Synthesis, antimicrobial and cytotoxic evaluation of 4-(1-aryl-5-halo-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides

Mahesh Kumar; Balasubramanian Narasimhan; Kalavathy Ramasamy; Vasudevan Mani; Rakesh Kumar Mishra; Abu Bakar Abdul Majeed

doi:10.1016/j.arabjc.2013.11.009

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Original article

10 (

2_suppl

); S2845-S2852

doi:

10.1016/j.arabjc.2013.11.009

Synthesis, antimicrobial and cytotoxic evaluation of 4-(1-aryl-5-halo-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides

Mahesh Kumar^{^a}, Balasubramanian Narasimhan^{^a,⁎}, Kalavathy Ramasamy^{^b}, Vasudevan Mani^{^c}, Rakesh Kumar Mishra^{^c}, Abu Bakar Abdul Majeed^{^c}

a Faculty of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, India

b Collaborative Drug Discovery Research Group, Faculty of Pharmacy, Campus Puncak Alam, Universiti Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor, Malaysia

c Brain Research Laboratory, Faculty of Pharmacy, Campus Puncak Alam, Universiti Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor, Malaysia

⁎Corresponding author. Tel.: +91 1262 272535; fax: +91 1262 274133. naru2000us@yahoo.com (Balasubramanian Narasimhan)

Received: 2012-12-24, Accepted: 2013-11-16, Published: 2013-05-01

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

In the present study, a series of 4-(1-aryl-5-chloro-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides (1–20) was synthesized and screened for their in vitro antimicrobial activity against Gram positive, Gram negative bacterial and fungal strains indicating that compound 19 (N-(4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl)-4-isopropoxybenzamide) was found to be the most active antimicrobial agent. The anticancer activity of synthesized compounds against mouse leukemic monocyte macrophage cell line (RAW 264.7) and colon cancer (HCT116) cell lines indicated that compound 16 (4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzene sulfonamide) was found to be the most potent cytotoxic agent against HCT116 and compounds 17 (4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(6-methoxypyridazin-3-yl)benzene sulfonamide) and 19 (N-(4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl)-4-isopropoxybenzamide) were found to be the most potent cytotoxic agents against RAW264.7 cancer cell lines.

Keywords

5-Haloisatin

Synthesis

Antimicrobial

Cytotoxicity

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1 Introduction

Infectious diseases are the main cause of mortality in the world and the rapid increase of antimicrobial resistance among pathogenic strains (bacterial and fungal) is becoming a serious public health problem because microbes replicate very rapidly and get mutated which help the microbes to survive in the presence of an antimicrobial drug, these will quickly become predominant throughout the microbial population. These concerns have led to major research efforts to discover new antibacterial agents that could be used to combat bacterial infections (Amin et al., 2010).

The development of new anticancer agents is one of the fundamental goals in medicinal chemistry. Cytotoxicity and genotoxicity of anticancer drugs to the normal cells are major problems in cancer therapy and engender the risk of inducing secondary malignancy. Therapeutic dose of almost all anticancer drugs is often toxic to the normal tissues and leads to many side effects, which in turn, limits its treatment efficacy. In recent years, there has been a concerned search for the discovery and development of novel selective anticancer agents, devoid of many of the unpleasant side effects of conventional anticancer agents (Gudipati et al., 2011).

The isatin (1H-indole-2,3-dione) is found as an endogenous molecule in human and other mammals and its analogs display diverse types of biological activities including antimicrobial (Kumar et al., 2012), anticonvulsant (Prakash et al., 2010), anti-inflammatory (Suleyman et al., 2003), anticancer and anti-HIV (Sriram et al., 2005) activities.

The literature rationale reveals that in particular, halogenated isatin derivatives have been reported to exhibit enhanced anticancer activity compared to the parent molecule. 5-Bromo-3-o-nitrophenyl isatin hydrazone and a series of 5-bromo-(2-oxo-3-indolinyl) thiazolidine-2,4-diones substituted by various Mannich bases were found to exhibit anticancer activity against Walker carcinoma-256 and P388 lymphocytic leukemia in mice, respectively. Moreover, N-benzylation of 5,7-dibromoisatin further increased the cytotoxicity against U937 (human monocyte-like histiocytic lymphoma) cells and a range of human cancer cell lines including a metastatic breast adenocarcinoma cell line (MDA-MB-231). In the recently approved drugs by FDA, a 5-fluoro-3-substituted-2-oxoindole, SU11248, is provided for the treatment of gastrointestinal stromal tumors and advanced renal-cell carcinoma (Singh et al., 2012).

Prompted by the above facts and in continuation of our efforts in developing novel antimicrobial and cytotoxic agents (Narang et al., 2012; Judge et al., 2012) we hereby report the synthesis, antimicrobial and cytotoxic evaluation of 4-(1-aryl-5-halo-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzenesulfonamides.

2 Results and discussion

2.1

2.1 Chemistry

The synthesis of 4-(1-aryl-5-halo-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzenesulfonamides (1–20) was accomplished by Scheme 1. The physicochemical characteristics of the synthesized compounds are presented in Table 1.

Scheme for the synthesis of 4-(1-aryl-5-halo-2-oxo-1, 2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides (1–20).

Table 1 Physicochemical characteristics and anticancer activity of the synthesized isatin derivatives.

Comp.	M. Pt. (°C)	M. formula	M. Wt.	R_f value^⁎	% Yield	IC₅₀ in μM
						HCT116	RAW 264.7
1	220–222	C₂₅H₁₆Cl₂N₄O₅S	555.39	0.62	76	149.44	14.40
2	128–130	C₂₃H₁₅Cl₂N₃O₅S	516.35	0.78	72	153.00	1.94
3	216–218	C₂₅H₁₅Cl₂N₅O₄S	552.39	0.66	60	152.07	14.48
4	248–250	C₂₆H₁₇Cl₂N₅O₄S	566.42	0.84	74	139.47	17.65
5	216–218	C₂₄H₁₄Cl₂N₄O₄S₂	557.43	0.74	68	52.02	16.15
6	166–168	C₂₇H₁₉Cl₂N₅O₆S	612.44	0.72	82	99.60	27.76
7	204–206	C₂₆H₁₇Cl₂N₅O₅S	582.41	0.68	85	96.15	15.45
8	196–198	C₂₆H₁₆Cl₂N₄O₅S	551.40	0.74	70	92.49	27.20
9	144–146	C₃₁H₂₃Cl₂N₃O₆S	636.50	0.76	78	98.98	80.13
10	152–154	C₂₂H₁₅Cl₂N₅O₄S	516.36	0.88	80	69.72	40.67
11	112–114	C₂₅H₁₆BrClN₄O₅S	599.84	0.68	78	140.04	50.01
12	177–179	C₂₃H₁₅BrClN₃O₅S	560.80	0.68	76	96.29	41.01
13	106–108	C₂₅H₁₅BrClN₅O₄S	596.84	0.76	82	103.88	16.75
14	188–190	C₂₆H₁₇BrClN₅O₄S	610.87	0.70	68	83.49	18.01
15	133–135	C₂₄H₁₄BrClN₄O₄S₂	601.98	0.74	78	56.49	11.63
16	173–175	C₂₇H₁₉BrClN₅O₆S	656.89	0.82	76	13.70	39.58
17	241–243	C₂₆H₁₇BrClN₅O₅S	626.87	0.68	75	127.62	3.19
18	217–217	C₂₆H₁₆BrClN₄O₄S	595.85	0.76	80	95.66	35.24
19	211–213	C₃₁H₂₃BrClN₃O₆S	680.95	0.74	76	45.52	1.47
20	139–141	C₂₂H₁₅BrClN₅O₄S	560.81	0.82	80	96.29	73.11
		Carboplatin				>100.00	>100.00
		5-Flourouracil				4.60	0.60

⁎ TLC mobile phase = Chloroform:Methanol (7:3).

The synthesized compounds were characterized by IR and ¹H NMR spectroscopy and the results are in accordance with the assigned molecular structures. IR stretching band ranging from 1693–1672 cm⁻¹ (C⚌O str., Ar—C⚌O) confirmed the acylation of isatin. IR stretching band at 1656–1582 cm⁻¹ (C⚌N str.) confirmed the formation of a Schiff base. In the ¹H NMR spectra the signals of the respective protons of the synthesized compounds were confirmed based on their chemical shifts and multiplicities. These spectra showed singlets at 3.33–4.76 ppm, which correspond to the SO₂NH protons and multipletes at 7.07–8.52 ppm showed aromatic protons.

2.2

2.2 Antimicrobial activity

The antimicrobial activity of the synthesized compounds was determined by the tube dilution method (Cappucino and Sherman, 1999) and the results are given in Table 2 which indicated that compound 19 demonstrated potent antibacterial activity against Staphylococcus aureus (pMIC_sa = 9.18 μM). In case of Bacillus subtilis compounds 9 and 16 emerged as most effective antibacterial agents with pMIC_bs values of 9.82 and 9.51 μM respectively. Against Gram-negative bacterium Escherichia coli, compounds 19 and 16 (pMIC_ec values 9.18 and 9.51 μM respectively) emerged as most active candidates among the synthesized compounds. In case of antifungal activity against Candida albicans and Aspergillus niger, compound 19 (pMIC_ca = 4.59 and pMIC_an values 9.18 μM) emerged as the most active candidate among the synthesized compounds. As antifungal activity of compound 19 against C. albicans (pMIC_ca = 4.59) was greater than standard drug fluconazole (pMIC_ca = 5.09), it may be taken as a lead molecule for the development of novel antifungal agents.

Table 2 Antimicrobial activity of synthesized isatin derivatives.

Comp.	Minimum inhibitory concentration (MIC, μM)
	MIC_sa	MIC_bs	MIC_ec	MIC_ca	MIC_an
1	22.51	22.51	11.25	5.63	11.25
2	12.10	12.10	12.10	6.05	12.10
3	11.31	11.31	11.31	5.66	11.31
4	11.03	11.03	11.03	5.52	11.03
5	22.42	22.42	11.21	5.61	11.21
6	20.41	20.41	10.21	5.10	10.21
7	21.46	10.73	10.73	5.37	10.73
8	22.67	11.33	11.33	5.67	11.33
9	9.82	9.82	9.82	4.91	9.82
10	24.21	12.10	12.10	6.05	12.10
11	20.84	20.84	10.42	20.84	10.42
12	11.14	11.14	11.14	22.29	11.14
13	10.47	10.47	10.47	20.94	10.47
14	10.23	10.23	10.23	5.12	10.23
15	10.38	10.38	10.38	5.19	10.38
16	9.51	9.51	9.51	4.76	9.51
17	9.97	9.97	19.94	4.99	9.97
18	10.49	20.98	10.49	5.24	10.49
19	9.18	18.36	9.18	4.59	9.18
20	11.14	22.29	11.14	11.14	11.14
Std.	4.87^a	4.87^a	4.87^a	5.09^b	5.09^b

a Norfloxacin.

b Fluconazole.

In general, according to the results of MBC/MFC studies (Table 3) the synthesized compounds were bacteriostatic and fungistatic in action as their MFC and MBC values were 3-fold higher than their MIC values (Emami et al., 2004).

Table 3 Minimum bactericidal/fungicidal concentration of synthesized isatin derivatives.

Comp.	Minimum bactericidal/fungicidal concentration (MFC/MBC, μ mol/ml)
	S. aureus	B. subtilis	E. Coli	C. albicans	A. niger
1	>0.09	>0.09	>0.09	>0.09	>0.09
2	>0.10	>0.10	>0.10	>0.10	>0.10
3	>0.09	>0.09	>0.09	>0.09	>0.09
4	>0.09	>0.09	>0.09	>0.09	>0.09
5	>0.09	>0.09	>0.09	>0.09	>0.09
6	>0.08	>0.08	>0.08	>0.08	>0.08
7	>0.09	>0.09	>0.09	>0.09	>0.09
8	>0.09	>0.09	>0.09	>0.09	>0.09
9	>0.08	>0.08	>0.08	>0.08	>0.08
10	>0.10	>0.10	>0.10	>0.10	>0.10
11	>0.08	>0.08	>0.08	>0.08	>0.08
12	>0.09	>0.09	>0.09	>0.09	>0.09
13	>0.08	>0.08	>0.08	>0.08	>0.08
14	>0.08	>0.08	>0.08	>0.08	>0.08
15	>0.08	>0.08	>0.08	>0.08	>0.08
16	>0.08	>0.08	>0.08	>0.08	>0.08
17	>0.08	>0.08	>0.08	>0.08	>0.08
18	>0.08	>0.08	>0.08	>0.08	>0.08
19	>0.07	>0.07	>0.07	>0.07	>0.07
20	>0.09	>0.09	>0.09	>0.09	>0.09
Std.	0.0049^a	0.0049^a	0.0049^a	0.0051^b	0.0051^b

a Norfloxacin.

b Fluconazole.

2.3

2.3 Cytotoxic activity

The cytotoxic activity of the synthesized isatin derivatives was determined against mouse leukemic monocyte macrophage (RAW264.7) and colon cancer (HCT116) cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay (Mosmann, 1983) and IC₅₀ values (concentration required to achieve 50 % inhibition of cancer cells) of the standard and test compounds are presented in Table 1. In general, most of the synthesized compounds were more active than standard drug carboplatin (IC₅₀ > 100 μM) against both HCT116 and RAW264.7 cancer cell lines and none of the synthesized compounds were found to be more active than the standard drug 5-FU (IC₅₀ = 4.6 and 0.60 μM against HCT116 and RAW264.7, respectively).

Results of cytotoxic studies indicated that compound 16 (IC₅₀ = 13.7 μM) was found to be the most potent cytotoxic agent against HCT116 cancer cell line and compounds 17 and 19 (3.19 and 1.47 μM respectively) were found to be most potent cytotoxic agents against RAW264.7 cancer cell line.

2.3.1

2.3.1 Structure–activity relationship

Results of antimicrobial and cytotoxic screening indicated that 5-bromo isatin derivatives were found to be more active antimicrobial and cytotoxic agents than 4-chloro isatin derivatives.
Results of antimicrobial study indicated that the presence of phenyl ring attached to benzenesulfonamide moiety (19) increased the antimicrobial potential of synthesized compounds against all the tested microbial strains, except in case of B. subtilis, against which pyrimidine ring attached to benzenesulfonamide moiety (16) was found to enhance the antibacterial potential. Further, the presence of electron releasing groups on pyrimidine/phenyl nucleus improved the antimicrobial potential of the synthesized compounds. The role of electron releasing groups in enhancing the antimicrobial activity of isatin derivatives is supported by study of Kamal et al. (2010).
Results of cytotoxic screening indicated that phenyl nucleus attached to benzenesulfonamide moiety increased the cytotoxic potential of the synthesized compounds against RAW264.7 cancer cell line, whereas its replacement with pyrimidine nucleus improved the cytotoxic potential of the synthesized isatin derivatives against HCT116 cancer cell line. Further, the presence of electron releasing groups on pyrimidine/phenyl nucleus improved the antimicrobial potential of the synthesized compounds. The role of electron releasing groups in improving cytotoxic activity is supported by the studies of Vine et al. (2007).
The presence of electron withdrawing groups, specially 4-Cl at benzoyl portion improved antimicrobial as well as cytotoxic potential of the synthesized isatin derivatives.
From the above mentioned antimicrobial and cytotoxic activity results, it can be concluded that different structural requirements are necessary for a compound to become active against different microbial and cancer targets. This is in accordance with the findings of Sortino et al. (2007).

The above findings are summarized in Fig. 1.

Structure–activity relationship for antimicrobial and anticancer activity of synthesized isatin derivatives.

3 Experimental

3.1

3.1 Chemistry

Starting materials were obtained from commercial sources and were used without further purification. Solvents were dried by standard procedures. Reaction progress was observed by thin layer chromatography. Melting points were determined in open capillary tubes on a Sonar melting point apparatus and are uncorrected. ¹H nuclear magnetic resonance (¹H NMR) spectra were determined by a Bruker 500 MHz NMR spectrometer in appropriate deuterated solvents and are expressed in parts per million (δ, ppm) downfield from tetramethylsilane (internal standard). NMR data are given as multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet) and number of protons. IR spectra were recorded on a Varian Resolutions Pro spectrophotometer in a KBr disk.

3.2

3.2 General procedure for the synthesis of 4-(1-Aryl-5-halo-2-oxo-1, 2-dihydro-indol-3-ylideneamino)-N-Substituted benzenesulfonamides (1–20)

Thionyl chloride 32.8 g (0.3 mol) was added to different aromatic acids (0.25 mol) in a round bottom flask. After addition, the mixture was refluxed for 1 h and 30 min. The excess of thionyl chloride was removed by distillation. To the solution of acyl chloride (1 mol, synthesized in previous step), was added 0.1 mol of haloisatin and the mixture was refluxed for 1 h. Then the reaction mixture was cooled and the resultant precipitate (N-acyl haloisatin) was collected, washed with hexane and recrystallized from ethyl acetate. A solution of 0.05 mol of different sulfonamides in warm ethanol was added to the solution of corresponding N-acyl haloisatins (0.05 mol) in the presence of small amount of glacial acetic acid. The mixture was refluxed for 4–5 h. Then the reaction mixture was allowed to cool at room temperature and the precipitate obtained was filtered, dried and recrystallized from ethanol.

3.2.1

3.2.1 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(5-methyl Isoxazol-3-yl)benzenesulfonamide (1)

IR (KBr pellets) cm⁻¹: 1515 (NH in plane bending, sec. amine), 1691 (C⚌O str., Ar—C⚌O), 1656 (C⚌N str.), 1176 (O⚌S⚌O str.), 1290 (–C–O–N str., isoxazole), 786 (C—Cl str., Ar—Cl), 838 (CH out of plane bending, isoxazole), 673 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.28–8.03 (m, 12H, ArH), 4.27 (s, 1H, SO₂NH), 2.29 (s, 3H, ArCH₃).

3.2.2

3.2.2 N-(4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino) phenylsulfonyl)acetamide (2)

IR (KBr pellets) cm⁻¹: 1515 (NH in plane bending, sec. amine), 1691 (C⚌O str., Ar—C⚌O), 1655 (C⚌N str.), 1177 (O⚌S⚌O str.), 1434 (CH₃ bending vibration, COCH₃), 786 (C—Cl str., Ar—Cl), 674 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.51–8.51 (m, 12H, ArH), 4.27 (s, 1H, SO₂NH), 2.50 (s, 3H, COCH₃).

3.2.3

3.2.3 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(pyrimidin-2-yl) benzenesulfonamide (3)

IR (KBr pellets) cm⁻¹: 1495 (NH in plane bending, sec. amine), 1682 (C⚌O str., Ar—C⚌O), 1648 (C⚌N str.), 1157 (O⚌S⚌O str.), 1582 (C⚌N str., pyrimidine), 786 (C—Cl str., Ar—Cl), 731 (CH out of plane bending, 4-sustituted pyrimidine), 674 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.07–8.52 (m, 15H, ArH), 4.27 (s, 1H, SO₂NH).

3.2.4

3.2.4 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(4-methyl pyrimidin-2-yl)benzenesulfonamide (4)

IR (KBr pellets) cm⁻¹: 1515 (NH in plane bending, sec. amine), 1691 (C⚌O str., Ar—C⚌O), 1656 (C⚌N str), 1177 (O⚌S⚌O str), 1583 (C⚌N str., pyridine), 786 (C—Cl str., Ar—Cl), 880 (CH out of plane bending, 4-sustituted pyrimidine), 674 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.50–7.73 (m, 14H, ArH), 4.27 (s, 1H, SO₂NH), 2.51 (s, 3H, ArCH₃).

3.2.5

3.2.5 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(thiazol-2-yl) benzenesulfonamide (5)

IR (KBr pellets) cm⁻¹: 1511 (NH in plane bending, sec. amine), 1693 (C⚌O str., Ar—C⚌O), 1650 (C⚌N str.), 1181 (O⚌S⚌O str.), 1578 (C⚌N str., thiazole), 782 (C—Cl str., Ar—Cl), 733 (C–S–C str., thiazole), 893 (CH out of plane bending, thiazole), 629 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 6.75–7.87 (m, 14, ArH), 4.27 (s, 1H, SO₂NH).

3.2.6

3.2.6 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (6)

IR (KBr pellets) cm⁻¹: 1516 (NH in plane bending, sec. amine), 1692 (C⚌O str., Ar—C⚌O), 1656 (C⚌N str.), 1178 (O⚌S⚌O str.), 1290 (C–OC str.), 1583 (C⚌N str., pyrimidine), 1609 (C⚌C str., pyrimidine), 786 (C—Cl str., Ar—Cl), 669 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.51–7.72 (m, 13H, ArH), 4.27 (s, 1H, SO₂NH), 2.31 (s, 6H, ArCH₃).

3.2.7

3.2.7 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(6-methoxy pyridazin-3-yl)benzenesulfonamide (7)

IR (KBr pellets) cm⁻¹: 1516 (NH in plane bending, sec. amine), 1691 (C⚌O str., Ar—C⚌O), 1658 (C⚌N str.), 1180 (O⚌S⚌O str.), 1292 (C–O–C str.), 1471 (N–N str., pyridazine), 788 (C—Cl str., Ar—Cl), 672 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.51–7.73 (m, 14H, ArH), 4.29 (s, 1H, SO₂NH), 3.35 (s, 3H, ArOCH₃).

3.2.8

3.2.8 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(pyridin-2-yl)ibenzenesulfonamide (8)

IR (KBr pellets) cm⁻¹: 1516 (NH in plane bending, sec. amine), 1691 (C⚌O str., Ar—C⚌O), 1658 (C⚌N str.), 1181 (O⚌S⚌O str.), 1583 (C⚌N str., pyridine), 1607 (C⚌C str., pyridine), 785 (C—Cl str., Ar—Cl), 673 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.37–7.73 (m, 16H, ArH), 4.27 (s, 1H, SO₂NH).

3.2.9

3.2.9 N-(4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl)-4-isopropoxybenzamide (9)

IR (KBr pellets) cm⁻¹: 1507 (NH in plane bending, sec. amine), 1691 (C⚌O str., Ar—C⚌O), 1653 (C⚌N str.), 1182 (O⚌S⚌O str.), 1165 (CH(CH₃)₂ bending), 1260 (C–O–C str.), 783 (C—Cl str., Ar—Cl), 677 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.50–7.82 (m,16H, ArH), 4.72 (s, 1H, SO₂NH), 4.27 (s, 1H, CH), 1.28 (d, 6H, CH(CH₃)₂)

3.2.10

3.2.10 1-(4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl)guanidine (10)

IR (KBr pellets) cm⁻¹: 1513 (NH in plane bending, sec. amine), 1690 (C⚌O str., Ar—C⚌O), 1655 (C⚌N str.), 1177 (O⚌S⚌O str.), 785 (C—Cl str., Ar—Cl), 670 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.53–7.94 (m, 12H, ArH), 4.30 (s, 1H, SO₂NH), 3.31 (s, 3H, COCH₃).

3.2.11

3.2.11 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(5-methyl isoxazol-3-yl)benzenesulfonamide (11)

IR (KBr pellets) cm⁻¹: 1517 (NH in plane bending, sec. amine), 1678 (C⚌O str., Ar—C⚌O), 1620 (C⚌N str.), 1166 (O⚌S⚌O str.), 545 (C—Br str., Ar—Br), 814 (CH out of plane bending, isoxazole), 628 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.46–7.95 (m, 12H, ArH), 4.27 (s, 1H, SO₂NH), 2.28 (s, 3H, ArCH₃).

3.2.12

3.2.12 N-(4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl) acetamide (12)

IR (KBr pellets) cm⁻¹: 1491 (NH in plane bending, sec. amine), 1678 (C⚌O str., Ar—C⚌O), 1588 (C⚌N str.), 1174 (O⚌S⚌O str.), 544 (C—Br str., Ar—Br), 1421 (CH₃ bending vibration, COCH₃), 628 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.39–7.96 (m, 14H, ArH), 4.27 (s, 1H, SO₂NH), 2.37 (s, 3H, COCH₃).

3.2.13

3.2.13 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(pyrimidin-2-yl) benzenesulfonamide (13)

IR (KBr pellets) cm⁻¹: 1490 (NH in plane bending, sec. amine), 1677 (C⚌O str., Ar—C⚌O), 1587 (C⚌N str.), 1158 (O⚌S⚌O str.), 544 (C—Br str., Ar—Br), 1610 (C⚌N str.,pyrimidine), 758 (CH out of plane bending, 4-sustituted pyrimidine), 630 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.56–8.51 (m, 14H, ArH), 3.35 (s, 1H, SO₂NH).

3.2.14

3.2.14 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(4-methyl pyrimidin-2-yl)benzenesulfonamide (14)

IR (KBr pellets) cm⁻¹: 1492 (NH in plane bending, sec. amine), 1678 (C⚌O str., Ar—C⚌O), 1589 (C⚌N str.), 1173 (O⚌S⚌O str.), 544 (C—Br str., Ar—Br), 1608 (C⚌N str., pyrimidine), 759 (CH out of plane bending, 4-sustituted pyrimidine), 628 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.93–8.33 (m, 13H, ArH), 3.33 (s, 1H, SO₂NH), 2.33 (s, 3H, ArCH₃).

3.2.15

3.2.15 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(thiazol-2-yl)ibenzenesulfonamide (15)

IR (KBr pellets) cm⁻¹: 1490 (NH in plane bending, sec. amine), 1672 (C⚌O str., Ar—C⚌O), 1589 (C⚌N str.), 1149 (O⚌S⚌O str.), 538 (C—Br str., Ar—Br), 1570 (C⚌N str., thiazole), 742 (C–S–C str., thiazole), 894–636 (CH out of plane bending, thiazole), 667 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.56–8.00 (m, 13, ArH), 3.32 (s, 1H, SO₂NH).

3.2.16

3.2.16 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylipyrimidin-2-yl)benzenesulfonamide (16)

IR (KBr pellets) cm⁻¹: 1493 (NH in plane bending, sec. amine), 1676 (C⚌O str., Ar—C⚌O), 1590 (C⚌N str.), 1155 (O⚌S⚌O str.), 544 (C—Br str., Ar—Br), 1281 (C–O–C str.), 614 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.58–7.94 (m, 12H, ArH), 3.28 (s, 1H, SO₂NH), 2.57 (s, 6H, ArCH₃).

3.2.17

3.2.17 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(6-methoxyipyridazin-3-yl)benzenesulfonamide (17)

IR (KBr pellets) cm⁻¹: 1524 (NH in plane bending, sec. amine), 1677 (C⚌O str., Ar—C⚌O), 1588 (C⚌N str.), 1181 (O⚌S⚌O str.), 1278 (C–O–C str.), 1470 (N–N str., pyridazine), 546 (C—Br str., Ar—Br), 616 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.33–7.96 (m, 13H, ArH), 4.08 (s, 1H, SO₂NH), 3.34 (s, 3H, ArOCH₃).

3.2.18

3.2.18 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(pyridin-2-yl)ibenzenesulfonamide (18)

IR (KBr pellets) cm⁻¹: 1493 (NH in plane bending, sec. amine), 1679 (C⚌O str., Ar—C⚌O), 1631 (C⚌N str.), 1174 (O⚌S⚌O str.), 547 (C—Br str., Ar—Br), 1592 (C⚌N str., pyridine), 614 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.16–8.03 (m, 15H, ArH), 3.33 (s, 1H, SO₂NH).

3.2.19

3.2.19 N-(4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl)-4-isopropoxybenzamide (19)

IR (KBr pellets) cm⁻¹: 1522 (NH in plane bending, sec. amine), 1679 (C⚌O str., Ar—C⚌O), 1661 (C⚌N str.), 1178 (O⚌S⚌O str.), 1133(CH(CH₃)₂ bending), 1284 (C–O–C str.), 542 (C—Br str., Ar—Br), 618 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.56–8.01 (m, 15H, ArH), 3.32 (s, 1H, SO₂NH), 2.64 (s, 1H, CH), 1.25 (d, 6H, CH(CH₃)₂).

3.2.20

3.2.20 1-(4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl)guanidine (20)

IR (KBr pellets) cm⁻¹: 1498 (NH in plane bending, sec. amine), 1678 (C⚌O str., Ar—C⚌O), 1627 (C⚌N str.), 1164 (O⚌S⚌O str.), 549 (C—Br str., Ar—Br), 643 (CH out of plane bending, indole); ¹H NMR (DMSO) δ: 7.57–7.96 (m, 11H, ArH), 4.73 (s, 1H, SO₂NH), 3.30 (s, 3H, COCH₃).

3.3

3.3 Evaluation of antimicrobial activity

3.3.1

3.3.1 Determination of MIC

The antimicrobial activity was performed against Gram-positive bacteria: S. aureus, B. subtilis, the Gram-negative bacterium E. coli and fungal strains: C. albicans and A. niger using the tube dilution method (Cappucino and Sherman, 1999). Dilutions of test and standard compounds were prepared in double strength nutrient broth – I.P. (bacteria) or Sabouraud dextrose broth – I.P. (fungi) (Pharmacopoeia of India, 2007). The samples were incubated at 37 °C for 24 h (bacteria), at 25 °C for 7 d (A. niger) and at 37 °C for 48 h (C. albicans) and the results were recorded in terms of minimum inhibitory concentration (MIC).

3.3.2

3.3.2 Determination of MBC/MFC

The minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC) were determined by sub culturing 100 μL of culture from each tube (which remained clear in the MIC determination) on fresh medium. MBC and MFC values represent the lowest concentration of compound that produces a 99.9% end point reduction (Rodriguez-Arguelles et al., 2005).

3.3.3

3.3.3 Cytotoxic studies

The cytotoxic activity of the synthesized 4-(1-aryl-5-halo-2-oxo-1, 2-dihydro-indol-3-ylideneamino)-N-substituted benzenesulfonamides was determined against mouse leukemic monocyte macrophage (RAW264.7) and colon cancer (HCT116) cell lines. Cancer cell lines were purchased from the American Type Culture Collection (ATCC), Manassas, VA, USA. All cell lines were cultured in RPMI 1640 (Sigma) supplemented with 10% heat inactivated fetal bovine serum (FBS) (PAA Laboratories) and 1% penicillin/streptomycin (PAA Laboratories). Cultures were maintained in a humidified incubator at 37 °C in an atmosphere of 5% CO₂. Cytotoxicity of the synthesized compounds at various concentrations was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) (Sigma) assay, as described by Mosmann (Mosmann, 1983) but with minor modification, following 72 h of incubation. Assay plates were read using a spectrophotometer at 520 nm. Data generated were used to plot a dose–response curve of which the concentration of test compounds required to kill 50% of the cell population (IC₅₀) was determined. Cytotoxic activity was expressed as the mean IC₅₀ of three independent experiments.

4 Conclusion

A series of 4-(1-aryl-5-halo-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzenesulfonamide derivatives (1–20) was synthesized in appreciable yield and characterized by physicochemical as well as spectral means. The synthesized compounds were evaluated for their in vitro antimicrobial and cytotoxic activities. Results of antimicrobial study indicated that the presence of phenyl ring attached to benzene sulfonamide moiety 19 increased the antimicrobial potential of synthesized compounds against all the tested microbial strains. Further, the presence of electron releasing groups on pyrimidine/phenyl nucleus improved the antimicrobial potential of the synthesized compounds. As antifungal activity of compound 19 against C. albicans (pMIC_ca = 4.59) was greater than standard drug fluconazole (pMIC_ca = 5.09), it may be taken as a lead molecule for the development of novel antifungal agents. Cytotoxic activity results indicated that most of the synthesized compounds were more active than the standard drug carboplatin against both the cancer cell lines (HCT116 and RAW264.7) but less active than the standard drug 5-FU. Compound 16 was found to be the most potent cytotoxic agent against HCT116 and compounds 17 and 19 were found to be most potent cytotoxic agents against RAW264.7 cancer cell lines. In general the presence of elcectron withdrawing groups, especially 4-Cl at benzoyl portion improved antimicrobial as well as cytotoxic potential of the synthesized isatin derivatives.

References

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Introduction

Results and discussion

Chemistry
Antimicrobial activity
Cytotoxic activity

Experimental

Chemistry
General procedure for the synthesis of 4-(1-Aryl-5-halo-2-oxo-1, 2-dihydro-indol-3-ylideneamino)-N-Substituted benzenesulfonamides (1–20)
Evaluation of antimicrobial activity

Conclusion

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[1] Amin R., Krammer, Kader N.A., Verwanger T., Ansary A.E., . Antibacterial effect of some benzopyrone derivatives. Eur. J. Med. Chem.. 2010;45:372-378.
[Google Scholar]

[2] Cappucino J.G., Sherman N., . Microbiology-a Laboratory Manual. California: Addison Wesley; 1999. p. 263

[3] Emami S., Falahati M., Banifafemi A., Shafiee A., . Stereoselective synthesis and antifungal activity of (Z)-trans-3-azolyl-2-methylchromanone oxime ethers. Bioorg. Med. Chem.. 2004;12:5881-5889.
[Google Scholar]

[4] Gudipati R., Anreddy R.N.R., Manda S., . Synthesis, characterization and anticancer activity of certain 3-{4-(5-mercapto-1,3,4-oxadiazole-2-yl)phenylimino}indolin-2-one derivatives. Saudi Pharm. J.. 2011;19:153-158.
[Google Scholar]

[5] Judge V., Narasimhan B., Ahuja M., Sriram D., Yogeeswari P., DeClercq E., Pannecouque C., Balzarini J., . Synthesis, antimycobacterial, antiviral, antimicrobial activity and QSAR studies of isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazides. Med. Chem. Res.. 2012;21(8):1935-1952.
[Google Scholar]

[6] Kamal A., Srikanth Y.V.V., Khan M.N.A., Shaik T.B., Ashraf M., . Synthesis of 3,3-diindolyl oxyindoles efficiently catalysed by FeCl₃ and their in vitro evaluation for anticancer activity. Bioorg. Med. Chem. Lett.. 2010;20:5229-5231.
[Google Scholar]

[7] Kumar R., Kumar P., Kumar M., Narasimhan B., . Synthesis, anti-microbial evaluation, and QSAR studies of 4-amino-3-hydroxy-naphthalene-1-sulfonic acid derivatives. Med. Chem. Res.. 2012;21:4301-4310.
[Google Scholar]

[8] Mosmann T., . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods. 1983;65:55-63.
[Google Scholar]

[9] Narang R., Narasimhan B., Sharma S., Sriram D., Yogeeswari P., DeClercq E., Pannecouque C., Balzarini J., . Synthesis, antimycobacterial, antiviral, antimicrobial activity and QSAR studies of nicotinic acid benzylidene hydrazide derivatives. Med. Chem. Res.. 2012;21(8):1557-1576.
[Google Scholar]

[10] Pharmacopoeia of India, 2007. vol. I, Controller of Publications, Ministry of Health Department, Govt. Of India, New Delhi, p. 37.

[11] Prakash C.R., Raja S., Saravanan G., . Synthesis, characterization and anticonvulsant activity of novel Schiff base of isatin derivatives. Int. J. Pharm. Pharm. Sci.. 2010;4:177-181.
[Google Scholar]

[12] Rodriguez-Arguelles M.C., Lopez-Silva E.C., Sanmartin J., Pelagatti P., Zani F., . Copper complexes of imidazole-2-, pyrrole-2- and indol-3-carbaldehyde thiosemicarbazones: inhibitory activity against fungi and bacteria. J. Inorg. Biochem.. 2005;99:2231-2239.
[Google Scholar]

[13] Singh P., Sharma P., Anand A., Bedi P.M.S., Kaur T., Saxena A.K., Kumar V., . Azide-alkyne cycloaddition en route to novel 1H-1,2,3-triazole tethered isatin conjugates with in vitro cytotoxic evaluation. Eur. J. Med. Chem.. 2012;55:455-461.
[Google Scholar]

[14] Sortino M., Delgado P., Jaurez S., Quiroga J., Abonia R., Insuasey B., Rodero M.N., Garibotto F.M., Enriz R.D., Zaccino S.A., . Synthesis and antifungal activity of (Z)-5-arylidenerhodanines. Bioorg. Med. Chem. Lett.. 2007;15:484-494.
[Google Scholar]

[15] Sriram D., Bal T.R., Yogeeswari P., . Newer aminopyrimidinimino isatin analogues as non-nucleosidem HIV-1 reverse transcriptase inhibitors for HIV and other opportunistic infections of AIDS: design, synthesis and biological evaluation. Il Farmaco. 2005;60:377-384.
[Google Scholar]

[16] Suleyman H., Gul H.I., Asoglu M., . Anti-inflammatory activity of 3-benzoyl-1-methyl-4-phenyl-4-piperidinol hydrochloride. Pharmacol. Res.. 2003;47:471-475.
[Google Scholar]

[17] Vine K.L., Locke J.M., Ranson M., Pyne S.G., Bremner J.B., . In vitro cytotoxicity evaluation of some substituted isatin derivatives. Bioorg. Med. Chem.. 2007;15:931-938.
[Google Scholar]

Synthesis, antimicrobial and cytotoxic evaluation of 4-(1-aryl-5-halo-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides

Abstract

Keywords

5-Haloisatin

Synthesis

Antimicrobial

Cytotoxicity

1 Introduction

2 Results and discussion

2.1 Chemistry

2.2 Antimicrobial activity

2.3 Cytotoxic activity

2.3.1 Structure–activity relationship

3 Experimental

3.1 Chemistry

3.2 General procedure for the synthesis of 4-(1-Aryl-5-halo-2-oxo-1, 2-dihydro-indol-3-ylideneamino)-N-Substituted benzenesulfonamides (1–20)

3.2.1 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(5-methyl Isoxazol-3-yl)benzenesulfonamide (1)

3.2.2 N-(4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino) phenylsulfonyl)acetamide (2)

3.2.3 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(pyrimidin-2-yl) benzenesulfonamide (3)

3.2.4 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(4-methyl pyrimidin-2-yl)benzenesulfonamide (4)

3.2.5 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(thiazol-2-yl) benzenesulfonamide (5)

3.2.6 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (6)

3.2.7 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(6-methoxy pyridazin-3-yl)benzenesulfonamide (7)

3.2.8 4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(pyridin-2-yl)ibenzenesulfonamide (8)

3.2.9 N-(4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl)-4-isopropoxybenzamide (9)

3.2.10 1-(4-(5-Chloro-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl)guanidine (10)

3.2.11 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(5-methyl isoxazol-3-yl)benzenesulfonamide (11)

3.2.12 N-(4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl) acetamide (12)

3.2.13 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(pyrimidin-2-yl) benzenesulfonamide (13)

3.2.14 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(4-methyl pyrimidin-2-yl)benzenesulfonamide (14)

3.2.15 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(thiazol-2-yl)ibenzenesulfonamide (15)

3.2.16 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylipyrimidin-2-yl)benzenesulfonamide (16)

3.2.17 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(6-methoxyipyridazin-3-yl)benzenesulfonamide (17)

3.2.18 4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)-N-(pyridin-2-yl)ibenzenesulfonamide (18)

3.2.19 N-(4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl)-4-isopropoxybenzamide (19)

3.2.20 1-(4-(5-Bromo-1-(4-chlorobenzoyl)-2-oxoindolin-3-ylideneamino)phenylsulfonyl)guanidine (20)

3.3 Evaluation of antimicrobial activity

3.3.1 Determination of MIC

3.3.2 Determination of MBC/MFC

3.3.3 Cytotoxic studies

4 Conclusion

References

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