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ABSTRACT
Thiophene nucleus has been established as the potential entity in the largely growing chemical world of heterocyclic compounds possessing promising pharmacological characteristics. The similar compounds synthesized through different routes bear variable magnitudes of biological activities. In the same way compounds with azitidinone moiety possess a varied number of biological activities. In view of this it is worthwhile to prepare different thiophene derivatives that bear an azitidinone moiety at C-2. Different 2-amino thiophene-3-carboxylic acid ethyl esters were prepared by using Gewalds reaction. 2-amino thiophene 3-caboxy hydrazides were prepared by condensing Phenyl hydrazine with 2-amino thiophene-3-carboxylic acid ethyl esters. From 2-amino thiophene 3-caboxy hydrazides different Schiffs bases were prepared by reacting with various aromatic aldehydes (viz. Benzaldehyde, Cinnamaldehyde, Para amino Dimethyl Benzaldehyde, Indole-3caboxaldehyde). Finally the Schiffs bases thus obtained were treated with chloroacetylchloride in presence of triethyl amine to afford the title compounds. The title compounds were subjected to evaluate for their antibacterial and anti-fungal activities. Key words: Thiophene, azitidinone, anti-bacterial activity and anti-fungal activity.
INTRODUCTION Thiophene nucleus is a biologically important heterocyclic moiety and attracting attention in chemistry research due to its diverse range of biological activities. An intensive literature review on thiophene, azitidinone and their derivatives revealed that they were found to possesses different biological activities such as antibacterial1, mycolytic1 antimicrobial activity2,3, anti-mitotic4, antidepressant activity5. Azetidinone derivatives which contain -lactam ring in their structure show potent anti-cunvulsant6, atni-tubercular7, antiinflammatory and anti-tumor activities.8 In view of the biological importance and the past research on the thiophene, azitidinone and their derivatives; it is worthwhile to synthesize some novel azatidinone incorporated thiophene derivatives. The synthesis of title compounds was achieved by a systematic approach is outlined in the Scheme-I.
MATERIALS AND METHODS Melting points of all the compounds were determined in open capillaries using Toshniwal and Cintex melting point apparatus and are uncorrected. IR spectra of the compounds were recorded on SCHIMADZU FT-IR Spectrophotometer by using KBr discs. Progress of the each reaction in the present investigation was monitored by TLC using E-Merck 0.25mm silica gel plates.
EXPERIMENTAL METHODS Synthesis of 2-amino-4,5-sustituted thiophene-3carboxylate (Ib&Ic): An equimolar mixture of sulphur (0.1moles), ethyl cyano acetate (0.1mole) and ketone (cyclohexanone for I and buta-2-one for II), (0.1mole), were taken in a conical flask containing 10 to 15mL of ethanol. The mixture was stirred for 5minutes and morpholine (0.1mole) was slowly added with stirring for 15minutes. This was irradiated at 180W for four minutes and it was cooled to room temperature and kept in refrigerator
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Aromatic aldehydes (0.36gms) and irradiated at 350W for three minutes, it was allowed to cool to room temperature. The crystals were collected by filtration under reduced pressure and recrystallized using ethanol. Synthesis of 2[(3-chloro, 4-aryl azetidine-2-one)]4,5-substituted thiophene-3-carboxy hydrazide: The products of the previous step 2[(aryl)methylene amino] 4,5-substituted thiophene-3carboxyhydrazides (IIIa-h) were dissolved in benzene separately. An equimolar mixture of chloroacetylchloride and tri ethylamine was added to above solution by keeping the conical flask in an Ice bath. Later it was allowed to cool to room temperature and irradiated at 600W for 4minutes. The reaction mixture was poured on to 200gm of crushed ice. The crude compound thus obtained was collected by filtration and dried. All the final compounds obtained were purified by recrystallisation.
CN
S + H 2C
+
COOC 2H 5
R1
H2 C
R2
ETHANOL, MORPHOLINE
R1
O C OC 2H 5
180W, 4 MIN
O R1 C
H N
H N
E, ZIN RA Y D OL H Y L AN EN ET H IN PH 3M W, 30 0
R2
NH2
Ia & Ib
R2
NH2
O R1 C
H N
H N
Chloroacetyl Chloride, TEA
O R1 C
H N
H N
R2
N S
H C
Ar R2 S N
H C
Ar
IIIa-h
IVa-h
Cl
Scheme I
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Table 1: Physical data table Compound Ic Ib IIb IIc IIIa IIIb IIIc IIId IIIe IIIf IIIg IIIh IVa IVb IVc IVd IVe IVf IVg IVh Molecular formula C11H15NO2S C9H13NO2S C13H15N3OS C15H7N3OS C22H21N3OS C24H26N4OS C24H23N3OS C24H22N4OS C20H19N3OS C22H24N4OS C22H21N3OS C22H20N4OS C24H22N3O2S C26H27ClN4O2S C26H27ClN3O2S C26H23ClN4O2S C22H20ClN3O2S C24H25ClN4O2S C24H22ClN3O2S C24H21ClN4O2S Melting point 108-1100C 92-960C 125-1300C 182-1850C 70-720C 75-760C 70-730C 90-960C 73-780C 76-800C 90-950C 110-1150C 90-950C 94-1000C 101-1030C 104-1100C 120-1280C 110-1130C 112-1160C 110-1150C Yield (%) 75.8 75 75 65 73 70 71 76 78 76 69 74 76 74 76 74 73 72 72 78 Molecular weight 225.31 199.27 261.34 287.38 375.49 418.55 401.52 414.52 349.45 392.52 375.49 388.49 451.97 495.04 478.01 491.00 425.93 469.00 451.97 464.97
Table 2: Antibacterial and Anti-fungal data of title compounds Compound (1000g/mL) IVa IVb IVd IVe IVf IVg IVh Standard(100 g/mL) E.Coli 12 12 16 12 17 11 15 22 Zone of inhibition(in mm) P.aeruginosa C. albicans 11 13 12 12 15 16 11 12 16 15 13 11 16 17 23 24 S. cerevisiae 10 11 17 11 16 12 16 21
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