Synthesis and Anticancer Activity of Some New Derivatives of Coumarin and Quinolinyl Mercaptotriazoles

Journal of Chemistry, Jun 2019

Pechmann condensation of ethylacetoacetate with derivatives of phenol by heating in absence of solvent and with montmorillonite clays K-10 afforded coumarin derivatives (1a-e) in good yields which on reaction with thiosemicarbazide in anhydrous pyridine yielded coumarin-quinolinyl mercaptotriazole (2a-e). The latter compounds were evaluated for their antimicrobial and anticancer activities. The newly synthesized compounds were characterized by IR, 1HNMR and mass spectra.

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Synthesis and Anticancer Activity of Some New Derivatives of Coumarin and Quinolinyl Mercaptotriazoles

CODEN ECJHAO E-Journal of Chemistry 2012 0973-4945 Synthesis and Anticancer Activity of Some New Derivatives of Coumarin and Quinolinyl Mercaptotriazoles MONA A. HOSNY 0 HYAM A. RADWAN 0 EMTITHAL A. EL-SAWI 0 0 Department of Chemistry, Faculty of Women for Arts Science and Education, Ain Shams University , Cairo , Egypt Pechmann condensation of ethylacetoacetate with derivatives of phenol by heating in absence of solvent and with montmorillonite clays K-10 afforded coumarin derivatives (1a-e) in good yields which on reaction with thiosemicarbazide in anhydrous pyridine yielded coumarin-quinolinyl mercaptotriazole (2a-e). The latter compounds were evaluated for their antimicrobial and anticancer activities. The newly synthesized compounds were characterized by IR, 1HNMR and mass spectra. Coumarin; Mercaptotriazole; Thiol Introduction In the past decades, the problem of multidrug resistant microorganisms has reached on alarming level around the world, and the synthesis of new anti-infective compounds has become an urgent need for the treatment of microbial infections. The 1, 2, 4-triazole nucleus has been incorporated into a wide variety of therapeutically important agents1, mainly displaying anti-microbial2-5 anti inflammatory activities6-9. On the other hand a new class of mercapto 1, 2, 4-triazole were submitted10 and were indicated powerful pharmacological activities.11 In view of these findings, and in continuation to our interest in the synthesis and biological activities 1, 2, 4 triazole12. There have been many synthetic routes to the and Witting18,19 reactions. The present investigation describes the synthesis as potential antimicrobial agents of new series of mercapto 1, 2, 4-triazole were certain coumarin and quinolinyl mercaptotriazoles derivatives are remarkably effective compounds both with respect to their bioactivity of certain pharmacological activities regulating effect as well as anticancer activity. Montmorillonite clays have been used as efficient catalysts for a variety of organic reactions20. They are inexpensive non toxic powders which can be filtered easily from reaction mixtures and may be reused. In connection with our work on montmorillonite clays catalyses21,22. We describe an environmentally friendly procedure for the synthesis of coumarins via Pechman reaction catalysed by montmorillonite K-10. Experimental Melting points were taken on Gallen kamp melting point apparatus and were uncorrected. Thin layer chromatography was performed with fluorescent silica gel plates HF254 (Merck), and plates were viewed under UV254 and 265 light. Infrared spectra (?-cm-1) were recorded on Bruker vector Germany and on Mattson FT-IR 1000, using KBr disks, mass spectra are measured on GCQ Finnigan MAT and 1H-NMR spectra were recorded on Gemini-200 MHZ NMR spectrometer in DMSO-d6 spectra were internally referenced to TMS. Peaks are reported in ppm. Downfield of TMS. The antibacterial activity was determined in microanalytical center Cairo University and anticancer activity was done in National Cancer Institute, Cancer Biology Department, Pharmacology, Cairo University. Different phenols, ethyl aceto acetate and thiosemicarbazide were obtained from Fluka or Aldrich. Syntheses General Procedure for Compound (1a-e) A mixture of phenolic compound 1 (5 mmol) and ethylaceto acetate (5 mmol) and montmorillonite K-10 (30 wt % to 1 and ethylacetoacetate) was heated at 150 oC for those reactions in the absence of solvent with constant stirring for 12 hours. The montmorillonite was filtered off and washed with hot ethanol. The solvent was removed under reduced pressure to afford the new product. The crude product was purified and crystallized from ethanol to give the pure related coumarin (1a-e) as in (scheme 1). General Procedure for Compounds (2a-e) Compound 2a or 2b or ?.. ? 2e (0.2 mol) and thiosemicarbazide (0.2 mol) in anhydrous pyridine (50 mL) was tested under reflux for 2 h. Subsequently, the reaction mixture was poured into crushed ice containing concentrated hydrochloric acid (10 mL). A dark brown solid separated out and was left for 1 h, then filtered, washed, dried and crystallized from methanol to give the pure related quinolinyl mercaptotriazoles ( 2a-e), as in (Scheme 1). a = Where R = a-e COOH OH NH2 c = HO N O O 1b HN S N HS N N N N N N N OH OH R b = CH3 HO CH3 HO CH3 2b 2c OH O + CO2Et COOH O O NH2 CH3 1a O N Scheme 1. Synthesis of coumarin from phenolic compounds with ethylaceto acetate catalyzed by CH3 COOH O O + K - 10 In absence of solvent 1c + S NH2NHCNH2 H3C N N H N S d = e = O 1d COOH N HN 2d COOH OH O OH N H3C O O 1e N N S H3C N 2e N NH S N montmorillonite. Characterization data of coumarine derivatives (1a-e) and coumarin-quinolinyl mercaptotriazole (2a-e) Compound 1a: Deep brown solid, (yield: 70%), mp 151-153oC. IR (KBr) (cm-1): ?:, 34853200(NH2), 3134 (OH-carboxylic acid), 3049 (ArC-H),1710, 1685(C=O); MS (m/z%): 219 (9.53%), 175 (100%); 1H-NMR, (DMSO-d6) ?: 11.4 (1H, COOH), 6.4-7.41 (2H, Ar), 5.9 (1H, =CH-C=O), 3.8 (2H, NH2), 2.17 (3H, CH3). Compound 1b: Brown solid, (yield: 83%), mp 55-56 oC. IR (KBr) (cm-1): ?: 3061 (Ar-CH Str), 2858 (aliphaticCHstr.), 1685 (C=O), 1544 (C=N), 1382 (C-H bend.); MS (m/z %): 123 (68.63%), 95 (100%); 1H-NMR, (DMSO-d6) ?: 8.4- 7.7 (3H, Ar), 6.19 (1H, =CH-C=O), 2.1 (3H, CH3). Compound 1c: Pale Bage solid, (yield 86%), mp 275oC. IR (KBr) (cm-1): ?:3390 (OH), 2925 (aliphaticCHstr.), 1733 (C=O), 1609 (C=C), 1474 (C-H bend); MS (m/z %): 252 (0.4%), 186 (100%); 1H ? NMR (DMSO-d6 ?:8.39- 6.79 (7H, Ar), 5.60 (C-OH, Ar)6.1(1H,=CH-C=O), 1.29 (3H, CH3). Compound 1d: Brown solid, (yield: 79%), mp 183-185oC. IR (KBr) (cm-1): ?: 3288 (OHcarboxylic acid), 1713 (C=O), 1601 (Ar C=C); MS (m/z %): 190 (0.09%), 121 (100%); 1HNMR (DMSO-d6) ?: 10 (1H, COOH), 7.86 -6.9 (5H, Ar), (1H,=CH-C=O) Compound 1e: Brown solid (yield: 85%), mp 65-67oC. IR (KBr) (cm-1): ?: 3047(ArCH), 3020,2975-2850 (aliphaticCHst.), 1730 (C=O), 1592 (C=N), 1600 (Ar C=C), 1433(C-H bend); MS (m/z%): 211 (25%), 186 (100%); 1H-NMR (DMSO-d6) ?: 8.84 - 7.53 (5H, Ar), 6.2 (1H,=CH-C=O), 2.06 (3H, CH3). Compound 2a: deep brown solid (yield: 90%), mp 220oC IR (KBr) (cm-1): ?:3500-3195 (NH2), 2985-2879 (aliphaticCHstr.), 1690 (C=O), 1601 (ArC=C), 1578 (C=N), 1463(C-H bend); 1229 (C=S), MS (m/z %): 258 (M+2, 5.25 %), 175 (100%); 1H-NMR (DMSO-d6) ?: 7.45- 6.16 (2H, Ar), 5.92 (1H, -CH-C=N), 4.12 (2H, NH2), 2.1 (3H, CH3). Compound 2b: Yellow solid (yield: 90%) mp above 300. IR (KBr) (cm-1): ?: 3396 (NH), 2985-2850 (aliphaticCHstr.), 1624 (C=N), 1475(C-H bend),1190 (C=S), ,; MS (m/z%): 57 (100%), 1H-NMR (DMSO-d6) ?: 1.24 (1H, -CH=C-), 7.31, 8.22 - 7.95 (3H, Ar), 3.20 (1H, SH), 1.2 (3H, CH3). Compound 2c: Yellow solid (yield: 85%) mp 280oC, IK (KBr) (cm-1): ?: 3370 (OH), 3032 (ArCH), 2985-2879(aliphaticCHstr.),2570(SH), 1594 (C=N), 1453(C-H bend).1240 (C=S); MS (m/z %): 186 (100%), 1H-NMR (DMSO-d6) ?: 7.44 - 6.82 (8H, Ar), 3.1 (3H, CH3), 2.6 (1H, SH). Compound 2d: Brown solid (yield: 82%) mp 260oC, IR (KBr) (cm-1): ?: 3184 (OH- acid), 1725 (C=O), 1595 (C=N),1215 (C=S), MS (m/z %): 245 (0.57%), 121 (100%), 1H-NMR (DMSO-d6) ?: 12.66 (1H, COOH), 7.58 -7.05 (4H, Ar),6.9(1H,ArCH=, 5.3(1H,CHC=N),2.7 (1H,NH). Compound 2e: Brown solid (yield: 85%) mp 298oC, IR (KBr) (cm-1): ?: 3280 (NH), 2985-2850 (aliphaticCHstr.), 1600 (Ar C=C), 1594 (C=N), 1470 (C-H bend),1294 (C=S), MS (m/z %): 267 (M+1, 10%), 64 (100%), 1H-NMR (DMSO-d6) ?: 9.02( ),8.4-7.01 (Ar protons),5.1(1H,=CH-(C=N)N) 2.06(1,H,NH),1.9 (3H, CH3). N H Biological Activity Standard discs of Tetracycline (Antibacterial agent), amphotericin B (Antifungal agent) served as positive controls for antimicrobial activity but filter discs impregnated with 10 ?L of solvent (distilled water, chloroform, DMSO) were used as a negative control. The agar used is Meuller-Hinton agar that is rigorously tested for composition and pH. Further the depth of the agar in the plate is a factor to be considered in the disc diffusion method. This method is well documented and standard zones of inhibition have been determined for susceptible and resistant values. Blank paper disks (Schleicher and Schuell, Spain) with a diameter of 8.0 mm were impregnated 10 ? of tested concentration of the stock solutions. When a filter paper disc impregnated with a tested chemical is placed on agar the chemical will diffuse from the disc into the agar. This diffusion will place the chemical in the agar only around the disc. The solubility of the chemical and its molecular size will determine the size of the area of chemical infiltration around the disc. If an organism is placed on the agar it will not grow in the area around the disc if it is susceptible to the chemical. This area of no growth around the disc is known as a "Zone of inhibition" or "clear zone". Af: Aspergillus flavus, Ca-Candida albicans, Ec ? Escherichia coli, Sa ? Staphylococcus aureus , US: Unsporulated area. Compound No. Tetracycline antibacterial agent d ra Amphotericin d n antifungal agent a t S B 1a 1b 1c 1d 1e 2a 2b 2c 2d 2e ? 18 13 14 11 13 48 (US) ? 20 18 33 12 13 13 13 33 ? 10 9 12 52 14 13 15 14 17 32 ? 10 12 12 60 14 13 16 15 19 Antitumour Screening Chemotherapy is a major therapeutic approach for the treatment of both localized and metastasized cancers. In the present work selected compounds related to coumarin derivatives and comarin quinolinyl mercaptotriazoles were evaluated as inhibitors of the growth of breast cancer cell line in comparison to the known anticancer drug: doxorubicin as a trial to get more effective and les toxic agent. 10 20 Concentrati3o0n ?g/mL 40 50 60 MCF7-DOX MCF7-2a MCF7-DOX MCF7-2b MCF7-2c MCF7-2d MCF7-2e 1.1 1 0.9 Figure ( 1 ): Drug cytotoxicity of product 2a, 2b, 2c, 2d and 2e compared to doxorubicin. Preliminary experiments were done using the human tumor cell line to identify the potential toxicity of five selected newly synthesized compounds (2a-e) (Figure 1) in comparison to the known anticancer drug doxorubicin by SRB using the method Skehan et al.23. ? ? ? ? ? ? ? Cells were plated in 96-multiwell plate (104 cells/well) for 24 hours before treatment with compounds to allow attachment of cell to the wall of the plate. Different concentration of the compound under test (0, 1, 2.5, 5 and 10 ?g/mL) were added to the cell monolayer triplicate wells prepared for each individual does. Monolayer cells were incubated with the compounds for 48 hours at 37 oC and atmosphere of 5% CO2. After 48hours, cells were fixed, washed and stained with Sulfo-Rhodamine-? stain. Excess stain was washed with acetic acid and attached stain was recovered with Tris EDTA buffer. Color intensity was measured in an ELISA reader. The relation between surviving fraction and drug concentration is plotted to get the survival curve of each tumour cell line after the specified compound. Results and Discussion Condensation of ethylacetoacetate with different phenols in absent of solvent and in present of montmorillonite clays which have been used as efficient catalysts for a variety of organic reactions20 derivatives of coumarin which have been considered an environmentally friendly procedure via pechmann reaction. In the presence of montmorillonite clays21, several phenols and ethyl acetoacetate were heated in the absence of solvent to give the corresponding coumarins in good yields (1a-e) which on reaction with thiosemicrbazide in anhydrous pyridine yielded quinolinyl mercapto triazole derivatives (2a-e). The synthetic pathway is given in Scheme 1. From the experimental results, it can be proved that phenols having electron donating substituents in the position meta to the phenol hydroxyl group promote the condensation. The +E effects of these substituents support formation of the reactive polarized carbonation in the ortho position. An alkyl group is not strong enough to furnish the activation needed and thus gives a low yield (1a) in contrast, electron-withdrawing groups inhibit the reaction. The following table showing the same effect but with different IC50 for standard Doxourubicin: Compound Doxorubicin 2b 2c 2d 2e Conclusion In this work, it was of interest to synthesize new series of some novel coumarin quinolinyl mercapto triazole. First, the synthesis of coumarin derivatives (1a-e) were dependent at the use of environmentally friendly procedure by montmorillonite clay which have been used as efficient catalysts and are inexpensive non toxic powders. Second the series compounds of quinolinyl mercaptotriazole (2a-e) were found exhibiting a highly biological and antitumor effect. The antitumor activity results indicated that all the second five derivatives (2a-e) showed antitumor activity against the tested breast cancer cell line but with varying intensities in comparison to the known anticancer drug: doxorubicin. Moreover compound 2e showed the highest cytotoxic activity (IC50 equal 3.43 ?/mL) which was more effective than Doxorubicin (IC50 equal 3.13 ?/mL). 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 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Mona A. Hosny, Hyam A. Radwan, Emtithal A. El-Sawi. Synthesis and Anticancer Activity of Some New Derivatives of Coumarin and Quinolinyl Mercaptotriazoles, Journal of Chemistry, DOI: 10.1155/2012/365647