Oxindole Derivatives: Synthesis and Antiglycation ... - IngentaConnect

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681

Oxindole Derivatives: Synthesis and Antiglycation Activity Khalid Mohammed Khan*,a, Momin Khana,b, Nida Ambreena, Muhammad Tahaa, Fazal Rahima, Saima Rasheeda, Sumayya Saiedc, Humaira Shafic, Shahnaz Perveend, and Muhammad Iqbal Choudharya,e a

H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan b c

Department of Chemistry, University of Karachi, Karachi-75270, Pakistan

d e

Department of Chemistry, Abdul Wali Khan University, Mardan, Khyber Pukhtunkhwa, Pakistan

PCSIR Laboratories Complex Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi-75280, Pakistan

Department of Chemistry, King Saud University Riyadh, Saudi Arabia Abstract: Oxindole derivatives 3-25 have been synthesized from commercially available oxindole by refluxing with different aromatic aldehydes in good yields. Their in vitro antiglycation potential has been evaluated. They showed a varying degree of antiglycation activity with IC50 values ranging between 150.4 - 856.7 M. 3-[(3-Chlorophenyl)methylidene]1,3-dihydro-2H-indol-2-one (IC50 = 150.4 ± 2.5 M) is the most active compound among the series, better than the standard rutin with an IC50 value 294.5 ± 1.50 M. The structures of the compounds were elucidated by 1H-NMR and mass spectroscopy and elemental analysis. A limited structure-activity relationship has been developed.

Keywords: Oxindole, benzaldehydes, antiglycation, rutin, AGEPs. INTRODUCTION In the recent past a number of patents have been reported related to oxindole and their biological activities [1]. A large number of synthetic compounds with oxindoles moiety exhibit useful pharmaceutical properties, including growth hormone secretagogues [2], analgesic [3], anti-inflammatory [4], and serotonergic [5]. Most of these compounds contain a variety of substituents at the C-3 position of oxindole, among which some are 3-spirooxindoles [6]. These C-3 substituted oxindole derivatives possess P-glycoprotein-mediated multiple drug resistance inhibitors [7], antibacterial, antiprotozoa [8], anti-inflammatory [9], serotonergic [10], antitumor, and human NKI receptor inhibitors [11]. In the present study, in vitro antiglycation activity of a series of oxindole derivatives 3-25 was evaluated, in continuation of our efforts towards designing effective antiglycation agents [12,13]. Discovery of antiglycation agents is an emerging approach for the prevention of late diabetic complications. Currently, the number of effective antiglycating agents is very limited with less than satisfactory performance, therefore discovery of new antiglycating agents is still an active area of research [14,15]. The injurious effects of type-2 diabetes are mostly attributed to the formation of sugar-derived substances called ad-

vanced glycation end products (AGEPs) [16], which are important pathogenic mediators of almost all diabetic complications [17]. Reaction between protein and glucose without any enzyme forms Schiff bases which then convert into Amadori product. Extensive effort has been focused on the discovery of new inhibitors of glycation [18]. Certain molecules have been developed that can cleave AGEPs cross-links and thus open the possibility of reversing the steady process of diabetic complications [19]. It has been found that aged garlic extract (AGE) inhibits the formation of AGEPs in vitro, and prevents the formation of glycation-derived free radicals. SAllylcysteine is a very important component of aged garlic extract that acts as a potent antioxidant, and thus inhibits the AGEPs formation [14,20,21]. Aminoguanidine, an inhibitor of AGEPs formation was found to prevent retinopathy in diabetic animals and protect them from developments of diabetic vascular complications. However, aminoguanidine has encountered some toxicity problems in phase III clinical trials [22]. Efforts have now been made to develop new and safe synthetic antiglycation agents [23]. It has been demonstrated that polyamines, spermine and spermidine have potent antiglycation effects, comparable to those of aminoguanidine, and carnosine [24]. RESULTS AND DISCUSSION

*Address correspondence to this author at the H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan; Tel: 00922134824910; Fax: 00922134819018; E-mails: [email protected]; [email protected] 1875-6638/13 $58.00+.00

Chemistry 3-Oxindole derivatives 3-25 were synthesized in good yields from commercially available oxindole by refluxing © 2013 Bentham Science Publishers

Khan et al.

682 Medicinal Chemistry, 2013, Vol. 9, No. 5

O

Piperidine/EtOH

O N H

R R

H

Reflux, 3 h

O

N H

Scheme 1. Synthesis of oxindole derivatives 3-25.

mers were also isolated. The E and Z isomers of the compounds were separated by column chromatography and were identified on the basis of their chemical shift value, further elaborated by NOE experiment which assign specific chemical shift value (7.45 -7.84 for the E isomers and 7.85–8.53 for the Z isomers) for C-2' and C-6' [26]. The structures of synthesized compounds 3-25 were determined by using different spectroscopic techniques; including 1H NMR and EI MS. Elemental analysis results were also found to be satisfactory.

with different aromatic aldehydes in ethanol, in the presence of a catalytic amount of piperidine (Scheme 1) [25]. Generally, a mixture of oxindole (1 mmol), substituted aldehyde (2 mmol), and piperidine (0.1 mmol) was refluxed for 3 h. The progress of reaction was monitored by TLC and after cooling, reaction mixture was concentrated under reduced pressure. The solid 3-oxindole derivatives thus obtained were then washed with 1:1 mixture of hexane-ethyl acetate (25 mL) and dried under vacuum to afford compounds 3-25 in good yields (Scheme 1). In general, the reaction gave the E isomers as the major products, and in only two cases Z isoTable 1. In Vitro Antiglycation Activity of Compounds 3-25d

R N H Comp. #

IC50 ± SEMa (M)

R

O

Comp. #

1'

1' 282.2 ± 7.3

3

5'

N.A.b

15

5'

OH

4'

2'

6'

2'

6'

Cl Cl

8'

1'

7'

2'

b

N.A.

4

4'

1'

194.4 ± 2.5

16

267.6 ± 5.4

150.4 ± 2.5

17

5'

OC2H5

1' 3'

9'

456.0 ± 4.8

7'

6'

2'

5'

3'

N.A.b

18

4'

8' 5'

6'

NO2

1'

1'

2'

6'

b

N.A.

7

Cl

4'

2'

10'

2'

6'

5

4'

4'

1'

OH

5'

3'

Me

5'

6'

N.A.b

19

Cl

OH

OH

6'

3'

5'

OH

6'

6'

3'

6

IC50 ± SEMa (M)

R

3' 4'

Oxindole Derivatives: Synthesis and Antiglycation Activity

Medicinal Chemistry, 2013, Vol. 9, No. 5

683

Table 1. Contd… Comp. #

IC50 ± SEMa (M)

R

Comp. #

1'

1'

2'

6'

b

N.A.

8

2'

6' 5'

1'

1'

OMe

Cl

6' N.A.b

9

856.7 ± 4.8

21

5'

3'

5'

NO2

4'

OEt

6'

N.A.b

20

3'

5'

IC50 ± SEMa (M)

R

3'

4'

Cl 1'

1'

6'

2'

5'

3'

379.3 ± 1.4

10

N.A.b

22

5'

3' Cl

F 1'

1'

2'

6'

211.4 ± 4.1

11

6'

2'

5'

3'

N.A.b

23

3'

5'

Cl

F

1'

1'

F

6'

N.A.

12

OH

6' b

284.8 ± 5.3

24

5'

3'

5'

Cl

6'

3' 4'

4'

1' 6'

2'

5'

3'

1' 2'

6'

N.A.b

13

5'

N.A.b

25

3' SM

12'

8'

11'

9' 10'

1' 6'

OH Rutin c

374.3 ± 1.1

14

5' 4'

294.5 ± 1.50

OMe

SEMa is the standard error of the mean, NAb Not active, Rutin,c standard inhibitor for antiglycation activity, dEach of the assay was carried out in triplicate.

R

Antiglycation Activity

R

N

Recently, we reported Schiff and bis-Schiff bases of isatin with antiglycation potential [12,13], herein we are reporting the antiglycation potential of oxindole derivatives 325 (Table 1). The study is intended to develop new and potent antiglycating agents, based on the structures of our previously reported antiglycating agents 1 and 2 (Fig. 1).

N

N

O

O N H 1

N H 2

Fig. (1). Reported Schiff and bis Schiff bases of isatins with antiglycation potential [12,13].

Khan et al.


The in vitro antiglycation potential of oxindole derivatives 3-25 has been evaluated. They showed a varying degree of antiglycation activity having IC50 values ranging between 150.4 - 856.71 M. Compounds 17 (IC50 = 150.4 ± 2.5 M), 16 (IC50 = 194.4 ± 2.5 M), 11 (IC50 = 211.4 ± 4.1 M), 5 (IC50 = 267.6 ± 5.4 M), 3 (IC50 = 282.2 ± 7.3 M), and 24 (IC50 = 284.8 ± 5.3 M) showed an excellent activity better than the standard rutin having an IC50 value 294.5 ± 1.50 M. Compounds 14 (IC50 = 374.3 ± 1.1 M), 6 (IC50 = 456.0 ± 4.8 M), and 10 (IC50 = 379.3 ± 1.4 M) showed moderate antiglycation potential. Compound 21 (IC50 = 856.7 ± 4.8 M) was found to be least active among the series. Nonetheless, rest of compounds 4, 7-9, 12, 13, 15, 18-20, 22, 23, and 25 showed less than 50% antiglycation activity and therefore were not further studied. Compound 17 was found to be the most active derivative of the series with IC50 = 150.4 ± 2.5 M, having a metachloro group. Surprisingly, our reported meta-chloro analog of Schiff base of isatin [12], was found to be less active (IC50 = 675 ± 0.12 M), than newly synthesized alkylidene system 17. Since meta-chloro derivatives were found to be active in both the series therefore suggesting that alkylidene substitution at oxindole enhances the antiglycation potential. Generally, all the newly synthesized alkylidene derivatives found to have more antiglycation potential than previously reported Schiff bases of the closely related skeleton. In addition, meta and para-dichloro analogs of both the series were also evidenced to be completely inactive in both the series. Compounds 21 and 22 having ortho, and para-dichloro substitution at E and Z isomers showed an interesting antiglycating activity. The Z isomer 21 showed a weak activity, whereas E isomer 22 exhibited no activity at all. Compound 23 having a para-cholro substitution was also found to be inactive. The activity pattern of chloro substituted methylidene-1,3dihydro-2H-indol-2-ones demonstrated that the position of chloro group at phenyl ring is crucial for antiglycation activity. The actual mechanism of antiglycation activity of these chloro containing analogs is yet unknown. Compound 16 containing ortho-hydroxy and metamethyl groups, was found to be the second most active antiglycating agent with an IC50 = 194.4 ± 2.5 M. Activity related to this compound might be due to the hemiacetal formation between hydroxy analog 16 and the carbonyl group of methylglyoxal. Compound 3, a meta-hydroxy analog and compound 24, an ortho-hydroxy derivative showed comparable activity with IC50 values of 282.2 ± 7.3 M and 284.8 ± 5.3 M, respectively. A sharp decline in antiglycation activity of compound 24, as compared to compound 16 is suggests that the meta-methyl residue in compound 16 also contributes in antiglyacation activity by one or the other way. The decrease in activity of compound 3 may be due to different position of hydroxyl group. Compound 5, having a meta-ethoxy substituent in addition to ortho-hydroxyl, showed an IC50 = 267.6 ± 5.4 M, contrary, a closely related compound 14 with a methoxy group instead of ethoxy group demonstrated a decline in activity with an IC50 value 374.26 ± 1.1 M. Nevertheless, analogous compound 19 with an ortho-hydroxyl, but chloro as meta substituents was found to be completely inactive. Compound 7 closely related to the second most active compound 16, having a para-hydroxyl

substitution instead of ortho-hydroxy which showed no activity, suggesting that the position of hydroxyl group has a pivotal role in antiglycation activity. Compound 8, a paraethoxy and compound 9 an ortho-methoxy derivatives, were found to be completely inactive as suitable groups at specific position were critical for antiglycation activity. In flouro containing derivatives, E isomer 11 was found to be active with an IC50 value of 211.4 ± 4.1 M, and Z isomer 10 showed a marked decrease in antiglycating activity with an IC50 value of 379.3 ± 1.4 M, however, when position of para substituent changed to ortho, as in compound 12, it completely lost its antiglycation potential. Compound 6 with an anthracene moiety showed an IC50 = 456.0 ± 4.8 M, while its naphthyl analog found to be completely inactive. Rest of the compounds showed less than 50% activity and thus were not screened for their IC50 values. Conclusively, it is drawn that 3-[(3-3hlorophenyl)methyllidene]-1,3-dihydro-2H-indol-2-one (IC50 = 150.40 ± 2.5 M) and 3-[(2-hydroxy-5-methylphenyl) methylidene]-1,3dihydro-2H-indol-2-one (IC50 = 194.40 ± 2.5 M) may serve as lead molecule for further research on this class of compounds. MATERIAL AND METHOD Assay for Antiglycation Chemicals Bovine serum albumin (BSA) was purchased from Merck Marker Pvt. Ltd. Rutin, methyl glyoxal (MGO) (40% aqueous solution), sodium dihydrogen phosphate (NaH2PO4), disodium hydrogen phosphate (Na2HPO4), and dimethyl sulfoxide (DMSO) were purchased from Sigma Aldrich. Protocol This test was used to evaluate the ability of the candidate compounds to inhibit the methyl glyoxal mediated development of fluorescence of BSA. Activity was performed by using the reported method [14,15] with the following modifications: Triplicate samples of BSA 10 mg/mL, 14 mM MGO, 0.1 M phosphate buffer (pH 7.4) containing NaN3 (30 mM) were incubated under aseptic conditions (in such a way that each well of 96-well plate contains 50 L BSA solution, 50 L MGO, and 20 L test sample) at 37 °C for 9 days in the presence or absence of various concentrations of the compounds. After 9 days of incubation, each sample was examined for the development of specific fluorescence (excitation, 330 nm; emission, 440 nm), against sample blank on a microtitre plate spectrophotometer (Spectra Max, Molecular Devices, CA USA). Rutin was used as a positive control (IC50 = 294 ± 1.5 M) [17]. The percent inhibition of AGE formation in the test sample versus control was calculated for each inhibiting compound by using the following formula: % inhibition = (1- fluorescence of test sample/ Fluorescence of the control group)x100.


General Experimental Melting points were determined on a Büchi 434 melting point apparatus and were uncorrected. NMR experiments were performed on Avance Bruker AM 300, 400, and 500 MHz. CHN analysis was performed on a Carlo Erba Strumentazion-Mod-1106, Italy. Ultraviolet (UV) spectra were recorded on Perkin-Elmer Lambda-5 UV/VIS spectrophotometer in MeOH. Infrared (IR) spectra were recorded on JASCO IR-A-302 spectrophotometer as KBr (disc). Electron impact mass spectra (EI MS) were recorded on a Finnigan MAT-311A, Germany. Thin layer chromatography (TLC) was performed on pre-coated silica gel aluminum plates (Kieselgel 60, 254, E. Merck, Germany). Chromatograms were visualized by UV at 254 and 365 nm. General Procedure for the Synthesis of Compounds 3-25 The preparation of compounds 3-25 was carried out by refluxing oxindole with different aromatic aldehydes in ethanol in the presence of a catalytic amount of piperidine were refluxed for 3 h. After cooling reaction mixture was concentrated at reduced pressure to obtain solid of 3oxindole derivatives, then washed with 1:1 mixture of hexane-ethyl acetate (25 mL) and dried to afford titles compounds in good yields (Table 1). Only in two cases (10 and 21), both E and Z isomers were obtained, these isomers were separated by column chromatography using 1:9 ethyl acetate : hexane as eluent. The structures of synthetic compounds 325 were elucidated by 1H NMR and EI MS. Elemental analysis results were also found to be satisfactory. 3-[(3-Hydroxyphenyl) methylidene]-1,3-dihydro-2Hindol-2-one (3)


685

1H, J4',5' = 7.5 Hz, H-4'), 6.84 (m, 3H, H-5'/5/7); MS: m/z (rel. abund. %), 281 (M+, 100), 264 (27), 252 (42), 236 (31), 196 (18), 167 (17); Anal. calcd. for C17H15NO3 (281.31): C, 72.58; H, 5.37; N, 4.98; O, 17.06; Found: C, 72.58; H, 5.39; N, 4.97. 3-[9-Anthrylmethylidene]-1,3-dihydro-2H-indol-2-one (6) Yield: 0.20g (62%); 1H-NMR (300 MHz, DMSO-d6): 10.71 (s, 1H, NH), 8.71 (s, 1H, H-6'), 8.30 (s, 1H, =CH), 8.22 (d, 2H, J5',4' = 7',8' = 7.8 Hz, H-5'/7'), 7.91 (d, 2H, J2',3' = 10',9' = 7.8 Hz, H-2'/10'), 7.50 (m, 3H, H-3'/4'/9'), 7.11 (t, 1H, J5/4,6 = 7.5 Hz, H-5), 7.01 (t, 1H, J6/5,7 = 7.5 Hz, H-6), 6.81 (d, 1H, J7,6 = 7.5 Hz, H-7), 6.30 (t, 1H, J8'/7', 9' = 7.8 Hz, H-8'), 5.61 (d, 1H, J4,5 = 7.2 Hz, H-4); MS: m/z (rel. abund. %), 321 (M+, 100), 304 (65), 291 (25), 161 (9), 146 (12); Anal. calcd. for C23H15NO (321.37): C, 85.96; H, 4.70; N, 4.36; O, 4.98; Found: C, 85.98; H, 4.69; N, 4.35. 3-[(4-Hydroxyphenyl)methylidene]-1,3-dihydro-2Hindol-2-one (7) Yield: 0.16g (68%); 1H-NMR (300 MHz, DMSO-d6): 10.51 (s, 1H, NH), 10.11 (s, 1H, OH), 7.68 (d, 1H, J4,5 = 7.5 Hz, H-4), 7.62 (d, 2H, J2',3'/6',5' = 8.4 Hz, H-2'/6'), 7.51 (s, 1H, =CH), 7.20 (t, 1H, J6/5,7 = 7.5 Hz, H-6), 6.90 (d, 2H, J3',2'/5',6' = 8.4 Hz, H-3'/5'), 6.81 (m, 2H, H-5/7); MS: m/z (rel. abund. %), 237 (M+, 70.9), 209 (21), 189 (53), 121 (100), 93 (36), 65 (29); Anal. calcd. for C15H11NO2 (237.25): C, 75.94; H, 4.67; N, 5.90; O, 13.49; Found: C, 75.92 H, 4.67 N, 5.92. 3-[(4-Ethoxyphenyl) methylidene]-1,3-dihydro-2H-indol2-one (8)

Yield: 0.15g (63%); H-NMR (300 MHz, DMSO-d6): 10.58 (s, 1H, NH), 9.71 (s, 1H, O-H), 7.57 (d, 1H, J6',5' = 7.8 Hz, H-6'), 7.52 (s, 1H, =CH), 7.31 (t, 1H, J5'/4',6' = 7.8 Hz, H-5'), 7.22 (t, 1H, J6/5,7 = 7.8 Hz, H-6), 7.10 (d, 1H, J4,5 = 7.8 Hz, H-4), 6.80 (s, 1H, H-2'), 6.80 (m, 3H, H-4'/5/7); MS: m/z (rel. abund. %), 237 (M+, 100), 209 (27), 180 (13), 144 (30); Anal. calcd. for C15H11NO2 (237.25): C, 75.94; H, 4.67; N, 5.90; O, 13.49; Found: C, 75.92 H, 4.68 N, 5.91.

Yield: 0.19g (72%); 1H-NMR: (300 MHz, DMSO-d6): 10.52 (s, 1H, NH), 7.61 (d, 2H, J2',3'/6',5' = 8.7 Hz, H-2'/6'), 7.64 (d, 1H, J4,5 = 8.0 Hz, H-4), 7.50 (s, 1H, =CH), 7.21 (t, 1H, J6/5,7 = 8.0 Hz, H-6), 7.05 (d, 2H, J3',2'/5',6' = 8.7 Hz, H3'/5'), 6.80 (m, 2H, H-5/7), 4.12 (q, 2H, OCH2), 1.30 (t, 3H, CH3); MS: m/z (rel. abund. %), 265 (M+, 100), 236 (60), 209 (40), 180 (14), 144 (26); Anal. calcd. for C17H15NO2 (265.31): C, 76.96; H, 5.70; N, 5.28; O, 12.06; Found: C, 76.98; H, 5.69; N, 5.28.

3-[2-Naphthylmethylidene]-1,3-dihydro-2H-indol-2-one (4)

3-[(2-Methoxyphenyl) methylidene]-1,3-dihydro-2Hindol-2-one (9)

Yield: 0.18g (66%); 1H-NMR (500 MHz, MeOH-d4): 8.20 (s, 1H, H-2'), 7.98 (d, 1H, J5',6' = 8.5 Hz, H-5'), 7.92 (m, 2H, H-4/6'), 7.80 (s, 1H, =CH), 7.76 (dd, 1H, J8',2' = 2.0, J8',7' = 8.5 Hz, H-8'), 7.61 (d, 1H, J4',3' = 7.5 Hz, H-4'), 7.52 (m, 2H, H-5/7'), 7.20 (td, 1H, J6,4 = 1.0, J6/5,7 = 7.5 Hz, H-6), 6.91 (d, 1H, J7,6 = 7.5 Hz, H-7), 6.82 (t, 1H, J3'/2',4' = 7.5 Hz, H-3'); MS: m/z (rel. abund. %), 271 (M+, 100), 243 (32), 215 (24), 144 (36), 108 (10); Anal. calcd. for C19H13NO (271.31): C, 84.11; H, 4.83; N, 5.16; O, 5.90; Found: C, 84.13 H, 4.82; N, 5.16.

Yield: 0.18g (72%); 1H-NMR: (300 MHz, DMSO-d6): 10.61 (s, 1H, NH), 7.70 (d, 1H, J6',5' = 7.5 Hz, H-6'), 7.62 (s, 1H, =CH), 7.51 (td, 1H, J6,4 =1.5, J6/5,7 = 8.7 Hz, H-6), 7.42 (d, 1H, J4,5 = 7.8 Hz, H-4), 7.21 (t, 1H, J5/4,6 = 7.5 Hz, H-5), 7.14 (d, 1H, J7,6 = 8.4 Hz, H-7), 7.01 (t, 1H, J5'/4',6'= 7.5 Hz, H-5'), 6.81 (d, 1H, J3',4' = 7.5 Hz, H-3'), 6.72 (t, 1H, J4'/5',3' = 7.5 Hz, H-4'), 3.81 (s, 3H, OCH3); MS: m/z (rel. abund. %), 251 (M+, 36), 220 (100), 145 (10), 85 (32); Anal. calcd. for C16H13NO2 (251.28): C, 76.48; H, 5.21; N, 5.57; O, 12.73; Found: C, 76.49; H, 5.20; N, 5.57.

3-[(3-Ethoxy-2-hydroxyphenyl) methylidene]-1,3dihydro-2H-indol-2-one (5)

(E) 3-[(4-Fluorophenyl) methylidene]-1,3-dihydro-2Hindol-2-one (10)

Yield: 0.18g (64%); 1H-NMR (300 MHz, DMSO-d6): 10.53 (s, 1H, NH), 9.11 (s, 1H, OH), 7.68 (s, 1H, =CH), 7.50 (d, 1H, J6',5' = 7.5 Hz, H-6'), 7.21 (m, 2H, H-4/6), 7.00 (d,

Isolated Yield: 0.06g (25%, eluent 1:9 ethyl acetate:hexane); 1H-NMR: (300 MHz, DMSO-d6): 10.63 (s, 1H, NH), 8.48 (dd, 2H, J3',2'/5',6' = 6.0 Hz, J3',F/5',F = 5.7 Hz, H-

1


3'/5'), 7.81 (s, 1H, =CH), 7.72 (d, 1H, J4,5 = 7.5 Hz, H-4), 7.31 (t, 2H, J2'/3',F = J6'/5',F = 9.0 Hz, H-2'/6'), 7.22 (t, 1H, J6/5,7 = 7.5 Hz, H-6), 7.01 (t, 1H, J5/4,6 = 7.5 Hz, H-5), 6.81 (d, 1H, J7,6 = 7.5 Hz, H-7); MS: m/z (rel. abund. %), 239 (M+, 72), 211 (30), 183 (24), 133 (36), 85 (100), 63 (22); Anal. calcd. for C15H10FNO (239.24): C, 75.30; H, 4.21; F, 7.94; N, 5.85; O, 6.69; Found: C, 75.31; H, 4.19; N, 5.86. (Z) 3-[(4-Fluorophenyl) methylidene]-1,3-dihydro-2Hindol-2-one (11) Isolated Yield: 0.10g (42% eluent 1:9 ethyl acetate:hexane); 1H-NMR: (300 MHz, DMSO-d6): 10.61 (s, 1H, NH), 7.75 (dd, 2H, J3',2'/5',6' = 5.7 Hz, J3',F/5',F = 5.7 Hz, H3'/5'), 7.60 (s, 1H, =CH), 7.58 (d, 1H, J7,6 = 7.5 Hz, H-7), 7.35 (t, 2H, J2'/3',F = J6'/5',F = 9.0 Hz, H-2'/6'), 7.23 (t, 1H, J5/4,6 = 7.5 Hz, H-5), 6.81 (m, 2H, H-4/6); MS: m/z (rel. abund. %), 239 (M+, 100), 220 (35), 211(47), 183 (46), 144 (100), 133 (33), 85 (22), 78 (25); Anal. calcd. for C15H10FNO (239.24): C, 75.30; H, 4.21; F, 7.94; N, 5.85; O, 6.69; Found: C, 75.30; H, 4.19; N, 5.87. 3-[(2-Fluorophenyl) methylidene]-1,3-dihydro-2H-indol2-one (12) Yield: 0.14g (59%); 1H-NMR: (300 MHz, DMSO-d6): 10.62 (s, 1H, NH), 7.75 (t, 1H, J6/5,7 = 7.5 Hz, H-6), 7.53 (m, 2H, =CH / H-5'), 7.37 (m, 2H, H-3'/7), 7.23 (m, 2H, H-4/4'), 7.31 (m, 2H, H-5/6'); MS: m/z (rel. abund. %), 239 (M+, 72), 211 (30), 183 (46), 133 (36), 85 (100), 63 (22); Anal. calcd. for C15H10FNO (239.24): C, 75.30; H, 4.21; F, 7.94; N, 5.85; O, 6.69; Found: C, 75.28; H, 4.19; N, 5.88. 3-[[4-(Methylsulfanyl) phenyl] methylidene}-1,3-dihydro2H-indol-2-one (13) Yield: 0.19g (71%); 1H-NMR: (300 MHz, DMSO-d6): 10.57 (s, 1H, NH), 7.67 (d, 2H, J3',2'/5',6'= 8.4 Hz, H-3'/5'), 7.60 (d, 1H, J4,5 = 7.8 Hz, H-4), 7.56 (s, 1H, =CH), 7.41 (d, 2H, J2',3'/6',5' = 8.4 Hz, H-2'/6'), 7.20 (t, 1H, J6/5,7 = 7.8 Hz, H6), 6.87 (d, 1H, J7,6 = 7.8 Hz, H-7), 6.85 (t, 1H, J5/4,6 = 7.8 Hz, H-5), 2.43 (s, 3H, S-CH3); MS: m/z (rel. abund. %), 267 (M+, 100), 224 (31), 152 (43), 133 (41), 104 (37), 83 (33), 51 (28); Anal. calcd. for C16H13NOS (267.35): C, 71.88; H, 4.90; N, 5.24; O, 5.98; S, 11.99; Found: C, 71.89; H, 4.88; N, 5.22. 3-[(2-Hydroxy-3-methoxyphenyl) methylidene]-1,3dihydro-2H-indol-2-one (14) Yield: 0.18g (67%); 1H-NMR: (500 MHz, MeOH-d4): 7.81 (s, 1H, =CH), 7.58 (d, 1H, J6',5' = 7.5 Hz, H-6'), 7.20 (d, 1H, J4,5 = 8.0 Hz, H-4), 7.11 (td, 1H, J6,4 = 1.0 Hz, J6/5,7 = 8.0 Hz, H-6), 7.01 (dd, 1H, J7,5 = 1.0 Hz, J7,6 = 8.0 Hz, H-7), 6.86 (m, 3H, H-4'/5'/5), 3.92 (s, 3H, OCH3); MS: m/z (rel. abund. %), 267 (M+, 100), 250 (53), 196 (14), 167 (13), 103.5 (14); Anal. calcd. for C16H13NO3 (267.28): C, 71.90; H, 4.90; N, 5.24; O, 17.96; Found: C, 71.92; H, 4.89; N, 5.23. 3-[(3,4-Dichlorophenyl)methylidene]-1,3-dihydro-2Hindol-2-one (15) Yield: 0.18g (62%); 1H-NMR: (300 MHz, DMSO-d6): 10.61 (s, 1H, NH), 7.90 (d, 1H, J2',6' = 1.8 Hz, H-2'), 7.72 (d,

Khan et al.

1H, J5',6' = 8.4 Hz, H-5'), 7.61 (dd, 1H, J6',2' = 1.8, J6',5' = 8.4 Hz, H-6'), 7.55 (s, 1H, =CH), 7.4 (d, 1H, J4,5 = 7.5 Hz, H-4), 7.23 (t, 1H, J6/5,7 = 7.5 Hz, H-6), 6.88 (d, 1H, J7,6 = 7.5 Hz, H-7), 6.84 (t, 1H, J5/4,6 = 7.5 Hz, H-5); MS: m/z (rel. abund. %), 290 (M+, 100), 261 (30), 199 (25), 144 (100), 127 (25), 89 (27), 63 (24); Anal. calcd. for C15H9Cl2NO (290.14): C, 62.09; H, 3.13; Cl, 24.44; N, 4.83; O, 5.51; Found: C, 62.10; H, 3.12; N, 4.82. 3-[(2-Hydroxy-5-methylphenyl) methylidene]-1,3dihydro-2H-indol-2-one (16) Yield: 0.17g (68%); 1H-NMR: (500 MHz, MeOD-d4): 7.86 (s, 1H, =CH), 7.56 (d, 1H, J3',4' = 8.0 Hz, H-3'), 7.45 (d, 1H, J6',4' = 2.0 Hz, H-6'), 7.18 (td, 1H, J6,4 = 1.0 Hz, J6/5,7 = 8.5 Hz, H-6), 7.10 (dd, 1H, J4,6 = 2.0 Hz, J4,5 = 8.5 Hz, H-4), 6.90 (d, 1H, J4',3'= 8.0 Hz, H-4'),6.85 (td, 1H, J5,7 = 1.0 Hz, J6/5,7 = 8.5 Hz, H-7), 6.82 (d, 1H, J7,6 = 8.5 Hz, H-7) (m, 3H, H-4'/5/7), 2.27 (s, 3H, -CH3); MS: m/z (rel. abund. %), 251 (M+, 100), 234 (99), 194 (24), 180 (21), 152 (19), 89 (21), 77 (23), 63 (38); Anal. calcd. for C16H13NO2 (251.28): C, 76.48; H, 5.21; N, 5.57; O, 12.73; Found: C, 76.50; H, 5.20; N, 5.55. 3-[(3-Chlorophenyl)methylidene]-1,3-dihydro-2H-indol2-one (17) Yield: 0.16g (62%); 1H-NMR: (300 MHz, DMSO-d6): 10.60 (s, 1H, NH), 7.72 (s, 1H, H-2'), 7.66 (m, 1H, H-5'), 7.57 (s, 1H, =CH), 7.56 (m, 2H, H-4'/7), 7.39 (d, 1H, J = 7.5 Hz, H-4), 7.23 (t, 1H, J6/5,7 = 7.5 Hz, H-6), 6.85 (m, 2H, H5/6'); MS: m/z (rel. abund. %), 256 (M+, 27), 255 (86), 227 (37), 165 (38), 144 (100), 89 (22), 78 (25), 63 (42); Anal. calcd. for C15H10ClNO (255.70): C, 70.46; H, 3.94; Cl, 13.87; N, 5.48; O, 6.26; Found: C, 70.47; H, 3.92; N, 5.48. 3-[(4-Nitrophenyl)methylidine]-1,3-dihydro-2H-indol-2one (18) Yield: 0.20g (75%); 1H-NMR: (500 MHz, MeOH-d4): 8.31 (d, 2H, J3',2'/5',6' = 8.5 Hz, H-3'/5'), 7.90 (d, 2H, J2',3'/6',5' = 8.5 Hz, H-2'/6'), 7.72 (s, 1H, =CH), 7.41 (d, 1H, J4,5 = 8.0 Hz, H-4), 7.20 (td, 1H, J6,4 = 1.0 Hz , J6/5,7 = 8.0 Hz, H-6), 6.91 (d, 1H, J7,6 = 8.0 Hz, H-7), 6.80 (td, 1H, J5,7 = 1.0 Hz, J5/4,6 = 8.0 Hz, H-5); MS: m/z (rel. abund. %), 266 (M+, 100), 238 (11), 219 (22), 191 (48), 165 (48), 144 (79), 89 (21), 63 (37); Anal. calcd. for C15H10N2O3 (266.25): C, 67.67; H, 3.79; N, 10.52; O, 18.03; Found: C, 67.65; H, 3.80; N, 10.51. 3-[(5-Chloro-2-hydroxyphenyl)methylidine]-1,3-dihydro2H-indol-2-one (19) Yield: 0.18g (66%); 1H-NMR (300 MHz, DMSO-d6): 10.56 (s, 1H, NH), 10.44 (s, 1H, OH), 7.58 (d, 1H, J6',4' = 2.7 Hz, H-6'), 7.54 (s, 1H, =CH), 7.35 (m, 2H, H-4'/4), 7.20 (t, 1H, J6/5,7 = 7.8 Hz H-6), 6.9 (d, 1H, J3',4' = 8.7 Hz, H-3'), 6.87 (m, 2H, H-5/7); MS: m/z (rel. abund. %), 272 (M+, 38), 271 (100), 254 (77), 214 (8), 208 (9), 180 (24), 152 (14); Anal. calcd. for C15H10ClNO2 (271.70): C, 66.31; H, 3.71; Cl, 13.05; N, 5.16; O, 11.78; Found: C, 66.32; H, 3.70; N, 5.16.


3-[(3-Nitrophenyl)methylidine]-1,3-dihydro-2H-indol-2one (20) Yield: 0.19g (71%); 1H-NMR: (400 MHz, DMSO-d6): 10.72 (s, 1H, NH), 9.37 (s, 1H, H-2' ), 8.61 (d, 1H, J6',5' = 8.0 Hz, H-6'), 8.20 (dd, 1H, J4',6' = 1.6 Hz, J4',5' = 8.0 Hz, H-4'), 7.96 (s, 1H, =CH), 7.72 (t, 1H, J5'/6',4' = 8.0 Hz, H-5'), 7.42 (d, 1H, J4,5 = 7.5 Hz, H-4), 7.21 (t, 1H, J6/5,7 = 7.5 Hz, H-6), 7.01 (t, 1H, J5/4,6 = 7.5 Hz, H-5), 6.81 (d, 1H, J7,6 = 7.5 Hz, H-7); MS: m/z (rel. abund. %), 266 (M+, 100), 219 (27), 191 (41), 165 (30), 144 (63), 83 (65); Anal. calcd. for C15H10N2O3 (266.25): C, 67.67; H, 3.79; N, 10.52; O, 18.03; Found: C, 67.67; H, 3.80; N, 10.50. (E) 3-[(2,4-Dichlorophenyl)methylidine]-1,3-dihydro-2Hindol-2-one (21) Isolated Yield: 0.13g (45%, eluent 1:9 ethyl acetate:hexane) ; 1H-NMR: (400 MHz, DMSO-d6): 10.57 (s, 1H, NH), 8.11 (d, 1H, J6',5' = 8.4 Hz H-6'), 7.75 (s, 1H, =CH), 7.71 (s, 1H, H-3'), 7.70 (d, 1H, J5',6' = 7.5 Hz, H-5'), 7.42 (dd, 1H, J4,6 = 2.0 Hz, J4,5 = 8.0 Hz, H-4), 7.21 (t, 1H, J6/5,7 = 8.0 Hz, H-6), 6.92 (t, 1H, J5/4,6 = 7.6 Hz, H-5), 6.81 (d, 1H, J7,6 = 8.0 Hz, H-7); MS: m/z (rel. abund. %), 289 (M+, 5), 254 (100), 219 (13), 190 (19), 163 (18), 89 (20), 63 (23); Anal. calcd. for C15H9Cl2NO (290.14): C, 62.09; H, 3.13; Cl, 24.44; N, 4.83; O, 5.51; Found: C, 62.10; H, 3.13; N, 4.82. (Z) 3-[(2,4-Dichlorophenyl)methylidine]-1,3-dihydro-2Hindol-2-one (22) Isolated Yield: 0.08g (28%, eluent 1:9 ethyl acetate:hexane); 1H-NMR: (400 MHz, DMSO-d6): 10.66 (s, 1H, NH), 7.81 (d, 1H, J3',5' = 2.0 Hz, H-3'), 7.72 (d, 1H, J6',5' = 8.4 Hz, H-6'), 7.58 (dd, 1H, J5'3' = 2.0 Hz, J5',6' = 8.4 Hz, H5'), 7.49 (s, 1H, =CH), 7.21 (t, 1H, J6/5,7 = 7.6 Hz, H-6), 7.12 (d, 1H, J4,5 = 7.6 Hz, H-4), 6.87 (d, 1H, J7,6 = 7.6 Hz, H-7), 6.82 (t, 1H, J5/4,6 = 7.6 Hz, H-5); MS: m/z (rel. abund. %), 289 (M+, 5), 254 (100), 219 (13), 190 (19), 163 (18), 89 (20), 63 (23); Anal. calcd. for C15H9Cl2NO (290.14): C, 62.09; H, 3.13; Cl, 24.44; N, 4.83; O, 5.51; Found: C, 62.10; H, 3.11; N, 4.82. 3-[(4-Chlorophenyl)methylidine]-1,3-dihydro-2H-indol-2one (23) Yield: 0.16g (63%); 1H-NMR: (400 MHz, DMSO-d6): 10.61 (s, 1H, NH), 7.72 (d, 2H, J3',2'/5',6' = 8.4 Hz, H-3'/5'), 7.58 (s, 1H, =C-H), 7.57 (d, 2H, J2',3'/6',5' = 8.4 Hz, H-2'/6'), 7.41 (d, 1H, J4,5 = 7.6 Hz, H-4), 7.22 (t, 1H, J6/5,7 = 7.6 Hz, H-6), 6.87 (d, 1H, J7,6 = 7.6 Hz, H-7), 6.82 (t, 1H, J5/4,6 = 7.6 Hz, H-5); MS: m/z (rel. abund. %), 257 (M+2, 33.92), 256 (M+, 33), 255 (100), 227 (34), 190 (18), 165 (35), 144 (55), 110 (17), 89 (27), 63 (16); Anal. calcd. for C15H10ClNO (255.70): C, 70.46; H, 3.94; Cl, 13.87; N, 5.48; O, 6.26; Found: C, 70.46; H, 3.93; N, 5.48. 3-[(2-Hydroxyphenyl)methylidine]-1,3-dihydro-2H-indol2-one (24) Yield: 0.16g (67%); 1H-NMR: (300 MHz, DMSO-d6): 10.51 (s, 1H, NH), 10.10 (s, 1H, OH), 7.67 (s, 1H, =CH), 7.62 (d, 1H, J6',5' = 7.5 Hz, H-6'), 7.41 (d, 1H, J4,5 = 7.8 Hz, H-4), 7.31 (td, 1H, J4',6' = 1.5 Hz, J4'/3',5' = 8.4 Hz, H-4'), 7.12


687

(t, 1H, J6/5,7 = 7.5 Hz, H-6), 6.88 (m, 4H, H-5/7/3'/5'); MS: m/z (rel. abund. %), 237 (M+, 100), 220 (79), 209 (16), 180 (43), 152 (19), 89 (16), 63 (11); Anal. calcd. for C15H11NO2 (237.25): C, 75.94; H, 4.67; N, 5.90; O, 13.49; Found: C, 75.94 H, 4.68 N, 5.91. 3-[(1,1-Biphenyl)-4-yl-methylidine]-1,3- dihydro-2Hindol-2-one (25) Yield: 0.19g (64%); 1H-NMR: (300 MHz, DMSO-d6): 10.62 (s, 1H, NH), 8.51 (d, 2H, J2',3'/6',5' = 8.4 Hz, H-2'/6'), 7.81 (s, 1H, =CH), 7.72 (m, 5H, H-4/3'/5'/10'/12'), 7.53 (t, 2H, J9'/8',10', 11'/10',12' = 7.5 Hz, H-9'/11'), 7.41 (d, 1H, J8',9' = 7.5 Hz, H-8'), 7.20 (t, 1H, J6/5,7 = 7.5 Hz, H-6), 7.01 (t, 1H, J5/4,6 = 7.5 Hz, H-5), 6.81 (d, 1H, J7,6 = 7.5 Hz, H-7); MS: m/z (rel. abund. %), 297 (M+, 100), 269 (25), 241 (9), 220 (10), 144 (30), 89 (12); Anal. calcd. for C21H15NO (297.35): C, 84.82; H, 5.08; N, 4.71; O, 5.38; Found: C, 84.83; H, 5.07; N, 4.70. CONFLICT OF INTEREST Declared none. ACKNOWLEDGEMENTS The authors are thankful to Organization for Prohibition of Chemical Weapons (OPCW) Netherlands for providing financial support for this research work. REFERENCES [1]

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Received: May 14, 2012

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Revised: September 23, 2012

Accepted: November 20, 2012