{"id":1719,"date":"2015-03-28T08:20:11","date_gmt":"2015-03-28T08:20:11","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=1719"},"modified":"2020-04-26T07:15:57","modified_gmt":"2020-04-26T07:15:57","slug":"synthesis-of-bis-amide-and-hydrazide-containing-derivatives-of-malonic-acid-and-thiophenoladducts-of-acidhydrazones-derived-from-2-n-acetyl-2-5-dichloroanilido-acetohydrazide","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol4no1\/synthesis-of-bis-amide-and-hydrazide-containing-derivatives-of-malonic-acid-and-thiophenoladducts-of-acidhydrazones-derived-from-2-n-acetyl-2-5-dichloroanilido-acetohydrazide\/","title":{"rendered":"Synthesis of Bis-Amide and Hydrazide Containing Derivatives of Malonic Acid and Thiophenoladducts of Acidhydrazones Derived from 2-[(N-acetyl) 2, 5-dichloroanilido] Acetohydrazide"},"content":{"rendered":"

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

Acidhydrazides and their condensation products possessing an azometine -NHN=CH- Proton constitute an important class of compounds for new drug development. In the past several years, numerous compounds with diverse structural features have been reported.\u00a0 Therefore, many researchers have synthesized these compounds as target structures and evaluated their biological activities.\u00a0 Hydrazides, hydrazones and their adducts\u00a0 have displayed diverse range of biological properties such as potential biological activities [1-6],\u00a0 anti-viral [7-8],\u00a0 anti-tuberculosis [9-10], anti-tumor [11-18], anti-fungal [19-20],\u00a0 anti-convulsant [21], anti-helmintic [22], anti-malarial [23], anti- Inflammatory [24], anti-cancer[25-26], anti-proliferative [27-29], anti-oxidant [30], agricultural agents [31]. Therapeutic protocols for the treatment of HIV infection are mainly based on the combined use of reverse transcriptase, protease, and more recently, of cell fusion and entry inhibitors. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, the rapid emergence of resistant variants, often cross-resistant to the members of a given class, limits the efficacy of existing antiretroviral drugs. Therefore, it is critical to develop new agents directed against alternate sites in the viral life cycle. Moreover, many selectively chloro-substituted organic compounds show peculiar pharmacological and agrochemical properties. The work reported herein was aimed at the preparation of some new thiophenoladducts of acidhydrazones with anticipated biological activities.<\/p>\n

Materials and methods<\/strong><\/p>\n

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

Anhydrous solvents and all reagents were purchased from, Sigma-Aldrich, B.D.H., Excel-R, Extra pure E. Merk quality, Acros or Carlo Erba. Reactions involving air- or moisture-sensitive compounds were performed under a nitrogen atmosphere using oven-dried glassware and syringes to transfer solutions. Melting points (m.p.) were determined using an electrothermal melting point or a K\u00f6fler apparatus and are uncorrected. Infrared (IR) spectra were recorded as thin films or nujol mulls on KBr plates with a Perkin-Elmer-781 IR or 983 -Spectrophotometer and are expressed in \u03bd (cm-1<\/sup>). Nuclear magnetic resonance spectra (1<\/sup>H-NMR) was determined in DMSO and recorded on a Varian XL-200 (200 MHz) or a Varian VXR-300 (300 MHz). Chemical shifts (\u03b4 scale) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS) used as internal standard. Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; brs, broad singlet; dd, double doublet. The assignment of exchangeable protons (-OH <\/em>and -NH<\/em>) was confirmed by addition of D2<\/sub>O. Analytical thin-layer chromatography (TLC) was carried out on Merck silica gel, F-254 plates. For flash chromatography Merck Silica gel-60 was used as stationary phase with a particle size 0.040-0.063 mm (230-400 mesh ASTM). Elemental analyses were performed on a Perkin-Elmer-2400 spectrometer, and were within \u00b10.5% of the theoretical values.<\/p>\n

Synthesis of <\/strong>Ethyl-2-(2, 5-dichloroanilido) ethanoate [1]<\/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, 5-dichlorodianilide 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.\u00a0\u00a0 Yield: 83%, M. P.: 900<\/sup>C, M. W.: 276. Anal. Calculation for C11 <\/sub>H11<\/sub> N1 <\/sub>O3<\/sub> Cl2<\/sub><\/em><\/strong>: Found: C 47.7, H: 4.0, O: 17.2, N: 5.1, Cl: 25.4,\u00a0\u00a0 Calcd.\u00a0 C: 47.8, H: 4.0, O: 17.4, N: 5.1, Cl: 25.7.\u00a0 IR [KBr] Vmax<\/sub>\u00a0 Cm-1<\/sup><\/em> :\u00a0 1665-1660 [C=O diketone], 1290\u00a0 [-O- Ester],\u00a0 760-755 [2,5-disubstituted benzene], 1090\u00a0 [C-Cl Stretching], 1590, 1520 , 1440\u00a0 [C=C ring stretching],\u00a0 3150 [N-H Stretching],\u00a0 3040[C-H aromatic],\u00a0 1330-1320 [C-H Stretching].\u00a0 PMR (DMSO):<\/em> \u03b4 4.45 (2H, s, CO-CH2<\/sub>-CO), 4.0 (2H, s, NH2<\/sub>), 7.4-8.7 (3H, m, Ar-H), 9.4 (1H, s, CO-NH D2<\/sub>O exchangeable), 10.4 [1H, s, Ar-NH D2<\/sub>O exchangeable].<\/p>\n

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

Acetyl chloride (4.74 gm; 0.06 mol), dioxane (6 ml), Ethyl-2-(2, 5-dichloroanilido) ethanoate (16.56 gm; 0.06 mol) and\u00a0 triethylamine (5.7 gm; 0.06 mol) were placed in a round bottomed flask carrying reflux condenser having calcium chloride guard tube. The contents were heated on a boiling water bath for two hours and kept over night when triethylamine hydrochloride separated. It was filtered under suction and the filtrate was poured on to crushed ice (Ca180 g) and stirred when ethyl-2-[(N-acetyl) 2, 5-dichloroanilido] ethanoate separated or solid. It was filtered under suction, dried and purified by recrystallization from aqueous methanol (1:1) in white crystals.\u00a0 Yield = 77 %, MP = 96\u00b0C\u00a0 Analytical calculation for C13 <\/sub>H13<\/sub> O4<\/sub> N1<\/sub> Cl2<\/sub><\/em><\/strong> : [FW = 318 ] , Calculated: N\u00a0 02.95 , C 45.64, H 03.38 , O 13.50 , Cl 15.00 , Found : N 02.94, C 45.62 , H 03.37 , O 13.52 , Cl 15.02.\u00a0 IR [KBr] Vmax<\/sub>\u00a0 cm-1<\/sup> : 1720 [ C=O diketone ], 1310 [ -C-O- Ester],\u00a0 765 [ 2,5- disubstituted benzene ], 1095 [ C-Cl Stretching ], 1590, 1525 , 1440\u00a0 [C=C Ring stretching ],\u00a0 3160 [N-H Stretching], 3040[C-H aromatic], 1330-1325 [C-H Stretching ].\u00a0 PMR (DMSO): \u03b4 4.42 [2H, s, CO-CH2<\/sub>-CO], 4.1 [2H, s, NH2<\/sub>], 7.2-8.5 [3H, m, Ar-H], 9.5 [1H, s, CO-NH D2<\/sub>O exchangeable], 10.8 [1H, s, Ar-NH D2<\/sub>O exchangeable].\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\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<\/em><\/strong><\/p>\n

Synthesis of 2-[(N-acetyl) 2, 5- dichloroanilido] acetohydrazide [3]<\/strong><\/p>\n

Ethyl-2-[(N-acetyl) 2, 5-dichloroanilido] ethanoate (9.54 gm; 0.03 mol), ethanol (10 ml) and hydrazine hydrate (15 ml; 80%) were mixed together and stirred for thirty five minutes.\u00a0\u00a0\u00a0\u00a0\u00a0 2-[(N-acetyl) 2, 5-dichloroanilido] acetohydrazide was filtered under suction and recrystallised from ethanol in white crystals.\u00a0 Yield; 74%, MP = 178\u00b0C, MW 304:\u00a0 Analytical calculation for C11<\/sub> H11 <\/sub>N3<\/sub> O3<\/sub> Cl2<\/sub><\/em> : Calculated ; N 09.04 ,C 41.32 ,H 03.01 ,O 10.33, Cl 15.28, Found; N\u00a0 09.01, C\u00a0 41.30, H\u00a0 03.00, O 10.31, Cl 15.27 . IR [KBr] Vmax<\/sub> cm-1<\/sup>: 3165 [N-H Stretching], 3050 [C-H aromatic], 1670 [C=O diketone], 1430 [C-Cl aromatic], 1595, 1520, 1445 [C=C ring stretching].\u00a0 PMR (DMSO): \u03b4 4.44 (2H, s, CO-CH2<\/sub>-CO), 4.4 (2H, s, NH2<\/sub>), 7.3-8.5 (3H, m, Ar-H), 9.5 (1H, s, CO-NH D2<\/sub>O exchangeable), 10.5 (1H, s, Ar-NH D2<\/sub>O exchangeable).<\/p>\n

Synthesis of 2-[(N-acetyl) 2, 5-dichloroanilido] acetohydrazones [4]<\/strong><\/p>\n

2-[(N-acetyl) 2, 5-dichloroanilido] acetohydrazide (0.001 mol) and (0.001 mol) of aromatic aldehyde or ketone [such as benzaldehyde] dissolve in absolute alcohol and added 2-drops of conc. H2<\/sub>SO4<\/sub> and stirred for 25 minutes. It was filtered under suction and recrystallised from hot ethanol.\u00a0 Color: Silver white,\u00a0 Yield: 86%, M.P= 218 0<\/sup>C, F.W: 392,\u00a0 Analytical calculation for C18<\/sub>H15<\/sub>O3<\/sub>N3<\/sub>Cl2<\/sub>, Calculated: N 12.04, C 54.85, H 03.71, O\u00a0 09.14, Cl 20.28, Found: N\u00a0 11.98, C\u00a0 54.82, H\u00a0 03.70, O 10.31, Cl 20.26.\u00a0 IR Absorption band (cm\u20131<\/sup>): 3160 (N\u2013H stretching), 2960\u20132975 (C\u2013H aliphatic), 1665\u20131660 (C=O Ketone), 795\u2013780 (C\u2013Cl Stretching), 765 (2, 5-disubstituted benzene).\u00a0 NMR Spectra: (d DMSO), 2.20(2 H, s, CH2<\/sub>), 4.22(1 H, s, NH), 6.96\u20137.2 (10 H, m, ArH. Synthetic strategy has been out lined in scheme-I. Mechanism for the formation of acid hydrazones is given in chart-I.<\/p>\n\n\n\n
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\"Scheme<\/td>\nScheme 1:<\/strong><\/p>\n

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

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

Newly synthesized thiophenoladducts of acidhydrazones were screened for their anti-bacterial activity against the gram positive bacteria S. albus, S. aureus<\/em> and gram negative bacteria E.coli<\/em> and Pseudomonas piosineus<\/em> by agar plate disc diffusion method at 30 \u03bcg\/mL concentration. Ampicillin and tetracycline<\/em> were used as a reference compounds. The compound (1, 5, 15, 16) <\/em><\/strong>shown significant activities and compound (2, 4, 9, 12, 14<\/em>) have shown moderate activity.<\/p>\n

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

The same compounds were tested for their antifungal activity against Candida albicans, Aspergillus niger and Alternaria alternata <\/em>at concentration of 30 mg\/ml using Savored dextrose agar media. The compound (3, 8, 11, 13) <\/em><\/strong>shown significant activity and compound (1, 7,<\/em> 10, 17) have<\/em> shown moderate activity against Candida albicans and Aspergillus niger.<\/strong><\/em> All the other compounds did not show significant activity against the fungi at the concentration used.\u00a0\u00a0\u00a0\u00a0 <\/em><\/strong><\/p>\n

Results and discussion<\/strong>\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0<\/strong><\/p>\n

Thiophenoladducts of various acidhydrazones have been synthesized by the reaction of 2-[N- (acetyl) 2, 5-dichloroanilido] acetohydrazide with various Carbonyl Compounds in 44 to 69% yield. Hydrazone-thiophenoladducts are white, brown and yellow colour solids, having high melting points. The structure of all the compounds are confirmed by\u00a0 IR, NMR, and Mass spectral data and are further supported by correct elemental analysis. Newly synthesized compounds have been tested for their antibacterial activity<\/em> against gram positive bacteria S. albus, S. aureus<\/em> and gram negative bacteria E.coli<\/em> and Pseudomonas piosineus<\/em>. The compound (1, 5, 15, 16)<\/em><\/strong>\u00a0 \u00a0\u00a0<\/strong><\/em>shown significant activities and compound (2, 4, 9, 12, 14<\/em>) have shown moderate activity. The same compounds were tested for their antifungal activity<\/em> against Candida albicans, Aspergillus niger and Alternaria alternata<\/em> at concentration of 30 mg\/mL using savored dextrose agar media. The compound (3, 8, 11, 13) <\/em><\/strong>shown significant activities and compound (1, 7,<\/em> 10, 17) have<\/em> shown moderate activity against Candida albicans and Aspergillus niger<\/em>. All the other compounds did not show significant activity against the fungi at the concentration used.<\/p>\n

Conclusions \u00a0<\/strong><\/p>\n

Newly synthesized compounds have been tested for their antibacterial activity<\/em> against gram positive bacteria S. albus, S. aureus<\/em> and gram negative bacteria E.coli and Pseudomonas piosineus<\/em> by agar plate disc diffusion method at 30 \u03bcg\/mL concentration. Ampicillin and tetracycline<\/em> were used as a reference compounds. The compound (1, 5, 15, 16) <\/em>shown significant activities and compound (2, 4, 9, 12, 14<\/em>) have<\/em> shown moderate activity. The same compounds were tested for their antifungal activity<\/em> against Candida albicans, Aspergillus niger and Alternaria alternata<\/em> at concentration of 30 albicans and Aspergillus niger.<\/em> All the other compounds did not show significant activity mg\/mL using Savored dextrose agar media. The compound (3, 8, 11, 13) <\/em>shown<\/em> significant activities and compound (1, 7,<\/em> 10, 17) <\/em>have shown moderate activity against Candida <\/em>against the fungi at the concentration used.<\/p>\n

Acknowledgements<\/strong><\/p>\n

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

References<\/strong><\/p>\n

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    Introduction Acidhydrazides and their condensation products possessing an azometine -NHN=CH- […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[],"class_list":["post-1719","post","type-post","status-publish","format-standard","hentry","category-vol4no1"],"_links":{"self":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/1719","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/comments?post=1719"}],"version-history":[{"count":5,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/1719\/revisions"}],"predecessor-version":[{"id":33205,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/1719\/revisions\/33205"}],"wp:attachment":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/media?parent=1719"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/categories?post=1719"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/tags?post=1719"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}