Synthesis, Characterization and Biological Evaluation Of 2-Azetidinone and 4-Thiazolidinone Derivatives.

Sethuvani, S (2012) Synthesis, Characterization and Biological Evaluation Of 2-Azetidinone and 4-Thiazolidinone Derivatives. Masters thesis, Adhiparasakthi College of Pharmacy, Melmaruvathur.


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The present study, we decided to synthesize a new series of azetidin-2- one and thiazolidin-4-one compounds with simple substitution and to screen the newly synthesized compounds for their anti antimicrobial, analgesic and anti-inflammatory activity. The development of drug resistance has limited the successful application of many antibiotics and therefore this phenomenon has given consequences to health. The design of potential reversers of microbial resistance has thus become a desirable goal in the field of medicinal chemistry. Moreover azetidinone and thiazolidinone are the pharmacophore of various molecules which occupies prominent places in the field of antimicrobial agents, the importance of which are documented in literature. In the present study, the appropriate aldehydes were reacted with p-amino benzoic acid to give the corresponding a Schiff bases (SB1-SB3) which undergoes reaction with chloroacetyl chloride in presence of tri ethylamine results in the formation of corresponding 2-azetidinone derivatives (SS1-SS3) by Staudinger reaction. Similarly, the Schiff bases (SB1-SB3) reacted with mercaptoacetic acid to give 4-thiazolidinone derivatives (SS4-SS6). Both 2-azetidinones and 4- thiazolidinones resulted in good to excellent yield. The purity of the synthesized compounds was checked by appearance of single spot in thin layer chromatography (Rf) and determining melting point. The structure of the synthesized compounds were established by spectral (IR, 1H NMR and Mass) analysis data. The N=C band (1679-1685 cm-1) and N=CH proton signal (δ 8.52-8.60) in IR and NMR spectrum respectively in the synthesized compounds (SB1-SB3), confirmed the formation of Schiff base nucleus. The C=O stretching band (1247-1295 cm-1), C-O-H bending vibration (1408-1437 cm-1) in IR spectrum and a singlet for 1 proton at δ 10.17-10.65 and multiplet for 4 protons at δ 7.15-8.17 in 1H NMR, indicated the presence of benzoic acid group in all the synthesized compounds. The C=O band (1659-1685 cm-1), CH-Cl band (773-775 cm-1) in IR spectrum and the N-CH proton signal (δ 4.58-4.76) and CH-Cl (δ 5.03-5.50) in 1H NMR spectrum in the synthesized compounds (SS1-SS3), confirmed the formation of 3- chloro-2-azetidinone nucleus. The C=O band (1658-1686 cm-1) and C-S-C band (691- 698 cm-1) in IR spectrum and N-CH proton signal (δ 4.52- 4.76) and CH2-S (δ 7.22- 7.36) in 1H NMR spectrum in the synthesized compounds (SS4-SS6) confirmed the formation of 4-thiazolidinone nucleus. In SB1, SS1 & SS4, showed a singlet for 6 protons at δ 2.91-3.02. and a multiplet for 4 protons at δ 6.60-7.42 in 1H NMR spectrum and a band at 1434-1456 cm-1 for N-(CH3)2 in IR spectrum, confirmed the substitution of dimethylamino phenyl group. In SB2, SS2 & SS5, presence of strong bands at 1517 cm-1 and 1316-1344 cm-1 corresponding to the asymmetric and symmetric O=N=O stretching in IR spectrum and a multiplet for 4 protons at δ 7.07-8.33 in 1H NMR, indicated the presence of Nitrophenyl group. In SB3, SS3 & SS6, the 1H NMR showed a singlet for 1 proton at δ 9.57-9.78 and muliplet for 4 protons at δ 6.59-7.42, whereas the IR spectrum of these compounds showed band at 3240-3309 cm-1 for OH stretching , indicated the presences of hydroxy phenyl group. The mass spectrum of the synthesized compounds produced (M+) Molecular ion peaks such as 344.79, 346.72, 317.72, 342.41, 344.34 and 314.34 for SS1, SS2, SS3, SS4, SS5 and SS6 respectively corresponds to their molecular formulas. The predicted chemical structure of titled compounds was further supported by the fragmentation peaks. Most the synthesized compounds exhibited good activity against the studied set of microorganisms. All the compounds showed good anti bacterial and antifungal activity even at less concentration. The SS1, 4-[3-chloro-2-[4-dimethylaminophenyl]- 4-oxoazetidin-1-yl] benzoic acid was found to be more active against Staphylococcus aureus (gram +ve bacteria). The SS3, 4-[3-chloro-2-(4-hydroxyphenyl)-4- oxoazetidin-1-yl] benzoic acid was found to be more potent active against Escherichia coli (gram –ve bacteria). The SS5, 4-{2-[4-nitrophenyl]-4-oxo-1, 3- thiazolidin-3-yl} benzoic acid was found to be active against Candida albicans. From the data, it is evident that the 2-azetidinones was more active against the bacterial strains and 4-thiazolidinones were more active against the fungal strains. The synthesized compounds SS5 & SS6 were screened for the anti-inflammatory by carrageenan induced paw edema method and the percentage reduction in the paw edema was measured using plethysmograph. The synthesized compounds are found to be highly significant (p<0.001) at 3 h. The compounds SS5 & SS6 exhibited maximum inhibition of 42.31 % and 47.32 % respectively where as the standard diclofenac sodium showed reduction in edema volume by 62.14 %. The analgesic activities of both the synthesized compounds were screened by Eddy’s hot plate method. The activity was studied at 50 mg/kg b.w. and their effects were measured at time intervals of 30, 60, 90, and 180 minutes. The synthesized compounds showed significant analgesic activity (p<0.001) at 90 min. The maximum analgesic activity and the percentage analgesia of SS5 & SS6 was found to be 51.54 % and 56.80 % respectively whereas 60.02 % analgesia was exhibited by the standard drug. However, in both evaluations, the compounds SS6, 4-[2-(4-hydroxyphenyl)-4- oxo-1, 3-thiazolidin-3-yl] benzoic acid showed better activity than SS5. This may be due to the presence of electron donating group such as hydroxy group at the 2nd position of 4-thiazolidinone than the electron withdrawing group NO2 group at SS5. The synthesized compounds have exhibited significant biological activities; their efficacy is not enough to develop them into clinically useful agents. However these compounds need special attention because of their marked activity. Therefore, the further modification of these compounds is quiet desirable and since acute anti-inflammatory screening and central nociceptive activity was performed, further experiments were needed to elucidate their exact mechanism of activity. It can be concluded that these compounds certainly holds great promise towards good active leads in medicinal chemistry.

Item Type: Thesis (Masters)
Uncontrolled Keywords: Biological Evaluation; 2-Azetidinone; 4-Thiazolidinone Derivatives; Hydroxy Phenyl group
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Ravindran C
Date Deposited: 17 Aug 2017 06:44
Last Modified: 17 Aug 2017 06:44

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