A Facile and An Efficient Synthesis of 3,3-Disubstituted Oxindole Scaffolds and their Cytotoxic Properties

 

Sasikala Maadwar*^1,2, Rajitha Galla¹, Santhosh K. G²

¹Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam, Tirupati, India.

²Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad, India.

 

ABSTRACT:

A facile and an efficient synthesis of 3,3-disubstituted oxindole derivatives were synthesised by treating isatins with electron rich benzene derivatives at room temperature. The compounds were evaluated for cytotoxic activity against human breast cancer cells (MCF7) and human ovarian carcinoma cells (SKVO3) by using MTT assay. Compounds 5(9.2μM and 9.5μM) and 7(8.0μM and 10.4μM) exhibited relatively higher cytotoxic activity against both MCF7 and SKVO3 cell lines, respectively.

 

 

 

1. INTRODUCTION:

Cancer is characterised by a change in controlled mechanisms that manage cell proliferation, differentiation and is continuing to be a major health problem in developing as well as undeveloped countries. Malignancy is caused by abnormalities in cells, which might be due to inherited genes or caused by exogenous agents including chemicals, radiation and some infectious agents¹.

 

Organic compounds with an oxindole framework are represented in a large family of a pharmaceutically active compounds and bioactive natural products. Particularly, spirooxindole and 3, 3-disubstituted derivatives were present in a number of alkaloids which possess significant biological activities. Such as anticancer², antidepressant³, anticonvulsant⁴, antifungal⁵, anti-HIV⁶, anti-inflammatory⁷. During past decades, researchers have embarked on the development of new oxindole based anticancer agents^8-10.

 

5-fluoro-3-substituted-2-oxoindole derivative compound SU11248 [Sutent] received FDA approval for the treatment of gastrointestinal stromal tumors and advanced renal cell carcinoma¹¹. Due to the importance of oxindole motifs, several methods have been developed for the construction such structural motifs^12-19. Despite of effectiveness, these methods involve use of expensive catalysts^20-22, long reaction time^16,17,19,23, tedious work up, vigorous reaction conditions¹⁵ and poor yield¹⁹. Therefore there is need to develop efficient, convenient and practical protocol to synthesize oxindole scaffolds.

 

In the present investigation, we have developed a rapid and efficient method for synthesis of methoxy benzene substituted oxindole derivatives using boron trifluoride diethyl etherate as catalyst. The newly synthesized 3,3-disubstited oxindole derivatives are evaluated for their cytotoxic potentials against wild type human breast cancer cell line (MCF7) and human ovarian carcinoma cells (SKVO3).

 

2. MATERIALS AND METHODS:

2.1 Chemistry:

All the starting materials procured from Sigma Aldrich and used without further purification.  Solvents were of analytical grade. All the reactions were carried out with the use of standard techniques and were monitored by analytical TLC performed on pre-coated silica.

Scheme :

 

 

 

Probable Reaction Mechanism for the Formation of 3,3-Disubstituted Oxindole Scaffold

 

 

2.1.1. General procedure for synthesis of 3,3-disubstituted oxindole derivatives:

To 1.0 equivalent of isatin 1.5 equivalent of di methoxy benzene was added in DCM in a RBF, stirred it for 2min, 0.2ml of [BF₃O(Et)₂] was added and stirred it for another 5-10 min (Scheme 1). Reaction was monitored by TLC, excess of reagent was quenched with solid sodium bicarbonate and directly loaded on to column. The structure of the compounds were confirmed by ¹H NMR, ¹³CNMR, IR and Mass-spectroscopy.

 

3,3-bis(2,4-dimethoxyphenyl)-1-methylindolin-2-one (1):

White solid; Mp 107-109 ^oC;¹H NMR (300 MHz, CDCl₃): d 3.26 (s, 3H), 3.44 (s, 3H), 3.61 (s, 3H), 3.76 (s, 6H), 6.31-6.38 (m, 1H), 6.43 (s, 2H), 6.79 (d, J = 3.66 Hz, 2H), 6.91 (t, J = 7.78 Hz, 1H), 7.15 (d, J =  7.62 Hz, 1H), 7.17-7.25 (m, 3H) ppm. ¹³CNMR (75 MHz, CDCl₃): d 26.5, 55.2, 55.7, 56.3, 58.8, 99.7, 100.1, 104.1, 104.2, 107.1, 121.7, 125.2, 127.1, 129.6, 130.7, 134.6, 143.6, 158.4, 158.9, 159.8, 160.1, 178.7 ppm. IR (KBr): ν = 737, 819, 932, 1039, 1202, 1288, 1466, 1611, 1721 cm^-1.MS-ESI: m/z = 420 [M+H]⁺, 442 [M+Na]⁺.

 

1-benzyl-3,3-bis(2,4-dimethoxyphenyl)indolin-2-one (2):

White solid; Mp 135-137 ^oC;¹H NMR (300 MHz, CDCl₃): d 3.38 (s, 3H), 3.51 (s, 3H), 3.77 (s, 6H), 4.96 (q, J = 2.45 Hz, 2H), 6.36 (dd, J = 2.28 Hz and 8.69 Hz, 1H), 6.41-6.46 (m, 3H), 6.71 (d, J = 7.62 Hz, 1H), 6.79 (d, J = 8.54 Hz, 1H), 6.88 (td, J = 1.06 Hz and 7.62 Hz, 1H), 7.08 (td, J = 1.22 Hz and 7.62 Hz, 1H), 7.18 (d, J = 8.39 Hz, 1H), 7.23 (t, J = 7.17 Hz, 2H), 7.29 (t, J = 7.47 Hz, 2H), 7.38 (d, J = 7.17 Hz, 2H) ppm. ¹³CNMR (75 MHz, CDCl₃): d 44.0, 55.1, 55.2, 55.4, 58.9, 99.7, 99.9, 104.0, 104.2, 108.1, 120.5, 120.7, 121.7, 125.1, 126.9, 127.2, 128.4, 129.7, 130.8, 134.7, 136.5, 142.6, 158.5, 158.8, 159.9, 160.1, 178.4 ppm. IR (KBr): ν = 768, 1027, 1149, 1251, 1351, 1510, 1620, 1710 cm^-1. MS-ESI: m/z = 496 [M+H]⁺, 518 [M+Na]⁺

 

3,3-bis(2,4-dimethoxyphenyl)-1-ethylindolin-2-one (3):

White solid; Mp 148-150 ^oC;¹H NMR (300 MHz, CDCl₃): d 3.43 (s, 3H), 3.62 (s, 3H), 3.76 (s, 3H), 3.77 (s, 3H), 3.78-3.85 (m, 2H), 6.33 (dd, J = 2.28 and  8.54 Hz, 1H), 6.39-6.45 (m, 3H), 6.77 (d, J = 8.54 Hz, 1H), 6.81 (d, J = 7.62 Hz, 1H), 6.90 (td, J = 0.91, J = 7.47 Hz, 1H), 7.14 (d, J = 8.54 Hz, 1H), 7.18 (td, J = 1.37, J = 7.78 Hz, 1H), 7.24 (dd, J = 1.06, J = 7.62 Hz, 1H) ppm. ¹³CNMR (75 MHz, CDCl₃): d 12.4, 34..7, 55.0, 55.2, 55.4, 58.8, 99.6, 99.9, 103.9, 104.1, 107.2, 120.5, 120.8, 121.4, 125.3, 127.0, 129.6, 130.7, 134.9, 142.5, 158.4, 158.8, 159.8, 160.0, 178.0 ppm.IR (KBr): ν = 751, 832, 917, 1035, 1211, 1298, 1458, 1612, 1722 cm^-1.MS-ESI: m/z = 434 [M+H]⁺, 456 [M+Na]⁺.

 

1-allyl-3,3-bis (2,4-dimethoxyphenyl)indolin-2-one (4):

Light red solid; Mp 150-152 ^oC;¹H NMR (300 MHz, CDCl₃): d 3.44 (s, 3H), 3.61 (s, 3H), 3.76 (s, 6H), 4.28-4.51 (m, 2H), 5.17-5.32 (m, 2H), 5.81-5.96 (m, 1H), 6.34 (d, J = 8.49 Hz, 1H), 6.42 (d, J = 9.82 Hz, 3H), 6.75-6.82 (m, 2H), 6.90 (t, J = 7.36 Hz, 1H), 7.11-7.26 (m, 3H) ppm. ¹³CNMR (75 MHz, CDCl₃): d 42.5, 55.2, 55.5, 58.7, 99.7, 100.0, 104.1, 104.2, 108.0, 117.2, 120.7, 120.8, 121.6, 25.2, 126.9, 129.6, 130.7, 132.1, 134.6, 142.6, 158.4, 158.9,  159.9, 160.1, 178.1 ppm.IR (KBr): ν = 725, 1001, 1145, 1261, 1325, 1510, 1602, 1703 cm^-1. MS-ESI: m/z = 446 [M+H]⁺.

 

3,3-bis(3,4-dimethoxyphenyl)-1-methylindolin-2-one (5):

White solid; Mp 130-132^oC; ¹H NMR (300 MHz, CDCl₃): d 3.29 (s, 3H), 3.75 (s, 6H), 3.84 (s, 6H), 6.71-6.77 (m, 4H), 6.84 (d, J = 1.98 Hz, 2H), 6.93 (d, J = 7.78 Hz, 1H), 7.09 (td, J = 0.91 Hz, J = 7.62 Hz, 1H), 7.24 (d, J = 7.47 Hz, 1H), 7.32 (td, J = 1.06 Hz, J = 7.62 Hz, 1H) ppm. ¹³CNMR (75 MHz, CDCl₃): d 26.6, 55.7, 55.8, 61.5, 108.5, 110.5, 111.9, 120.5, 122.6, 125.7, 128.1, 133.2, 134.1, 142.8, 148.3, 148.7, 177.8 ppm. IR (KBr): ν = 740, 822, 927, 1034, 1209, 1284, 1467, 1609, 1708 cm^-1.MS-ESI: m/z = 420 [M+H]⁺, 442 [M+Na]⁺.

 

3,3-bis(3,4-dimethoxyphenyl)-1-ethylindolin-2-one (6):

Light brown solid; Mp 134-136^oC;¹H NMR (300 MHz, CDCl₃): d 1.31 (t, J = 7.17 Hz, 3H), 3.75 (s, 6H), 3.81-3.90 (m, 8H), 6.71-6.77 (m, 4H), 6.84 (d, J = 1.83 Hz, 2H), 6.95 (d, J = 7.93 Hz, 1H), 7.08 (t,7.47 Hz, 1H), 7.24 (d,7.32 Hz, 1H), 7.30 (td, J = 1.06 Hz, J = 7.78 Hz, 1H) ppm. ¹³CNMR (75 MHz, CDCl₃): d 12.6, 34.9, 55.8, 61.4, 108.6, 110.5, 111.9, 120.4, 122.4, 125.9, 128.1, 133.5, 134.2, 141.8, 148.2, 148.7, 177.4 ppm. IR (KBr): ν = 735, 822, 1023, 1242, 1462, 1621, 1715 cm^-1. MS-ESI: m/z = 434 [M+H]⁺, 456 [M+Na]⁺.

 

1-allyl-3,3-bis(3,4-dimethoxyphenyl)indolin-2-one (7):

Light red solid; Mp 130-132^oC;¹H NMR (300 MHz, CDCl₃): d 3.75 (s, 6H), 3.84 (s, 6H), 4.41-4.44 (m, 2H), 5.17-5.22 (m,2H), 5.84-5.93 (m, 1H), 6.73-6.78 (m, 4H), 6.84 (s, 2H), 6.91 (d, J = 7.62 Hz, 1H), 7.08 (t, J = 7.62 Hz, 1H), 7.23-7.30 (m,2H) ppm. ¹³CNMR (75 MHz, CDCl₃): d 42.3, 55.7, 61.5, 109.3, 110.5, 111.9, 117.2, 120.4, 122.6, 125.8, 128.0, 131.2, 133.2, 134.2, 141.9, 148.2, 148.7, 177.5 ppm. IR (KBr): ν = 721, 1004, 1142, 1258, 1331, 1521, 1607, 1708 cm^-1.MS-ESI: m/z = 446 [M+H]⁺.

 

3,3-bis(2,5-dimethoxyphenyl)-1-methylindolin-2-one (8):

White solid; Mp 186-188^oC;¹H NMR (300 MHz, CDCl₃): d 3.25 (s, 3H), 3.43 (s, 3H), 3.56 (s, 3H), 3.63 (s, 3H), 3.69 (s, 3H), 6.50 (d, J = 2.74 Hz, 1H), 6.72-6.77 (m, 2H), 6.78-6.83 (m, 4H), 6.93 (td, J = 0.91 Hz, J = 7.62 Hz, 1H), 7.20-7.26 (m, 2H) ppm. ¹³C NMR (75 MHz, CDCl₃): d 26.5, 55.5, 55.6, 56.3, 56.5, 59.7, 107.3, 112.2, 112.3, 113.3, 113.9, 115.7, 116.9, 121.9, 125.5, 127.6, 129.7, 133.4, 143.7, 151.6, 152.6, 153.2, 153.6, 177.6 ppm. IR (KBr): ν = 750, 829, 931, 1038, 1222, 1288, 1469, 1602, 1715 cm^-1. MS-ESI: m/z = 420 [M+H]⁺, 442 [M+Na]⁺.

 

1-benzyl-3, 3-bis(2,5-dimethoxyphenyl)indolin-2-one (9):

Light red solid; Mp 178-180^oC;¹H NMR (300 MHz, CDCl₃): d 3.38 (s, 3H), 3.45 (s, 3H), 3.63 (s, 3H), 3.66 (s, 3H), 4.90 (d, J = 15.71 Hz, 1H), 5.02 (d, J = 15.71 Hz, 1H), 6.50 (d, J = 2.89 Hz, 1H), 6.71-6.85 (m, 6H),  6.90 (t, J = 8.54 Hz, 1H), 7.10 (t, J = 7.78 Hz, 1H), 7.22-7.31 (m, 4H), 7.39 (d, J = 7.17 Hz, 2H) ppm.¹³CNMR (75 MHz, CDCl₃): d 44.0, 55.5, 55.6, 55.9, 56.2, 59.8, 108.3, 112.6, 113.2, 113.7, 115.4, 116.8, 122.0, 125.4, 127.3, 127.4, 127.7, 128.5, 129.3, 129.6, 133.7, 136.4, 142.7, 151.7, 152.4, 153.2, 153.6, 177.5 ppm. IR (KBr): ν = 751, 1012, 1139, 1253, 1347, 1516, 1608, 1697 cm^-1. MS-ESI: m/z = 496 [M+H]⁺.

 

3,3-bis(2,5-dimethoxyphenyl)-1-ethylindolin-2-one (10):

Light red solid; Mp 152-154^oC;¹H NMR (300 MHz, CDCl₃): d 1.30 (t, J = 7.32 Hz, 3H), 3.42 (s, 3H), 3.56 (s, 3H), 3.63 (s, 3H), 3.69 (s, 3H), 3.74-3.88 (m, 2H), 6.48 (d, J = 3.05 Hz, 1H), 6.73 (t, J = 2.74 Hz, 1H), 6.75 (t, J = 2.74 Hz, 1H), 7.78-7.83 (m, 4H), 6.92 (td, J = 1.06 Hz, J = 7.62 Hz, 1H) ppm.¹³CNMR (75 MHz, CDCl₃): d 12.4, 34.8, 55.5, 55.6, 55.9, 56.2, 59.7, 107.3, 112.2, 112.3, 113.0, 113.7, 115.7, 116.9, 121.7, 125.6, 127.4, 129.4, 129.7, 133.8, 142.6, 151.7, 152.5, 153.1, 153.5, 177.0 ppm.IR (KBr): ν = 733, 806, 1019, 1230, 1469, 1608, 1704 cm^-1. MS-ESI: m/z = 434 [M+H]⁺.

 

2.2. In vitro Cytotoxic Activity of Novel Isatin Derivatives:

Cell viability of the test compounds were determined on the basis of measurement of in vitro growth inhibition of cell lines by cell mediated reduction of tetrazolium salt to form water insoluble formazan crystals. The compounds were evaluated for cytotoxic activity against various cancer cell lines such as human breast cancer cells (MCF7) and human ovarian carcinoma cells (SKVO3) by using MTT assay²⁴. Briefly, the exponential growing cells were harvested and plated (1×10⁴) in 96-well microtiter plates and grown for a period of 24 h. The cells were treated with different concentrations of test compounds and incubated for 48 h. Later, the cells were incubated again for 2 h with 250 µg mL⁻¹of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). After incubation, the medium was replaced with 100 µL of DMSO and the absorbance was measured at 570 nm. The IC₅₀ values of the compounds were calculated from the dose-response curves. Doxorubicin was used as a positive control for both cancer and normal cell lines. Each experiment was performed in triplicates and the IC₅₀ values were expressed in mean ± SD.

 

3. RESULTS AD DISCUSSION:

Compounds were synthesised by reacting different substituted isatins with 1,2-dimethoxy benzenes, 1,3-dimethoxy benzenes and 1,4-dimethoxy benzenes using boron trifluoride diethyl etherate as catalyst. The completion of reaction was identified by TLC and all the compounds were purified by column chromatography and the synthesised compounds were confirmed by ¹H NMR, ¹³C NMR, IR and Mass spectroscopy. In the ¹H NMR spectra of newly synthesised compounds, the secondary amine peak was found at the range of 7.91-8.98 ppm. All the methoxy protons were found at the range of 3.26-3.85 ppm as a characteristic singlet signal. All the remaining aromatic and aliphatic proton peaks were observed at their expected regions. ¹³C NMR of the all the derivatives showed appropriate signals. Synthesised compounds were analysed by mass spectra under ESI, molecular ions were analysed in the form of M+1.

 

Formation of 3,3-disubstited oxindole motif is a Lewis acid catalysed nucleophlic addition elimination type of reaction (Figure 1). In this reaction, carbonyl oxygen present on 3^rd carbon of isatin molecule, donates an electron pair to Boron trifluoridediethyletherate which generates an electron deficiency on third carbon atom of isatin. Due to this the electron rich dimethoxy benzenes as a nucleophile attacks at that position of isatin, followed by regeneration and reattack of lewis acid at hydroxyl oxygen which again forms an electropositive centre on that carbon (3^rd position) which makes it possible for one more methoxy benzene to attack resulting in the formation of 3,3 di-substituted oxindole derivatives.

 

In vitro Cytotoxic Activity:

Novel 3,3-disubstituted oxindole derivatives were evaluated for cytotoxicity against human breast cancer cells (MCF7) and human ovarian carcinoma cell lines (SKVO3) using MTT assay, with doxorubicin as standard. Results (Table 1) revealed that both MCF7 and SKVO3 cell lines were susceptible to the evaluated compounds. Compounds 5 and 7 showed good activity with IC₅₀ Values 9.2, 8.0 μM respectively against MCF7 and 9.5, 10.4 μM respectively against SKVO3 cell lines, whereas, remaining all other compounds showed moderate activity against both cell lines.

 

Compound 5 having methyl at 1^st position on oxindole derivatives showed good activity Compound 7 having allyl group on position 1 of oxindole derivatives showed good activity than other groups it may be due to its resonance effect.

 

Table 1: In vitro Cytotoxic Activity of isatin Derivatives by MTT assay

Compound No.	R	IC50 values in (μM)
		MCF7	SKVO3
1	Me	13.9±0.56	16.1±0.42
2	Bn	15.4±0.27	14.1±0.20
3	Et	12.2±0.32	18.2±0.24
4	Allyl	12.4±0.41	18.3±0.33
5	Me	9.2±0.83	9.5±0.26
6	Et	11.9±0.27	17.8±0.29
7	Allyl	8.0±0.21	10.4±0.29
8	Me	14.7±0.29	19.1±0.34
9	Bn	12.2±0.31	11.1±0.24
10	Et	11.4±0.32	11.2±0.39
Doxorubicin		1.6±0.28	1.8±0.47

 

4. CONCLUSION:

In the current investigation, an efficient method was developed for synthesis of a series of novel 3,3-disubstituted oxindole derivatives using Boron trifluoride diethyl etherate as catalyst. This process is simple to operate, less time consuming with no work up and reaction conditions are mild. The newly developed   substituted oxindole derivatives resulted in considerable cytotoxic activity against both human breast cancer cell lines (MCF7) and human ovarian carcinoma cell lines (SKVO3). Of the developed set of molecules, compound 5 and 7 exhibited relatively higher cytotoxic activity against both MCF7 and SKVO3 cell lines.

5. ACKNOWLEDGEMENTS:

The authors would like to thank Dr. Sunil Misra (Senior Scientist, Biology Division, CSIR-IICT, and Hyderabad) for providing biological laboratory facilities to perform biological evaluation. We also thank Mrs. Swetha and Mr. Devender, (Discovery Labs, CSIR-IICT, Hyderabad), for providing facilities to perform chemical reactions. We would like to acknowledge Mr. Reddy G (ddlabs.in, Hyderabad), for writing assistance and editorial support.

 

6. DECLARATION OF INTEREST:

The authors report no conflicts of interest.

 

7. REFERENCES:

1.     Naresh Kumar R, et al. Synthesis of novel nicotinohydrazide and (1,3,4-oxadiazol-2-yl)-6-(trifluromethyl)pyridine derivatives as potential anticancer agents. Bioorganic Medicinal Chemistry Letters. 26; 2016: 4829-4831.

2.     Ibrahim HS et al. Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII. European Jounal of Medicinal Chemistry. 103; 2015: 583-593.

3.     Rohini R et al. Synthesis of mono, bis-2-(2-arylideneaminophenyl) indole azomethines as potential antimicrobial agents. Archives of Pharmcol  Research 34; 2011: 1077-1084.

4.     Verma M et al. Anticonvulsant activity of Schiff bases of isatin derivatives. Acta Pharmaceutica. 54; 2004: 49-56.

5.     Pandeya SN et al. Synthesis, antibacterial and antifungal activities of N-mannich bases of 3-[N2-pyrimethaminylimino] isatin. Indian Journal of Pharmaceutical Sciences. 64; 2002: 209-212.

6.     Selvam P et al. Synthesis and anti HIV activity of Novel Isatin-Sulphonamides. Indian Journal of Pharmaceutical Sciences. 70; 2008: 779-782.

7.     Sridhar SK and Ramesh A. Synthesis and pharmacological activities of hydrazones, Schiff and Mannich bases of isatin derivatives. Biological and Pharmaceutical Bulletin. 24; 2001: 1149-1152.

8.     Eldehna WM et al. Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents. European. Journal of Medicinal Chemistry. 90; 2015: 684-694.

9.     Sharma P et al. H₂O-mediated isatin spiroepoxide ring opening with NaCN: Synthesis of novel 3-tetrazolylmethyl-3-hydroxy-oxindole hybrids and their anticancer evaluation. European Journal of Medicinal Chemistry. 104; 2015: 11-24.

10.   Pervez H et al. Cytotoxic and Phytotoxic Effects of Some New N4-Aryl Substituted Isatin-3-thiosemicarbazones. Medicinal Chemistry. 2012, 8, 505-514.

11.   Hamdy AM et al. Regioselective synthesis Suziki-Miyaura reaction of 4,7-dichloro-N-methylisatin. Synthesis, anti-HIV activity and modelling studies. Rsc. Advances. 5; 2015: 107360-107369.

12.   Bandgar BP and Shaikh AK. Molecular iodine catalyzed efficient and highly rapid synthesis of bis(indolyl) methanes under mild conditions. Tetrahedron letters. 44; 2003: 1959-1961.

13.   Bandgar BP, Bettigeri SA and Joshi N S. Hexamethylenetetramine-Bromine Catalysed Rapid and Efficient synthesis of bis(indolyl) methanes. Monatshefte fur Chemie. 135; 2004: 1265-1273.

14.   Silveira CC et al. Glycerine and CeCl₃ 7H₂O:A new and efficient recyclable medium for the synthesis of  bis (indolyl) methanes. Tetrahedron letters. 50; 2009: 6060-6063.

15.   Xia M, Wang SB and Yuan WB. Lewis acid catalysed electrophillic substitution of indole with schiffs bases under microwave solvent free irradiation. Synthetic Communications. 34; 2004: 3175-3182.

16.   Babu G Sridhar N and Perumal PT. A convenient method of synthesis of bis(indolyl)methanes: Indium trichloride catalysed reaction of indoles with aldehydes and schiffs bases. Synthetic Communications. 30; 2000: 1609-1614.

17.   Bandgar BP and Shaikh KA.  Organic reactions in aqueous media: In F3 catalysed synthesis of bis(indolyl)methanes in water under mild conditions. Journal of Chemistry Research. Synopses. 34; 2004: 72-74.

18.   Reddy YT et al. Efficient synthesis of   Bis(indolyl)methanes catalysed byTiCl4. Indian Journal of Chemistry. 44B; 2005: 2393-2395.

19.   Kamal A and Qureshi AA. Synthesis of some substituted Di Indolyl methanes in aqueous medium at room temperature. Tetrahedron letters. 19; 1963: 513-520.

20.   Chen D, Yu L and Wang PG. Lewis acid catalysed reactions in protic media, Lanthanides-catalyzed reaction of indoles with aldehydes or ketones. Tetrahedron letters. 37; 1996: 4467-4470.

21.   Ji SJ et al. Efficient synthesis of Bis(indolyl)methanes catalysed by Lewis acids in ionic liquids. Synlett. 13; 2003: 2077-2079.

22.   ME XL et al. Simple and efficient method for synthesis of Bis(indolyl)methanes with Cu(BF4).SiO2 Under mild conditions. Tetrahedron letters. 45; 2004: 4567-4570.

23.   Yadav JS et al. Novel use of selectfluor^TM for th synthesis of cis- fused pyrano- and furano-tetrahydro quinoline. Advanced Synthesis and Catalysis.2003: 345-349.

24.   Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods. 65; 1983: 55-63.

 

 

 

 

Received on 25.10.2018         Modified on 18.11.2018

Accepted on 20.12.2018      © RJPT All right reserved