield 91%; orange red solid; mp 152–153 °C; ¹H NMR (CDCl_3, 500 MHz) δ 7.86 (d, J = 3.5 Hz, 2H), 7.42–7.40 (m, 2H), 7.30–7.24 (m, 5H), 5.06 (t, J = 7.5 Hz, 1H), 4.06–3.99 (m, 9H), 3.48–3.45 (m, 2H), 2.3 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 196.53, 145.28, 135.26, 134.21, 133.54, 130.41, 129.51, 128.82, 127.58, 70.15, 68.8, 68.4, 67.9, 67.7, 67.5, 67.0, 36.16, 20.91.IR (KBr): 3102, 2935, 1670, 1465, 1376 cm⁻¹. HR-MS (ESIMS) for C₂₆H₂₄FeNaO₃S (M + Na)⁺ Anal. Calcd 495.0693; found 495.0690. CHNS: Anal. calcd. for C₂₆H₂₄FeO₃S; C, 66.11; H, 5.12; S, 6.79. Found: C, 66.25; H, 5.09; S, 6.72.

2.5.3

2.5.3 1-(4-Methoxylphenyl)-3-ferrocenyl-3-phenylsulfonylpropan-1-one (19c)

Yield 94%; orange red solid; mp 165–166 °C; ¹H NMR (CDCl_3, 500 MHz) δ 7.92 (dd, J = 7 Hz, 2 Hz, 2H), 7.34–7.31 (m, 2H), 7.22–7.18 (m, 3H), 6.95 (dd, J = 7 Hz, 2 Hz, 2H), 5.06 (t, J = 7.5 Hz, 1H), 4.15–4.06 (m, 9H), 3.99 (s, 3H), 3.48–3.45 (m, 2H). ¹³C NMR (CDCl₃, 125 MHz): 199.54, 163.64, 134.31, 131.94, 130.51, 129.14, 128.37, 126.66, 114.17, 89.0, 67.78, 66.8, 66.6, 65.9, 63.51, 37.41. IR (KBr): 3060, 2919, 2843, 1679, 1489, 1404, 1325, 1142, 1010, 865 cm⁻¹. HR-MS (ESIMS) for C₂₆H₂₅FeO₄S (M + H)⁺ Anal. Calcd 489.0823; found 489.0812. CHNS: Anal. calcd. for C₂₆H₂₄FeO₄S; C, 63.94; H, 4.95; S, 6.57. Found: C, 63.99; H, 4.99; S, 6.69.

2.5.4

2.5.4 1-(3,4,5-Trimethoxylphenyl)-3-ferrocenyl-3-phenylsulfonylpropan-1-one (20c)

Yield 92%; orange red solid; mp 182–183 °C; ¹H NMR (CDCl_3, 500 MHz) δ7.26–7.15 (m, 5H), 6.92 (s, 2H), 4.95 (t, J = 6.5 Hz, 1H), 4.06 (s, 5H), 4.02–4.01 (m, 4H), 3.86 (s, 3H), 3.84 (s, 6H), 3.46 (d, J = 6.5 Hz, 2H). ¹³C NMR (CDCl₃, 125 MHz): 196.91, 154.21, 143.54, 134.35, 132.32, 130.8, 129.1, 127.5, 105.8, 69.84, 68.9, 68.02, 67.73, 67.1, 66.47, 61.0, 56.4, 56.12, 37.64. IR (KBr): 3096, 2927, 2843, 1659, 1489, 1404, 1325, 1131, 1010, 865 cm⁻¹. HR-MS (ESIMS) for C₂₈H₂₉FeO₆S (M + H)⁺ Anal. Calcd 549.1034; found 549.1039. CHNS: Anal. calcd. for C₂₈H₂₈FeO₆S; C, 61.32; H, 5.15; S, 5.85. Found: C, 61.22; H, 5.13; S, 5.91.

2.5.5

2.5.5 1-(3,4-Dimethylphenyl)-3-ferrocenyl-3-phenylsulfonylpropan-1-one (21c)

Yield 94%; orange red solid; mp 152–154 °C; ¹H NMR (CDCl_3, 500 MHz) δ 7.84–7.80 (m, 2H), 7.59–7.55 (m, 3H), 7.40 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 8 Hz, 1H), 5.03–5.01 (m, 1H), 4.19–4.10 (m, 4H), 4.09 (s, 5H), 3.85–3.84 (m, 1H), 3.56 (dd, 18 Hz, 4 Hz, 1H), 2.37 (s, 3H), 2.36 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 194.90, 143.42, 137.27, 136.80, 134.13, 133.55, 130.07, 129.47, 129.44, 128.59, 126.05, 81.19, 71.11, 69.18, 68.85, 68.45, 67.32, 61.65, 37.46, 20.14, 19.88. IR (KBr): 3021, 2910, 2852, 1671, 1441, 1417, 1311, 1142, 1051, 893 cm⁻¹. HR-MS (ESIMS) for C₂₇H₂₆FeNaO₃S (M + Na)⁺ Anal. calcd 509.0850; found 509.0862. CHNS: Anal. calcd. for C₂₇H₂₆FeO₃S; C, 66.67; H, 5.39; S, 6.59. Found: C, 66.60; H, 5.29; S, 6.72.

2.5.6

2.5.6 1-Phenyl-3-ferrocenyl-3-(phenylsulfonyl)propan-1-one (22c)

Yield 94%; orange red solid; mp 133–135 °C; ¹H NMR (CDCl_3, 500 MHz) δ7.52–7.50 (m, 2H), 7.32 (t, J = 8 Hz, 2H), 7.22–7.16 (m, 6H), 4.86 (m, 1H), 4.72–4.70 (m, 2H), 4.45–4.43 (m, 1H), 4.15 (s, 1H), 3.91 (s, 5H), 3.73–3.59 (m, 2H). ¹³C NMR (CDCl₃, 125 MHz): ¹³C NMR (CDCl₃, 125 MHz): 195.54, 144.43, 135.67, 131.73, 130.24, 129.9, 127.64, 127.35, 126.05, 90.05, 68.92, 67.95, 67.46, 67.12, 66.43, 61.3, 37.86. IR (KBr): 3096, 2927, 2843, 1659, 1489, 1404, 1325, 1131, 1010, 865 cm⁻¹. HR-MS (ESIMS) for C₂₅H₂₃FeO₃S (M + H)⁺ Anal. Calcd 459.0717; found 459.0699. CHNS: Anal. calcd. for C₂₅H₂₂FeO₃S; C, 65.51; H, 4.84; S, 7.00. Found: C, 65.49; H, 4.90; S, 7.15.

2.5.7

2.5.7 1-Ferrocenyl-3-phenyl-3-(phenylsulfonyl)propan-1-one (23c)

Yield 95%; orange red solid; mp 143–144 °C; ¹H NMR (CDCl_3, 500 MHz) δ 7.43–7.40 (m, 2H), 7.34 (t, J = 8 Hz, 2H), 7.21–7.16 (m, 6H), 4.85 (m, 1H), 4.75–4.72 (m, 2H), 4.46–4.44 (m, 1H), 4.15 (s, 1H), 3.94 (s, 5H), 3.66–3.60 (m, 2H).¹³C NMR (CDCl₃, 125 MHz) δ 200.69, 141.67, 135.64, 133.15, 130.41, 129.45, 128.61, 127.64, 127.35, 78.87, 78.01, 77.4, 76.98, 73.44, 72.38, 69.76, 69.42, 69.31, 60.59, 38.83. IR (KBr): 3096, 2927, 2843, 1659, 1489, 1404, 1325, 1131, 1010, 865 cm⁻¹. HR-MS (ESIMS) for C₂₅H₂₃FeO₃S (M + H)⁺ Anal. Calcd 459.0717; found 459.0725. CHNS: Anal. calcd. for C₂₅H₂₂FeO₃S; C, 65.51; H, 4.84; S, 7.00. Found: C, 65.55; H, 4.89; S, 7.13.

2.5.8

2.5.8 1-Ferrocenyl-3-(3,4dimethylphenyl)-3-(phenylsulfonyl)propan-1-one (24c)

Yield 93%; orange red solid; mp 170–172 °C; ¹H NMR (CDCl_3, 500 MHz) δ7.62 (d, J = 8 Hz, 2H), 7.56 (t, 7.5 Hz, 1H), 7.41 (t, 8 Hz, 2H), 7.03 (s, 1H), 7.0–6.96 (m, 2H), 4.86–4.83 (m, 1H), 4.78–4.76 (m, 2H), 4.51–4.50 (m, 2H), 3.99 (s, 5H), 3.67 (m, 2H), 2.17 (s, 3H), 2.16 (s, 3H). ¹³C NMR (CDCl₃, 125 MHz): 198.73, 137.42, 137.32, 136.66, 133.46, 130.88, 129.65, 128.93, 128.60, 127.27, 78.13, 72.50, 69.72, 69.35, 69.05, 65.78, 37.97, 19.65, 19.43. IR (KBr): 3021, 2921, 2852, 1652, 1443, 1400, 1361, 1131, 1038, 881 cm⁻¹. HR-MS (ESIMS) for C₂₇H₂₆FeNaO₃S (M + Na)⁺ Anal. calcd 509.0850; found 509.0858. CHNS: Anal. calcd. for C₂₇H₂₆FeO₃S; C, 66.67; H, 5.39; S, 6.59. Found: C, 66.78; H, 5.41; S, 6.71.

3 Results and discussion

3.1

3.1 Chemistry

Chalcones were prepared following the literature procedure by condensation of different acetophenones and aromatic aldehydes (Konduru and Ahmed, 2013). The chalcone based sulfides were synthesized by reacting chalcones with thiophenol in the presence of sodium-metal in dichloromethane at room temperature via thia Michael addition reaction (Schemes 1–4 ) (Konduru et al., 2013). Further, the sulfides were oxidized to sulfones using m-CPBA as oxidizing reagent in dichloromethane at 0 °C to room temperature in good yields (Schemes 1–4 ).

Synthesis of 2′-hydroxy, 2′-amino chalcone based sulfones (8c–11c) from corresponding sulfides.

Synthesis of 1-(4-(methylsulfonyl)phenyl)-3-aryl-3-(phenylsulfonyl)propan-1-one (9c–12c) and synthesis of (E)-3-aryl-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (14c–17c).

Synthesis of 3-ferrocenyl-1-phenyl chalcone based sulfones (18c–22c).

Synthesis of 1-ferrocenyl-3-phenyl chalcone based sulfones (23c–24c).

Here, we have synthesized different type of chalcone based sulfone derivatives such as 1–4c (2′-hydroxychalcone sulfones), 5–8c (2′-aminochalcone sulfones), 9–12c (bis-sulfones), 13–16c and 17–24c (ferrocenyl sulfones). Monosulfones (1–8c and 13–24c) and bis-sulfones (9–12c) were synthesized using corresponding sulfide and m-CPBA in 1:2.2 and 1:4.5 mol ratio respectively in an open atmosphere. However, ferrocenyl sulfones (17–24c) were obtained under inert atmosphere (Schemes 3 and 4). During the synthesis of sulfones and bis-sulfones, no significant substituent effects were observed and an excellent yield (90–98%) was obtained.

The assigned structures of new products (1–8c) were established from their spectroscopic data (IR, HRMS, ¹H, ¹³C NMR). For example, compound 1c was obtained as a white solid. The IR spectrum of 1c showed absorptions at 3450, 1707 cm⁻¹ for OH, carbonyl bond asymmetric stretching and 1315, 1154 cm⁻¹ for –SO₂– asymmetric, symmetric bond stretching, respectively. The HRMS of 1c supported a molecular composition of C₂₂H₂₁O₄S (M + H)⁺, representing 12° of unsaturation. In the ¹H and ¹³C NMR spectra, peaks resonating at δ_H 2.3 (s, 3H) and δ_C 21.28 indicate methyl group present. Peaks at δ_H 4.90 (dd, J = 9.5 Hz, 3.5 Hz, 1H), δ_C 62.94 correspond to CH–SO₂ in which vicinal coupling constants J = 9.5 Hz, and 3.5 Hz indicate methine proton (CH–SO₂) coupled with adjacent protons trans and cis coupling respectively. Peaks at δ_C 37.22, and δ_H 4.13 (dd, J = 16 Hz, 3.5 Hz, 1H) correspond to –CH₂–CH–SO₂, in which coupling constant J = 16 Hz indicates geminal coupling of methylene proton (–CH₂–CH–SO₂) and J = 3.5 Hz indicates vicinal coupling at δ_H 4.13 and 4.90 protons which confirms the product formation. Further, shift in δ_H value of proton (CH–SO₂) from 4.56 to 4.90 indicates sulfide (1b) conversion to sulfone (1c) (Table 1).

Compound 9c was obtained as a white solid. The IR spectrum of 9c showed absorptions at 1653, 1589, 1303, 1057 cm⁻¹ for carbonyl bond asymmetric and –SO₂– bond asymmetric and symmetric stretching respectively. The HRMS of 9c supported a molecular composition of C₂₂H₁₉ClNaO₅S₂ (M + Na)⁺ representing 13° of unsaturation. In the ¹H and ¹³C NMR spectra of 9c, peaks resonating at δ_H 3.01 (s, 3H) and δ_C 44.25 suggested that methyl group attached with -SO₂- group. Peak at δ_H 4.99 (dd, J = 8.5 Hz, 6 Hz, 1H) corresponds to –CH₂-CH–SO₂ in which coupling constants ³J = 8.5 Hz, and 6 Hz indicate trans and cis coupling of methine proton (–CH₂-CH–SO₂) with adjacent methylene protons (–CH₂-CH–SO₂) respectively. Peaks at δ_H 3.63–3.61 (m, 1H), and 3.59–3.56 (m, 1H) correspond to methylene protons (–CH₂–CH–SO₂), which confirms the product formation and shift in δ_H value of methine proton (CH–SO₂) from 4.58 to 4.99, shift in δ_H value of methyl proton (CH₃–SO₂) from 2.5 to 3.01 in sulfone indicates bis-sulfide (9b) conversion to bis-sulfone (9c) (Table 2).

Compound 13c was obtained as a white solid. The IR spectrum of 13c showed absorptions at 1726, 1298, 1143 cm⁻¹ for carbonyl asymmetric and –SO₂– asymmetric, and symmetric stretching, respectively. The HRMS of 13c supported a molecular composition of C₁₆H₁₃ClO₃NaS (M + Na)⁺ representing 10° of unsaturation. In the ¹H and ¹³C NMR spectra of 13c, peaks resonating at δ_H 3.03 (s, 3H) and δ_C 44.36 indicate –SO₂–CH₃ group present (Table 3).

Compound 17c was obtained as orange red solid. The IR spectrum of 17c showed absorptions at 3021, 1108, 1463, 1401 cm⁻¹ for ferrocene characteristic stretchings, and 1702, 1298, 1156 cm⁻¹ for carbonyl asymmetric and –SO₂– asymmetric, and symmetric stretchings, respectively. The HRMS of 17c supported a molecular composition of C₂₅H₂₂ClFeO₃S (M + H)⁺ representing 15° of unsaturation. In the ¹H NMR spectrum peaks at δ_H 4.19–4.10 (m, 4H), 4.09 (s, 5H) suggested that mono-substituted ferrocene moiety present. In the ¹H and ¹³C NMR spectrum peaks at δ_H 4.98 (t, J = 6.5 Hz, 1H), δ_C 66.9, correspond to methine group (CH–SO₂) in which coupling constant ³J = 6.5 Hz indicates methine proton cis coupling with adjacent methylene protons (–CH₂–CH–SO₂₎. Peaks at δ_H 3.85, 3.58 correspond to methylene protons (–CH₂–CH–SO₂₎, which confirms the product formation. Further, shift in δ_H-value from 4.50 to 4.98 and δ_C-value from 44.5 to 66.9 of methine group (CH–SO₂) in sulfone indicates ferrocenyl sulfide (13b) conversion to ferrocenyl sulfone (17c) (Table 4).

3.2

3.2 Antimicrobial activity

3.2.1

3.2.1 Microdilution assay

Minimum inhibitory concentration (MIC) values of the compounds against bacterial and fungal isolates were determined on the basis of micro-well dilution method following NCCLS recommendations (Zgoda and Porter, 2001). The stock solution of novel compounds was prepared at a concentration of 10 mg/mL in DMSO, which was further diluted to working solution of concentration 1 mg/mL solution in methanol. Using a micropipette, 100 μl of media into all wells of pre-sterilized 96 well microtiter plate was dispensed (experiment was done in triplicate). Twofold serial dilutions were made from the well # 1 to the well # 10 and excess media (100 μl) was discarded from the last well (# 10). The desired aliquot was harvested from culture of test organism (log phase) in corresponding medium (Yeast, Peptone, and D-Glucose for fungal growth and Luria Bertani Broth, Nutrient Broth for bacterial growth) for 12–18 h at 37 °C. Then optical density of liquid culture was determined at 600 nm and diluted in such a way that each well received 10⁴cfu/100 μl of fungal suspension and 10⁷cfu/100 μl of bacterial culture. Appropriate positive and negative controls were also included in the study. Positive control contained only microbial cells where as negative control contained only standard drug solution (Amphotericin-B and Nystatin for fungus and Ampicillin and Kanamycin for bacteria). All experimental procedures were performed under sterile condition using bio-safety hood and microtiter plates were incubated at 37 °C for 12–18 h.

3.2.2

3.2.2 In-vitro antimicrobial activity of novel synthesized compounds

During antimicrobial screening for novel compounds (1–24c), yeasts (Aspergillus niger, Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, Candida parapsilosis and Candida tropicalis), Gram positive bacteria (Bacillus subtilis, Staphylococcus aureus and Listeria monocytogenes) and Gram negative bacteria (Pseudomonas aeruginosa, Klebseilla pneumonia, Escherichia coli, Proteus vulgaris) strains were used. These compounds showed interesting antimicrobial activity against used strains; particularly the compounds 1c, 6c, 20c, and 24c have shown better antimicrobial activity than the standard drugs.

3.2.3

3.2.3 Antibacterial activity

Compounds 1–24c were evaluated for their antibacterial activity against Gram positive bacteria (B. subtilis, S. aureus, L. monocytogenes) and Gram negative bacteria (P. aeruginosa, K. pneumonia, E. coli, P. vulgaris). The minimum inhibitory concentration (MIC, μg/mL) was determined by microdilution method (Jorgensen and Lee, 1975) using Ampicillin and Kanamycin as standard drugs and the results are shown in Table 5.

Table 5 Minimum inhibitory concentration (MIC) in μg/mL of chalcone based sulfone derivatives against bacterial strains evaluated by micro-dilution method.

Entry	Drug	Gram positive bacteria			Gram negative bacteria
Entry	Drug	B. subtilis (μg/mL)	S. aureus (μg/mL)	L. monocytogenes (μg/mL)	P. aeruginosa (μg/mL)	K. pneumonia (μg/mL)	E. coli (μg/mL)	P. vulgaris (μg/mL)
1	Ampicillin	250	500	250	125	200	150	200
2	Kanamycin	7.81	500	100	250	50	100	125
3	1c	62.50	125	150	62.50	80.0	100	150
4	2c	125	125	150	250	100	125	200
5	3c	125	125	150	31.25	125	55.5	150
6	4c	62.50	7.81	150	62.50	80.0	25.5	150
7	5c	125	250	200	250	250	200	250
8	6c	3.90	1.95	7.81	31.25	25.5	25.5	30.50
9	7c	250	250	200	250	150	200	150
10	8c	125	62.50	100	62.50	150	80.0	80.0
11	9c	125	125	150	125	150	200	150
12	10c	62.50	62.50	125	250	80.0	100	125
13	11c	62.50	125	100	31.25	50.0	70.0	100
14	12c	125	125	200	62.50	100	125	150
15	13c	62.50	125	100	62.50	48.5	80.0	100
16	14c	62.50	125	150	125	100	150	150
17	15c	125	250	100	31.25	125	250	30.50
18	16c	125	125	100	62.50	100	100	70.0
19	17c	125	62.50	100	125	150	150	150
20	18c	125	250	250	250	150	200	200
21	19c	62.50	62.50	200	125	80.0	80.0	100
22	20c	3.90	3.90	15.0	250	1.95	10.0	25.0
23	21c	125	62.50	125	15.62	100	50.0	70.0
24	22c	125	125	150	125	150	125	125
25	23c	125	62.50	100	62.50	31.5	50.0	80.0
26	24c	7.81	62.50	150	1.95	31.5	3.90	25.0

Bold values indicate better highlights.

All compounds (1–24c) showed higher antibacterial activity (3.90–250 μg/mL) compared to reference drug ampicillin (MIC: 250 μg/mL) against B. subtilis. Compounds 6c (MIC: 3.90 μg/mL) and 20c (MIC: 3.90 μg/mL) showed higher and compound 24c (MIC: 7.81 μg/mL) showed equal antibacterial activity compared to positive control Kanamycin (MIC: 7.81 μg/mL), while remaining compounds showed moderate to low antibacterial activity against B. subtilis. Against S. aureus, compounds 1–24c exhibited higher antibacterial activity (MIC: 1.95–250 μg/mL) with respect to reference drugs ampicillin (MIC: 500 μg/mL) and kanamycin (MIC: 500 μg/mL). Compounds 4c (MIC: 7.81 μg/mL), 6c (MIC: 1.95 μg/mL) and 20c (MIC: 3.90 μg/mL) showed the highest antibacterial activity, while the compounds 8c, 10c, 17c, 19c, 21c, 23c, and 24c (MIC: 62.50 μg/mL) showed good antibacterial activity and remaining compounds gave moderate to low antibacterial activity against S. aureus. Against L. monocytogenes, all compounds exhibited higher antibacterial activity (MIC: 7–200 μg/mL) compare to standard drug ampicillin (MIC: 250 μg/mL). However, most of the compounds showed lower activity than reference drug kanamycin (MIC: 100 μg/mL). Compounds 6c (MIC: 7.81 μg/mL), 20c (MIC: 15 μg/mL) showed highest antibacterial activity and the remaining compounds showed moderate to low antibacterial activity against L. monocytogenes. Against P. aeruginosa, compounds 24c (MIC: 1.95 μg/mL), and 21c (MIC: 15.62 μg/mL) showed highest antibacterial activity, compounds 3c, 6c, 11c, and 15c (MIC: 31.25 μg/mL) showed good antibacterial activity, compounds 1c, 8c, 12c, 13c, 16c, and 23c (MIC: 62.50 μg/mL) showed better antibacterial activity while others showed moderate antibacterial activity (MIC ⩾ 125 μg/mL) compared to standard drugs (ampicillin (MIC: 125 μg/mL), kanamycin (MIC: 250 μg/mL)). Against K. pneumonia, most of these compounds showed better antibacterial activity (MIC: <150 μg/mL) compared to standard drug ampicillin (MIC: 200 μg/mL). Compound 20c (MIC: 1.95 μg/mL) showed highest antibacterial activity, compounds 6c (MIC: 25.5 μg/mL), 23c, and 24c (MIC: 31.5 μg/mL) showed good antibacterial activity, and compounds 11c, 13c, (MIC: <50 μg/mL) showed moderate antibacterial activity compare to standard drugs [ampicillin (MIC: 200 μg/mL), kanamycin (MIC: 80 μg/mL)]. Against E. coli, most of the tested compounds showed better antibacterial activity (MIC: ⩽100 μg/mL) compare to reference drugs (ampicillin (MIC: 150 μg/mL), kanamycin (MIC: 100 μg/mL)). Compounds 20c (MIC: 10.00 μg/mL), and 24c (MIC: 3.90 μg/mL) showed the highest antibacterial activity, compounds 4c, and 6c (MIC: 25.50 μg/mL) showed good antibacterial activity, compounds 21c, 23c (MIC: 50.0 μg/mL), and 3c, (MIC: 55.5 μg/mL) showed moderate antibacterial activity compare to standard drugs. Against P. vulgaris, most of these compounds showed equal to higher antibacterial activity (MIC: 25–250 μg/mL) compare to reference drugs [ampicillin (MIC: 200 μg/mL), kanamycin (MIC: 125 μg/mL)]. Compounds 20c, 24c (MIC: 25.00 μg/mL), 6c, and 15c (MIC: 30.50 μg/mL) showed highest antibacterial activity, compounds 16c, 21c (MIC: 70.00 μg/mL), 8c, and 23c (MIC: 80.00 μg/mL) showed moderate antibacterial activity, the remaining compounds showed lower activity compare to reference drugs. Compounds 6c and 20c gave the highest antibacterial activity against almost all tested bacterial strains (Table 5).

The antibacterial activity of chalcone based sulfones and bis-sulfones showed the substituents effect on chalcone nuclei. For example, 3-NO₂ substituted on B ring of 2′-hydroxychalcone based sulfones (4c) has enhanced antibacterial activity against S. aureus than the other substituents like 4-methyl, 4-Chloro, and 3,4,5-trimethoxy containing compounds. In the case of 2′-aminochalcone based sulfones (5–8c), 4-Chloro substituted on B ring (compound 6c) has enhanced antibacterial activity against S. aureus than the other substituents like 4-methyl, 3-nitro containing compounds. In bis sulfones (9–12c), 4-methyl substituted on B ring (compound 11c) has enhanced antibacterial activity against P. aruginosa than the other substituents like 4-Chloro, 3-NO₂ containing compounds. In ferrocenyl chalcone based sulfones (17–24c), 3,4,5-trimethoxy substituted on A ring (compound 20c) and 3,4-dimethyl substituted on B ring (compound 24c) have enhanced antibacterial activity against almost tested stains. Compound 24c showed 4-folds active against B. subtilis, compounds 4c, 6c and 20c showed 8-, 32-, 16-folds active against S. aureus respectively. Compounds 1c, 4c, 8c, 12c, 13c, 16c and 23c showed 2-folds active, compounds 3c, 6c, 11c and 15c showed 4-folds active and compounds 21c and 24c showed 8- and 64-folds active respectively against P. aruginosa from previous results (Simpkins, 1993). Comparative analysis of antibacterial activity (Gram positive and negative bacteria) of novel compounds with respect to reference drugs is shown in Figs. 2 and 3.

Gram (+) bacterial activity of the synthesized compounds and their comparison to standard drugs Ampicillin and Kanamycin.

3.2.4

3.2.4 Antifungal activity

Novel synthesized compounds (1–24c) were further evaluated for their antifungal activity against A. niger, C. albicans, A. fumigatus, C. neoformans, C. parapsilosis and C. tropicalis pathogens. The minimum inhibitory concentration (MIC, μg/mL) was determined by microdilution method (Jorgensen and Lee, 1975; Zgoda and Porter, 2001) using Amphotericin-B and Nystatin as standard drugs and the results are shown in Table 6.

Table 6 Minimum inhibitory concentration (MIC) in μg/mL of chalcone based sulfone derivatives against fungus evaluated by micro-dilution method.

Entry	Drug	A. niger (μg/mL)	C. albicans (μg/mL)	A. fumigatus (μg/mL)	C. neoformans (μg/mL)	C. parapsilosis (μg/mL)	C. tropicalis (μg/mL)
1	Nystatin	500	15.62	500	200	25.0	10.0
2	Amphotericin B	7.81	7.81	5.65	5.75	4.5	8.50
3	1c	62.50	62.50	67.25	75.5	80.0	80.0
4	2c	31.25	62.50	30.50	40.5	35.5	25.5
5	3c	125	62.50	95.0	50.0	75.5	15.5
6	4c	62.50	62.50	100.0	45.5	45.5	70.0
7	5c	62.50	250	100	75.0	75.0	75.0
8	6c	62.50	31.25	25.5	35.5	65.5	80.0
9	7c	125	62.50	31.5	50.0	25	25
10	8c	125	62.50	100	65	50	40
11	9c	125	62.50	70	70	80	25.5
12	10c	62.50	125	100	70	80	100
13	11c	125	250	125	200	150	150
14	12c	125	125	125	200	200	100
15	13c	250	62.50	100	80.0	100	150
16	14c	125	62.50	100	125	125	100
17	15c	125	125	200	125	125	100
18	16c	125	125	200	125	125	100
19	17c	125	250	200	150	100	150
20	18c	250	250	150	150	200	200
21	19c	62.50	62.50	70.0	70.0	50.0	45.5
22	20c	125	250	125	100	100	150
23	21c	125	125	125	150	100	100
24	22c	125	125	125	100	100	125
25	23c	125	250	150	125	100	100
26	24c	3.90	7.81	10.5	3.90	7.81	15.5

Bold values indicate better highlights.

All compounds (1–24c) showed higher antifungal activity (3.90–125 μg/mL) compare to reference drug Nystatin (MIC: 500 μg/mL) against A. niger. However, most of these compounds showed lower antifungal activity than the reference drug Amphotericin B (MIC: 7.81 μg/mL). Compounds 24c (MIC: 3.90 μg/mL) and 2c (MIC: 31.25 μg/mL) showed higher and compounds 1c, 4c, 5c, 6c, 10c and 19c (MIC: 62.5 μg/mL) showed moderate while the remaining compounds showed lower antifungal activity against A. niger. Against C. albicans, all compounds exhibited moderate antifungal activity (MIC: 7.81–250 μg/mL) compare to reference drugs Nystatin (MIC: 15.62 μg/mL) and Amphotericin B (MIC: 7.81 μg/mL). Compound 24c (MIC: 7.81 μg/mL) showed the highest antifungal activity, compound 6c (MIC: 31.25 μg/mL) showed good antifungal activity and the remaining compounds showed lower antifungal activity compare to reference drugs. Against A. fumigatus, all compounds exhibited higher antifungal activity (MIC: 10.5–100 μg/mL) compare to reference drug Nystatin (MIC: 500 μg/mL), but lower antifungal activity than reference drug Amphotericin B (MIC: 5.65 μg/mL). Compound 24c (MIC: 10.5 μg/mL) showed highest antifungal activity, compounds 2c (MIC: 30.5 μg/mL), 6c (MIC: 25.5 μg/mL), and 7c (MIC: 31.5 μg/mL) showed good antifungal activity and the remaining compounds showed moderate to low antifungal activity compare to reference drugs against A. fumigatus. Against C. neoformans, all compounds exhibited higher antifungal activity (MIC: 3.90–200 μg/mL) compare to reference drug Nystatin (MIC: 200 μg/mL), but lower antifungal activity compare to reference drug Amphotericin B (MIC: 5.75 μg/mL). Compound 24c (MIC: 3.90 μg/mL) showed the highest antifungal activity, compounds 2c (MIC: 40.5 μg/mL), 3c (MIC: 50.0 μg/mL), 4c (MIC: 45.5 μg/mL), 6c (MIC: 35.5 μg/mL), and 7c (MIC: 50.0 μg/mL) showed good antifungal activity while all other compounds showed moderate to low antifungal activity compare to reference drugs. Against C. parapsilosis, all compounds exhibited moderate antifungal activity (MIC: 7.81–80 μg/mL) compare to reference drugs Nystatin (MIC: 25.0 μg/mL) and Amphotericin B (MIC: 4.5 μg/mL). Compound 24c (MIC: 7.81 μg/mL) showed high antifungal activity compare to reference drugs. Against C. tropicalis, all compounds exhibited low antifungal activity (MIC: 15.5–200 μg/mL) compare to reference drugs Nystatin (MIC: 10.0 μg/mL) and Amphotericin B (MIC: 8.5 μg/mL). Compounds 3c and 24c (MIC: 15.5 μg/mL) showed high antifungal activity and compounds 2c, 9c (MIC: 25.5 μg/mL) and 7c (MIC: 25 μg/mL) showed moderate antifungal activity (Table 6).

The antifungal activity of chalcone based sulfones and bis-sulfones showed the substituents effect on chalcone nuclei. For example, 4-chloro substituted on B ring of 2′-hydroxychalcone based sulfones (2c) has enhanced antifungal activity against tested fungi pathogens than 4-methyl, 3-NO₂, 3,4,5-trimethoxy containing compounds. In the case of 2′-aminochalcone based sulfones (5–8c), 4-chloro substituted on B ring (compound 6c) has enhanced antifungal activity against A. niger, C. albicans, A. fumigatus, and C. neoformans and compound 7c (no substitution) showed enhanced antifungal activity against C. neoformans, C. parapsilosis, and C. tropicalis. In ferrocenyl chalcone based sulfones (17–24c), 3,4-dimethyl substituted on B ring (compound 24c) has 2-folds enhanced antifungal activity against tested stains from previous results (Simpkins, 1993). Comparative analysis of antifungal activity of novel synthesized compounds with respect to reference drugs is shown in Fig. 4. A Venn diagram is shown for all compounds which are active against Gram positive and negative bacteria and fungi in Fig. 5.

Anti-fungal activity of the synthesized compounds and their comparison to standard drugs Nystatin and Amphotericin B.

Venn diagram of microbial activity relation of synthesized compounds.

4 Conclusion

In conclusion, we have synthesized new class of ferrocenyl and organic chalcone based sulfones and bis-sulfones and evaluated their antibacterial and antifungal activities. The majority of the compounds have higher inhibitory activity against bacteria than the fungi. Compounds 6c, 20c, and 24c demonstrated the highest antibacterial activity against all Gram-positive and negative bacteria. Compound 24c showed higher antifungal activity against tested pathogens and the highest antifungal activity against A. niger, C. parapsilosis than the reference drugs nystatin and amphotericin B. Other sulfone derivatives showed fair to low antibacterial and antifungal activities. The antibacterial and antifungal activities of chalcone based sulfones and bis-sulfones also showed the substituents effect on chalcone nuclei. 3-NO₂ substituted 2′-hydroxychalcone sulfones, 4-chloro substituted 2′-aminochalcone sulfones, 3,4,5-trimethoxy and 3,4-dimethyl substituted ferrocenyl chalcone sulfones showed excellent antimicrobial activity. The order of antimicrobial activity in tested compounds: ferrocenyl chalcone sulfones > 2′-hydroxychalcone sulfones > 2′-aminochalcone sulfones > bis-sulfones.

Acknowledgments

NA is grateful to BRNS, BARC Mumbai and DST New Delhi for financial support and NKK for fellowship from Council of Scientific and Industrial Research (CSIR), New Delhi, India.

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Appendix A

Supplementary material

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2014.12.008.

Appendix A

Supplementary material

Supplementary data 1

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Introduction

Materials and methods

General
General procedure for synthesis of compounds (1–8c)
General procedure for synthesis of compounds (9–12c)
General procedure for synthesis of chalcone based sulfones (13–16c)
General procedure for synthesis of compounds (17c–24c)

Results and discussion

Chemistry
Antimicrobial activity

Conclusion

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[1] Ahmed N., Konduru N.K., Ahmad S., Owais M., . Synthesis of flavonoids based novel tetrahydropyran conjugates (Prins products) and their antiproliferative activity against human cancer cell lines. Eur. J. Med. Chem.. 2014;75:233-246.
[Google Scholar]

[2] Alba A.N.R., Companyo X., Rios R., . Sulfones: new reagents in organocatalysis. Chem. Soc. Rev.. 2010;39:2018-2033.
[Google Scholar]

[3] Arrayas R.G., Adrido J., Carretero J.C., . Recent applications of chiral ferrocene ligands in asymmetric catalysis. Angew. Chem. Int. Ed.. 2006;45:7674-7715.
[Google Scholar]

[4] Backvall J.E., Chinchilla R., Najera C., Yus M., . The use of sulfonyl 1,3-dienes in organic synthesis. Chem. Rev.. 1998;98:2291-2312.
[Google Scholar]

[5] Belofsky G., Percivill D., Lewis K., Tegos G.P., Ekart J., . Phenolic metabolites of dalea versicolor that enhance antibiotic activity against model pathogenic bacteria. J. Nat. Prod.. 2004;67:481-484.
[Google Scholar]

[6] Buehrdel G., Petrlikova E., Herzigova P., Beckert R., Goerls H., . Synthesis of new lipophilic sulfones and their use in cyclization reactions. Phosphorus Sulfur Silicon. 2009;184:1161-1174.
[Google Scholar]

[7] Caron G., Gaillard P., Carrupt P.A., Testa B., . Lipophilicity behavior of model and medicinal compounds containing a suilfide, sulfoxide, or sulfone moiety. Helv. Chim. Acta. 1997;80:449-462.
[Google Scholar]

[8] Carreno M.C., . Applications of sulfoxides to asymmetric synthesis of biologically active compounds. Chem. Rev.. 1995;95:1717-1760.
[Google Scholar]

[9] Ceylan M., Gurdere M.B., Karaman I., Gezegen H., . The synthesis and screening of the antimicrobial activity of some novel 3-(furan-2-yl)-1-(aryl)-3-(phenylthio) propan-1-one derivatives. Med. Chem. Res.. 2011;20:109-115.
[Google Scholar]

[10] Chinchilla R., Najera C., . Synthetic applications of sulfones as cationic reagents. Recent Res. Dev. Org. Chem.. 1997;1:437-467.
[Google Scholar]

[11] Choudary B.M., Bharathi B., Reddy C.V., Kantam M.L., . Tungstate-exchanged Mg-Al-LDH catalyst: an eco-compatible route for the oxidation of sulfides in aqueous medium. J. Chem. Soc. Perkin Trans.. 2002;1:2069-2074.
[Google Scholar]

[12] Fourie E., Erasmus E., Swarts J.C., Jakob A., Lang H., Joone G.K., Rensburg C.E.J.V., . Cytotoxicity of ferrocenyl–ethynyl phosphine metal complexes of gold and platinum. Anticancer Res.. 2011;31:825-830.
[Google Scholar]

[13] Frenanez I., Khiar N., . Recent developments in the synthesis and utilization of chiral sulfoxides. Chem. Rev.. 2003;103:3651-3760.
[Google Scholar]

[14] Ilic D., Damljanovic I., Stevanovic D., Vukicevic M., Blagojevic P., Radulovic N., Vukicevic R.D., . Sulfur-containing ferrocenyl alcohols and oximes: new promising antistaphylococcal agents. Chem. Biodivers.. 2012;9:2236-2253.
[Google Scholar]

[15] Jin C., Liang Y.J., He H., Fu L., . Synthesis and antitumor activity of novel chalcone derivatives. Biomed. Pharmacother.. 2013;67:215-217.
[Google Scholar]

[16] Jorgensen J., Lee J.C., . Microdilution technique for antimicrobial susceptibility testing of Haemophilus influenza. Antimicrob. Agents Chemother.. 1975;8:610-611.
[Google Scholar]

[17] Karaman I., Gezegen H., Ceylan M., Dilmac M., . Synthesis and screening antimicrobial activities of novel 1,3-diaryl-3-(phenylthio)propan-1-one derivatives. Phosphorus, Sulfur, Silicon. 2012;187:580-586.
[Google Scholar]

[18] Kirihara M.M., Yamamoto J., Noguchi T., Hirai Y., . Selective synthesis of sulfoxides and sulfones by tantalum(V) catalyzed oxidation of sulfides with 30% hydrogen peroxide. Tetrahedron Lett.. 2009;50:1180-1183.
[Google Scholar]

[19] Konduru N.K., Ahmed N., . Regioselective opening of chalcone epoxides with nitrogen heterocycles using indium(iii) chloride as an efficient catalyst. Synth. Commun.. 2013;43:2008-2018.
[Google Scholar]

[20] Konduru N.K., Day S., Ansari M.S., Owais M., Ahmed N., . Synthesis and antibacterial and antifungal evaluation of some chalcone based sulfones and bisulfones. Eur. J. Med. Chem.. 2013;59:23-34.
[Google Scholar]

[21] Kumar A., Tripathi V.D., Kumar P., Gupta L.P., Akanksha, Trivedi R., Bid H., Nayak V.L., Siddiqui J.A., Chakravarti B., Saxena R., Dwivedi A., Siddiquee M.I., Siddiqui U., Konwar R., Chattopadhyay N., . Design and synthesis of 1,3-biarylsulfanyl derivatives as new anti-breast cancer agents. Bioorg. Med. Chem.. 2011;19:5409-5419.
[Google Scholar]

[22] Li R., Kenyon G.L., Cohen F.E., Chen X., Gong B., Dominguez J.N., Davidson E., Kurzban G., Miller R.E., Nuzum E.O., Rosenthal P.J., McKerrow J.H., . In vitro antimalarial activity of chalcones and their derivatives. J. Med. Chem.. 1995;38:5031-5037.
[Google Scholar]

[23] Lin H.C., Lee S.S., . Dibenzocycloheptanoids from the leaves of Cinnamomum subavenium. J. Nat. Prod.. 2012;75:1735-1743.
[Google Scholar]

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Entry	Reaction time (h)	Yields (%)	Reaction time (h)	Yields (%)
1	1.5	90	3	90
2	1.5	92	4	95
3	2	90	3.5	91
4	2	93	3	92
5	2.5	90	2.5	94
6	3	95	3	95
7	3	91	3.5	93
8	2	92	3	91

Entry	Reaction time (min)	Yields (%)	Reaction time (min)	Yields (%)
9	20	95	20	95
10	20	96	20	96
11	20	94	20	91
12	20	95	20	92

Entry	Rxn.time (hr)	Yields (%)
14	3	96
15	3	95
16	3.5	96
17	3	98

Entry	Reaction time (hr)	Yields (%)	Reaction time (hr)	Yields (%)
18	1.5	92	4	92
19	2	91	4	91
20	2.5	93	4	94
21	1	89	4	92
22	1.5	94	4	94
23	2	96	4	94
24	2	96	4.5	95
25	2	95	4	93

Design, synthesis and antimicrobial activities of novel ferrocenyl and organic chalcone based sulfones and bis-sulfones

Abstract

Keywords

Ferrocenyl & organic chalcone sulfides

Sulfones

Bis-sulfones

Thia-Michael addition reaction

m-CPBA

Bactericidal & fungicidal activities

1 Introduction

2 Materials and methods

2.1 General

2.2 General procedure for synthesis of compounds (1–8c)

2.2.1 1-(2-Hydroxyphenyl)-3-(4-methylphenyl)-3-(phenylsufonyl)propan-1-one (1c)

2.2.2 1-(2-Hydroxyphenyl)-3-(4-chlorophenyl)-3-(phenylsufonyl)propan-1-one (2c)

2.2.3 1-(2-Hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)-3-(phenylsufonyl)propan-1-one (3c)

2.2.4 1-(2-Hydroxyphenyl)-3-(3-nitrophenyl)-3-(phenylsufonyl)propan-1-one (4c)

2.2.5 1-(2-Aminophenyl)-3-(4-methylphenyl)-3-(phenylsufonyl)propan-1-one (5c)

2.2.6 1-(2-Aminophenyl)-3-(4-chlorophenyl)-3-(phenylsufonyl)propan-1-one (6c)

2.2.7 1-(2-Aminophenyl)-3-phenyl-3-(phenylsulfonyl)propan-1-one (7c)

2.2.8 1-(2-Aminophenyl)-3-(3-nitrophenyl)-3-(phenylsufonyl)propan-1-one (8c)

2.3 General procedure for synthesis of compounds (9–12c)

2.3.1 1-[4-(methylsulfonyl)phenyl]-3(4-chlorophenyl)-3-(phenylsulfonyl)propan-1-one (9c)

2.3.2 1-[4-(methylsulfonyl)phenyl]-3(3-nitrophenyl)-3-(phenylsulfonyl)propan-1-one (10c)

2.3.3 1-[4-(methylsulfonyl)phenyl]-3(4-methylphenyl)-3-(phenylsulfonyl)propan-1-one (11c)

2.3.4 1-(4-(methylsulfonyl)phenyl)-3-phenyl-3-(phenylsulfonyl)propan-1-one (12c)

2.4 General procedure for synthesis of chalcone based sulfones (13–16c)

2.4.1 (E)-3-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (13c)

2.4.2 (E)-3-(3-nitrophenyl)-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (14c)

2.4.3 (E)-3-(4-methylphenyl)-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (15c)

2.4.4 (E)-3-phenyl-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (16c)

2.5 General procedure for synthesis of compounds (17c–24c)

2.5.1 1-(4-Chlorophenyl)-3-ferrocenyl-3-phenylsulfonylpropan-1-one (17c)

2.5.2 1-(4-Methylphenyl)-3-ferrocenyl-3-phenylsulfonylpropan-1-one (18c)

2.5.3 1-(4-Methoxylphenyl)-3-ferrocenyl-3-phenylsulfonylpropan-1-one (19c)

2.5.4 1-(3,4,5-Trimethoxylphenyl)-3-ferrocenyl-3-phenylsulfonylpropan-1-one (20c)

2.5.5 1-(3,4-Dimethylphenyl)-3-ferrocenyl-3-phenylsulfonylpropan-1-one (21c)

2.5.6 1-Phenyl-3-ferrocenyl-3-(phenylsulfonyl)propan-1-one (22c)

2.5.7 1-Ferrocenyl-3-phenyl-3-(phenylsulfonyl)propan-1-one (23c)

2.5.8 1-Ferrocenyl-3-(3,4dimethylphenyl)-3-(phenylsulfonyl)propan-1-one (24c)

3 Results and discussion

3.1 Chemistry

3.2 Antimicrobial activity

3.2.1 Microdilution assay

3.2.2 In-vitro antimicrobial activity of novel synthesized compounds

3.2.3 Antibacterial activity

3.2.4 Antifungal activity

4 Conclusion

Acknowledgments

References

Appendix A

Supplementary material

Appendix A

Supplementary material

Supplementary data 1

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