{"id":1168,"date":"2015-03-25T09:10:50","date_gmt":"2015-03-25T09:10:50","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=1168"},"modified":"2020-04-25T10:43:06","modified_gmt":"2020-04-25T10:43:06","slug":"synthesis-characterization-and-biological-activities-of-some-new-1-n-cinnamoyl-2-5-dichloroanilinomalonyl-3-5-dimethyl-4-unsubstitutedsubstituted-phenylazo-pyrazole-derivatives","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol3no1\/synthesis-characterization-and-biological-activities-of-some-new-1-n-cinnamoyl-2-5-dichloroanilinomalonyl-3-5-dimethyl-4-unsubstitutedsubstituted-phenylazo-pyrazole-derivatives\/","title":{"rendered":"Synthesis, characterization and Biological Activities of Some New 1-[(N-cinnamoyl) 2, 5-dichloroanilinomalonyl] 3, 5-dimethyl-4-(unsubstituted\/substituted phenylazo) pyrazole Derivatives"},"content":{"rendered":"

Introduction <\/strong><\/p>\n

Pyrazoles and their derivatives are important on account of use in therapy in different diseases1-12<\/sup> Antibacterial13-20<\/sup>, fungicidal21-27<\/sup>, antidiuretic28-30<\/sup>, anticancer31-37<\/sup> and anti-HIV38-42 <\/sup>\u00adantitumour43<\/sup>, antianalgesic-inflamatory44-48<\/sup>, anticonvulsant49, 50 <\/sup>properties of pyrazoles have been reported in the literature. Synthesis and interesting aspect of biological activity of arylazopyrazoles have been reported51-52<\/sup>. In view of potential biological activities of pyrazoles and arylazopyrazoles we report here in the synthesis of new 1-[(N-cinnamoyl) 2, 5-dichloro anilinomalonyl] 3, 5-dimethyl- 4 – (Unsubstituted\/substituted phenylazo) pyrazoles. The present communication deals with the reaction of acetyl acetone with diazotized aromatic primary amine in presence of sodium acetate which furnished 2,4-diketo-3- (Unsubstituted\/substituted phenylazo) pentane (I) which on treatment with ethyl-2-[(N-cinnamoyl)2, 5-dichloroanilido] acetohydrazide (II) in acetic acid medium resulted in the formation of 1-[(N-cinnamoyl) 2, 5-dichloroanilinomalonyl] 3, 5-dimethyl-4-(Unsubstituted\/substituted phenylazo) pyrazoles (5a-t) in varying yield 38-66% (Table-1). Antibacterial and antifungal activities of new arylazopyrazoles were determined.<\/p>\n

Experimental<\/strong><\/p>\n

All the chemicals were used for synthesis are of analytical reagent grade. Melting points are taken in open capillaries and are uncorrected. Purity of the compounds was checked by TLC. All the compounds gave satisfactory elemental analysis. IR Spectra were recorded on a Perkin-Elmer Spectrum RX1 FT IR Spectrophotometer using KBr pallatisation technique and NMR Spectra were recorded on Broker DRX-300 NMR Spectrophotometer. The NMR peaks were recorded on \u03b4 scale (ppm) against TMS. The solvent employed was DMSO (3.33-3.35 \u03b4).The elemental analysis of all the compounds done on elemental Vireo EL- III Carlo Erba 1108. 2, 4-Diketo-3- (Unsubstituted\/substituted phenylazo) pentane were synthesize by reported method53<\/sup>. Ethyl-2-[(N-cinnamoyl) 2, 5-dichloroanilido] acetohydrazide was prepared by an adaptation of the procedure given by Rathore and Ittyerah54<\/sup>.<\/p>\n

Synthesis of Ethyl-2-[2, 5-dichloroanilido] Ethanoate<\/strong><\/p>\n

A mixture of 2, 5-dichloroaniline (10ml) and diethylmalonate (20ml) was refluxed for forty five minutes in a round bottomed flask fitted with an air condenser of such a length (14″) that ethanol formed escaped and diethylmalonate flowed back into the flask. Contents were cooled, ethanol (30 ml) was added, when malon-2,5dichlorodianilide separated out. It was filtered under suction. The filtrate was poured on to crushed ice (Ca160g) and stirred when ethyl-2-(2, 5-dichloroanilido) ethanoate precipitated as green mass. On recrystallization from aqueous ethanol (50%), ester was obtained as white crystals. Yield;\u00a0 81%, M.P.880<\/sup>C, M.W.276. \u00a0Anal. Calculation for C11 <\/sub>H11<\/sub> N1 <\/sub>O3<\/sub> Cl2<\/sub> : Found ;\u00a0 C 39.20,\u00a0 N 4.14,\u00a0 Cl 21.5,\u00a0\u00a0\u00a0\u00a0 Calcd.\u00a0 C 39.21, Cl 21.6, \u00a0\u00a0N 04.15 \u00a0IR [KBr] Vmax<\/sub>\u00a0 cm-1<\/sup> :\u00a0 1665-1660 [ C=O diketone ], 1290\u00a0 [ -C-O- Ester],\u00a0 760-755 [ 2, 5- disubstituted benzene ], 1250\u00a0 [ C-Cl Stretching ], 1590, 1520 , 1440\u00a0 [C=C Ring stretching],\u00a0 3150 [N-H Stretching],\u00a0 3040[C-H aromatic],\u00a0 1330-1322[C-H Stretching ]. PMR (DMSO): \u03b4 4.42 (2H, s, CO-CH2<\/sub>-CO), 4.0 (2H, s, NH2<\/sub>), 7.4-8.6 (3H, m, Ar-H), 9.2 (1H, s, CO-NH D2<\/sub>O exchangeable), 10.6 [1 H, s, Ar-NH D2<\/sub>O exchangeable].<\/p>\n

Synthesis of Ethyl-2-[(N-<\/strong> cinnamoyl) 2, 5- dichloroanilido] ethanoate<\/strong><\/p>\n

Cinnamoyl chloride (10gm; 0.06mol), dioxane (6ml), Ethyl-2-(2,5-dichloroanilido) ethanoate (16.5 gm; 0.06 mol) and Triethylamine (6.06 gm; 0.06 mol) were placed in a round bottomed flask carrying reflux condensor having calcium chloride guard tube. The contents were heated on a boiling water bath for three hours and kept over night when triethylamine hydrochloride separated. It was filtered under suction and the filtrate was poured on to crushed ice (Ca180g) and stirred when Ethyl-2-[(N-cinnamoyl) 2, 5-dichloroanilido] ethanoate separated or solid. It was filtered under suction, dried and purified by recrystallisation from aqueous methanol (1:1) in white crystals.\u00a0 Yield = 74 %, MP = 97\u00b0C Anal. calculation for C20 <\/sub>H17<\/sub> N1<\/sub> O4<\/sub> Cl2<\/sub> : [FW = 406 ] , Calculated: N\u00a0 02.60 , C 43.7, H 03.10 , O 11.7 , Cl 12.9 , Found : N 02.64, C 43.6 , H 03.3 , O 11.5 , Cl 12.8. \u00a0IR [KBr] Vmax<\/sub>\u00a0 cm-1<\/sup> : 1740 [ C=O diketone ], 1310 [ -C-O- Ester],\u00a0 765[ 2, 5- disubstituted benzene ], 1095 [ C-Cl Stretching ], 1590, 1520 , 1440\u00a0 [C=C Ring stretching ],\u00a0 3170 [N-H Stretching], 3040[C-H aromatic], 1330-1320 [C-H Stretching].\u00a0 PMR (DMSO): \u03b4 4.5 [2H, s, CO-CH2<\/sub>-CO], 4.2 [2H, s, NH2<\/sub>], 7.2-8.5 [3H, m, Ar-H], 9.5 [1H, s, CO-NH D2<\/sub>O exchangeable], 10.7 [1H, s, Ar-NH D2<\/sub>O exchangeable].<\/p>\n

Synthesis of Ethyl-2-[(N-<\/strong> cinnamoyl) 2, 5-dichloroanilido] acetohydrazide<\/strong><\/p>\n

Ethyl-2-[(N- cinnamoyl) 2, 5-dichloroanilido] ethanoate (12.2 gm; 0.03 mol), ethanol (8 ml) and hydrazine hydrate (15 ml; 80%) were mixed together and stirred for forty five minutes. Ethyl-2-[(N-cinnamoyl) 2, 5-dichloroanilido] acetohydrazide was filtered under suction and recrystallised from ethanol in white crystals.\u00a0 Yield; 71%, MP = 184\u00b0C, MW 392\u00a0 \u00a0Anal. calculation for C18<\/sub> H15 <\/sub>N3<\/sub> O3<\/sub> Cl2<\/sub> : Calculated ; N 7.6 , C 39.1 , Cl 12.9, Found; N\u00a0 7.4, C\u00a0 38.9, Cl 12.7 .\u00a0 IR [KBr] Vmax<\/sub> cm-1<\/sup>: 3170 [N-H Stretching], 3055 [C-H aromatic], 1665 [C=O diketone], 1440 [C-Cl aromatic], 1590, 1530, 1440 [C=C ring stretching]. PMR (DMSO): \u03b4 4.4 (2H, s, CO-CH2<\/sub>-CO), 4.1 (2H, s, NH2<\/sub>), 7.3-8.6 (3H, m, Ar-H), 9.5 (1H, s, CO-NH D2<\/sub>O exchangeable), 10.8 (1H, s, Ar-NH D2<\/sub>O exchangeable).<\/p>\n

Synthesis of 2, 4- diketo-3-(phenylazo) pentane (R = H)<\/strong><\/p>\n

Aniline (9.3 ml, 0.1mol) was dissolved in aqueous hydrochloric acid (80 ml, 1:1). The contents were stirred, cooled (0-2\u02daC) and cold solution of sodium nitrite (12.0 g in 30 ml water) was slowly added maintaining the temperature between 0-2\u02daC.\u00a0 The cold diazotized solution was added drop wise with stirring to a well cooled mixture of acetyl acetone (0.1 mol, 10 ml) and sodium acetate (12 g dissolved in 10 ml of 50% aqueous ethanol). Stirring was further continued for forty five minutes, when yellow crystals separated. The product was filtered under suction, washed with water and recrystallised from aqueous ethanol.<\/p>\n

Analytical [%] for C11<\/sub>H12<\/sub>N2<\/sub>O2<\/sub>:\u00a0\u00a0 Found;\u00a0 C 38.17,\u00a0 H 03.47,\u00a0\u00a0 O\u00a0 9.25, N\u00a0 08.09,\u00a0\u00a0\u00a0\u00a0 Calcd.;\u00a0 C 38.16, H 03.46,\u00a0 O 9.23 ,\u00a0 N 8.00 ,\u00a0\u00a0 Yield;\u00a0 59 %,\u00a0 M.P.; 96\u02daC , [ MW 204], \u00a0Other 2, 4-diketo-3- (Unsubstituted\/substituted phenylazo) pentane were prepared by above mentioned procedure.<\/p>\n\n\n\n
\"Scheme<\/td>\n\n

Scheme 1<\/strong><\/p>\n

Click here to View scheme<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n\n
\"Scheme<\/td>\n\n

Scheme 2<\/strong><\/p>\n

Click here to View figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

Synthesis of 1-[(N-cinnamoyl) 2, 5-dichloroanilinomalonyl] 3, 5-dimethyl-4-phenylazo) pyrazoles<\/strong><\/p>\n

2, 4-diketo-3-(phenylazo) pentane (0.204g, 0.001 mol) and ethyl-2-[(N-cinnamoyl) 2, 5-dichloroanilido] acetohydrazide (0.392g, 0.001mol) were dissolved in glacial acetic acid (10ml) and the solution was refluxed for 14 hrs. The resulting solid was purified by repeated washing with acetic acid and recrystallized from acetic acid as yellow crystals. Yield; 57%,\u00a0\u00a0\u00a0\u00a0 M.P.; 262\u02daC Analysis (%) :\u00a0 Found; N\u00a0 7.1,\u00a0 Cl\u00a0 7.2\u00a0\u00a0\u00a0 C29<\/sub>H23<\/sub>N5<\/sub>O3<\/sub>Cl2<\/sub>\u00a0 [ FW 559] , Calculated; N 7.0, Cl 7.1\u00a0 IR (KBr) Vmax<\/sub> cm-1<\/sup>: 3270-3060 (N\u2014H Sec. amide hydrogen bond), 2980 \u00a0\u00a0(C\u2014H Stretching Aromatic), 1665 (C=N Pyrazole), 1560 (C=C Aromatic), 1060 (C\u2013Cl Aromatic). PMR (DMSO): \u03b4 2.4 (2H, s, CH2<\/sub>), 4.2 (1H, s, NH), 6.90-7.10 S (7H, s, Ar-H). Other 1-[(N-cinnamoyl) 2, 5-dichloroanilinomalonyl] 3, 5-dimethyl-4-((Unsubstituted\/substituted phenylazo) pyrazoles were prepared by above mentioned procedure.<\/p>\n

Table\u00a01<\/strong><\/p>\n

All compounds gave satisfactory elemental analysis.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
CS. No.<\/td>\nR<\/td>\nColor<\/td>\nM.P. (\u02daC)<\/td>\nYield (%)<\/td>\nMolecular Formula<\/td>\n<\/td>\n<\/tr>\n
5a.<\/td>\nH<\/td>\nYellow<\/td>\n262<\/td>\n57<\/td>\nC29<\/sub>H23<\/sub>N5<\/sub>O3<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5b.<\/td>\nCH3<\/sub>(o)<\/td>\nLight Yellow<\/td>\n245<\/td>\n62<\/td>\nC30<\/sub>H25<\/sub>N5<\/sub>O3<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5c.<\/td>\nCH3<\/sub>(m)<\/td>\nYellow<\/td>\n239<\/td>\n57<\/td>\nC30<\/sub>H25<\/sub>N5<\/sub>O3<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5d.<\/td>\nCH3<\/sub>(p)<\/td>\nLight Yellow<\/td>\n237<\/td>\n49<\/td>\nC30<\/sub>H25<\/sub>N5<\/sub>O3<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5e.<\/td>\nCl(o)<\/td>\nYellow<\/td>\n268<\/td>\n\u00a047<\/td>\nC29<\/sub>H23<\/sub>N5<\/sub>O3<\/sub>Cl3<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5f.<\/td>\nCl(m)<\/td>\nYellow<\/td>\n264<\/td>\n\u00a051<\/td>\nC29<\/sub>H23<\/sub>N5<\/sub>O3<\/sub>Cl3<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5g.<\/td>\nCl(p)<\/td>\nLight Yellow<\/td>\n270<\/td>\n\u00a053<\/td>\nC29<\/sub>H23<\/sub>N5<\/sub>O3<\/sub>Cl3<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5h.<\/td>\nO-CH3<\/sub>(o)<\/td>\nLight Yellow<\/td>\n265<\/td>\n\u00a058<\/td>\nC30<\/sub>H25<\/sub>N5<\/sub>O4<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5i.<\/td>\nO-CH3<\/sub>(m)<\/td>\nYellow<\/td>\n259<\/td>\n\u00a052<\/td>\nC30<\/sub>H25<\/sub>N5<\/sub>O4<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5j.<\/td>\nO-CH3<\/sub>(p)<\/td>\nLight Yellow<\/td>\n267<\/td>\n\u00a054<\/td>\nC30<\/sub>H25<\/sub>N5<\/sub>O4<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5k.<\/td>\n\u00a0F(p)<\/td>\nYellow<\/td>\n254<\/td>\n\u00a042<\/td>\nC29<\/sub>H23<\/sub>N5<\/sub>O3<\/sub>Cl2<\/sub>F1<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5l.<\/td>\n\u00a0Br(o)<\/td>\n\u00a0Dark brown<\/td>\n251<\/td>\n\u00a056<\/td>\nC29<\/sub>H23<\/sub>N5<\/sub>O3<\/sub>Cl2<\/sub>Br<\/em><\/td>\n<\/td>\n<\/tr>\n
5m.<\/td>\nO-C2<\/sub>H5<\/sub> (o)<\/td>\n\u00a0Brown<\/td>\n268<\/td>\n48<\/td>\nC31<\/sub>H27<\/sub>N5<\/sub>O4<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5n.<\/td>\nO-C2<\/sub>H5<\/sub> (m)<\/td>\nBrown<\/td>\n259<\/td>\n44<\/td>\nC31<\/sub>H27<\/sub>N5<\/sub>O4<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5o.<\/td>\nO-C2<\/sub>H5<\/sub> (p)<\/td>\nBrown<\/td>\n256<\/td>\n38<\/td>\nC31<\/sub>H27<\/sub>N5<\/sub>O4<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5p.<\/td>\nCO2<\/sub>H (o)<\/td>\nBrown<\/td>\n254<\/td>\n41<\/td>\nC30<\/sub>H23<\/sub>N5<\/sub>O5<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5q.<\/td>\nCO2<\/sub>H (m)<\/td>\nBrown<\/td>\n259<\/td>\n45<\/td>\nC30<\/sub>H23<\/sub>N5<\/sub>O5<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5r.<\/td>\nCO2<\/sub>H (p)<\/td>\nL. brown<\/td>\n261<\/td>\n42<\/td>\nC30<\/sub>H23<\/sub>N5<\/sub>O5<\/sub>Cl2<\/sub><\/em><\/td>\n<\/td>\n<\/tr>\n
5s.<\/td>\nBr(m)<\/td>\nBrown<\/td>\n249<\/td>\n51<\/td>\nC29<\/sub>H23<\/sub>N5<\/sub>O3<\/sub>Cl2<\/sub>Br<\/em><\/td>\n<\/td>\n<\/tr>\n
5t.<\/td>\nBr(p)<\/td>\nBrown<\/td>\n245<\/td>\n53<\/td>\nC29<\/sub>H23<\/sub>N5<\/sub>O3<\/sub>Cl2<\/sub>Br<\/em><\/td>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

Biological \u00a0Activities <\/strong><\/p>\n

Anti-bacterial activity \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0<\/strong><\/p>\n

Newly synthesized compounds (5a-t) have been tested for their anti-bacterial activity against gram-positive bacteria S.albus, S.aureus and gram negative bacteria E.Coli and Pseudomonas piosineus by agar plate disc diffusion method at 30 \u03bcg\/mL concentrations. Ampicillin and tetracycline were used as a reference compounds. The compound 5a, 5c, 5d, 5e, 5g and 5h shown significant activity and compound 5b, 5f, 5i ,5j, 5k, 5n, and 5p have shown moderate activity.<\/p>\n

Anti-fungal activity<\/strong><\/p>\n

The same compounds were tested for their anti-fungal activity against Candida albicans, Aspergillus Niger and Alternaria alternata at concentration of 30 mg\/ml using sabouraud dextrose agar media. Compounds 5a, 5c, 5d, 5g, 5j, 5m and 5p were found to be moderately active against Candida albicans and Aspergillus Niger. All the other compounds did not show significant activity against the fungi at the concentration used.<\/p>\n

Results and Discussion <\/strong><\/p>\n

1-[(N-cinnamoyl) 2, 5-dichloroanilinomalonyl] 3, 5-dimethyl-4-(Unsubstituted\/substituted phenylazo) pyrazoles have been synthesized by the reaction of 2, 4-diketo-3- (Unsubstituted\/substituted phenylazo) pentane with Ethyl-2-[(N-cinnamoyl) 2, 5-dichloroanilido] acetohydrazide in 38 to 66% yield, Pyrazoles are brown and yellow color solids, having high melting points. The structure of all the compounds are confirmed by\u00a0 IR, PMR, and Mass spectral data and are further supported by correct elemental analysis (Experimental part). All the newly synthesized compounds (5a-t) have been screened for their antibacterial activity against gram positive bacteria S.albus, S.aureus and gram negative bacteria E.Coli and Pseudomonas piosineus .The compound 5a, 5c, 5d, 5e, 5g and 5h shown significant activity and compound 5b, 5f, 5i, 5j, 5k, 5n, and 5p have shown moderate activity. The same compounds were screened for their antifungal activity against Candida albicans, Aspergillus Niger and Alternaria alternata at concentration of 30 mg\/ml using sabouraud dextrose agar media. Compounds 5a, 5c, 5d and 5g were found to be moderately active against Candida albicans and Aspergillus Niger. All the other compounds did not show significant activity against the fungi at the concentration used.<\/p>\n

Conclusion<\/strong><\/p>\n

Newly synthesized compounds (5a-t) have been tested for their anti-bacterial activity against gram positive bacteria S.albus, S.aureus and gram negative bacteria E.Coli and Pseudomonas piosineus by agar plate disc diffusion method at 30 \u03bcg\/mL concentrations. Ampicillin and tetracycline were used as a reference compounds. The compound 5a, 5c, 5d, 5e, 5g and 5h shown significant activity and compound 5b, 5f, 5i, 5j, 5k, 5n and 5p have shown moderate activity. The same compounds were tested for their anti-fungal activity against Candida albicans, Aspergillus Niger and Alternaria alternata at concentration of 30 mg\/ml using sabouraud dextrose agar media. Compounds 5a, 5c, 5d and 5g were found to be moderately active against Candida albicans and Aspergillus Niger. All the other compounds did not show significant activity against the fungi at the concentration used.<\/p>\n

Acknowledgement <\/strong><\/p>\n

The authors are thankful to principal SMS Government Model Science College, Gwalior for providing research facilities. We are also grateful to Director, C.D.R.I. Lucknow for elemental analysis, and Director, D.R.D.E. Gwalior for spectral studies and Director, Cancer Hospital and Research Institute, Gwalior for Biological activities.<\/p>\n

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