Synthesis, Characterization, and Study the Biological Activity of New Di-azetidinone Derivatives
Main Article Content
Keywords
β-lactam, Di-azetidinone, barbital, Schiff base, anticancer
Abstract
A series of new β-lactam derivatives were synthesized in two steps: The first step involves the synthesis of Schiff base derivatives from Veronal (Barbital) which is used as a sleeping aid (hypnotic) from 1903 until the mid-1950s, the compound (L3A) is synthesized by loading two molecules of formaldehyde on macrocycles compound as an initial step with absolute ethanol as solvent to form Hemiaminal compound, the reaction occurred on the two secondary amine molecules), after that treated the reaction product (L3A) with p-Toluenesulfonyl chloride in anhydrous pyridine to produce compound (L3B). While the preparation of the compound (L3C) involves removing the sulfonate groups of two sites in the compound (L3B) by gradually adding sodium amide with water. Imine derivatives (L3C1, L3C2, L3C3, and L3C4) were synthesized by reaction of Barbital derivatives free amino groups and corresponding substituted benzaldehyde in the presence of glacial acetic acid.
The second step is done through added chloroacetyl chloride to the Schiff base derivatives very slowly to prevent the compound from turning into something like bitumen, this is followed by adding the trimethylamine base to remove the proton and complete the closing process and form a β-lactam ring of derivatives (L3C5, L3C6, L3C7, and L3C8). Finally, in vitro anticancer activity of (L3C7, and L3C8) derivatives were investigated using SK-OV-3: Human Ovarian Cancer Cell Lines compared with 5-floro uracil (5-FU), the results showed the ability of these compounds to inhibit the infected cells in different proportions, depending on the concentrations used.
References
1. F.H. van der Steen and G.van koten, “Syntheses of 3-Amino-2-azetidinones: A Literature Survey,” Tetrahedron, vol. 41, no. 36, pp. 7503–7524, 2009.
2. J. A. Joule and K. Mills, Heterocyclic Chemistry, Fifth Edit. A John Wiley & Sons, Ltd., Publication, pp. 588-592, 2010.
3. S. Alfei and A. Maria Schito, “β-Lactam Antibiotics and β-Lactamase Enzymes Inhibitors, Part 2: Our Limited Resources,” pharmaceuticals, vol. 15, no. 476, 2022DOIoi: doi.org/10.3390/ph15040476.
4. K. Busha, “Past and Present Perspectives on b-Lactamases,” Antimicrob. Agents Chemother., vol. 62, no. 10 e01076-18, 2018DOIoi: DOI : .org/10.1128/AAC.01076-18.
5. Y. Sik Park et al., “Structural Study of Metal Binding and Coordination in Ancient Metallo-β-Lactamase PNGM-1 Variants,” Int. J. Mol. Sci., vol. 21, no. 14, 2020DOIoi: doi.org/10.3390/ijms21144926.
6. V. Güner, S. Yildirir, B. Özçelik, and U. Abbasoglu, “Synthesis and antimicrobial activity of 1,4-diaryl-2-azetidinones,” Farmaco, vol. 55, no. 2. pp. 147–150, 2000DOIoi: 10.1016/S0014-827X(99)00126-3.
7. M. Peng et al., “In vitro Combined Inhibitory Activities of β- Lactam Antibiotics and Clavulanic Acid Against blaKPC-2-Positive Klebsiella pneumoniae,” Infect. Drug Resist., vol. 14, pp. 361–368, 2021DOIoi: DOI: 10.2147/IDR.S292612.
8. M. Babic, A. M. Hujer, and R. A. Bonomo, “What’s new in antibiotic resistance? Focus on beta-lactamases,” Drug Resistance Updates, vol. 9, no. 3. pp. 142–156, 2006DOIoi: 10.1016/j.drup.2006.05.005.
9. Karaiskos, I. Galani, V. Papoutsaki, L. Galani, and H. Giamarellou, “Carbapenemase producing Klebsiella pneumoniae: implication on future therapeutic strategies,” Expert Review of Anti-Infective Therapy, vol. 20, no. 1. pp. 53–69, 2022DOIoi: 10.1080/14787210.2021.1935237.
10. Y. K. and M. Y. Shinichiro Yamachika, Chika Sugihara, “Correlation between penicillin-binding protein 2 mutations and carbapenem resistance in Escherichia coli,” J. Med.
Microbiol., vol. 62, pp. 429–463, 2013DOIoi: DOI 10.1099/jmm.0.051631-0.
11. M. Malebari et al., “β-Lactam analogues of combretastatin A-4 prevent metabolic inactivation by glucuronidation in chemoresistant HT-29 colon cancer cells,” European Journal of Medicinal Chemistry, vol. 130. pp. 261–285, 2017DOIoi: 10.1016/j.ejmech.2017.02.049.
12. D. Kuhn, C. Coates, K. Daniel, D. Chen, and Mohammad Bhuiyan, “Beta-lactams and their potential use as novel anticancer chemotherapeutics drugs,” Front. Biosci., vol. 9, no. 4, pp. 2605–2617, 2004DOIoi: doi.org/10.2741/1420.
13. C. A. Hobson et al., “impact of anticancer chemotherapy on the extension of beta-lactamase spectrum: an example with Kpc- type carbapenemase activity towards ceftazidime-avibactam,” Sci. Rep., vol. 10, p. 589, 2020DOIoi: doi.org/10.1038/s41598-020-57505-w.
14. J. L. Dong-Jun Fu, Y. F. Zhang, An-Qi Chang, “β-Lactams as promising anticancer agents: molecular hybrids, structure activity relationships and potential targets Dong-Jun,” Eur. J. Med. Chem., vol. 201, no. 1, 2020DOIoi: doi.org/10.1016/j.ejmech.2020.112510.
15. E. P. Luigino Troisi and C. Granito, “Novel and Recent Synthesis and Applications of b-Lactams,” Top Heterocycl Chem, vol. 22, pp. 101–209, 2010, doi: DOI 10.1007/7081_2009_12.
16. B. Mohan Sahoo and B. K. Banik, Therapeutic Potentials of β-Lactam : A Scaffold for New Drug Development. Synthetic Approaches to Nonaromatic Nitrogen Heterocycles- John Wiley & Sons Ltd, 2021.
17. Gupta and A. K. Halve, “Synthesis & Antifungal Screening of Novel Azetidin-2-ones,” Open Chemistry Journal, vol. 2, no. 1. pp. 1–6, 2015DOIoi: 10.2174/1874842201502010001.
18. Jarrahpour, P. Shirvani, V. Sin,ou and C. Latour “Synthesis and biological evaluation of some new b-lactam-triazole hybrids,” Med. Chem. Res., vol. 8, 2015DOIoi: DOI 10.1007/s00044-015-1474-x ORIGINAL.
19. S. S. Chhajed and C. D. Upasani, “Synthesis and in-silico molecular docking simulation of 3-chloro-4-substituted-1-(2- (1H-benzimidazol-2-yl)phenyl))-azetidin-2-ones as novel analgesic anti-inflammatory agent,” Arab. J. Chem., vol. 9, no. 2, pp. 1779–1785, 2016DOIoi: doi.org/10.1016/j.arabjc.2012.04.038.
20. J. W. Skiles and D. McNeil, “Spiro indolinone beta-lactams, inhibitors of poliovirus and rhinovlrus 3C-proteinases,” Tetrahedron Letters, vol. 31, no. 50. pp. 7277–7280, 1990DOIoi: 10.1016/S0040-4039(00)88543-3.
21. M. Ali et al., “Enamine barbiturates and thiobarbiturates as a new class of bacterial urease inhibitors,” Applied Sciences (Switzerland), vol. 10, no. 10. 2020DOIoi: 10.3390/app10103523.
22. J. Figueiredo et al., “Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents,” European Journal of Medicinal Chemistry, vol. 143. pp. 829–842, 2018DOIoi: 10.1016/j.ejmech.2017.11.070.
23. J. N. Suzana Apostolov1, Đ. Vaštag1, B. Matijević1and G. Mrđan, “Study Of The Biological Activity Descriptors Of The Barbituric Acid Derivatives,” Contemp. Mater., Vol. 11, No. 2, 2020DOIOI: Doi 10.7251/Comen2002077a.
24. Jabbar Radhi, E. Hussein Zimam and A. J. Almulla “New Barbiturate Derivatives as Potent in vitro α-Glucosidase Inhibitors,” Egypt. J. Chem., vol. 64, no. 1, pp. 117–123, 2021DOIoi: DOI: 10.21608/EJCHEM.2019.16210.1991.
25. B. Sokmen, S. Ugras, H. Y. Sarikaya, H. I. Ugras, and R. Yanardag, “Antibacterial, antiurease, and antioxidant activities of some arylidene barbiturates,” Applied Biochemistry and Biotechnology, vol. 171, no. 8. pp. 2030–2039, 2013DOIoi: 10.1007/s12010-013-0486-6.
26. W. Mohammed Najem, M. Zuheir, Sami E. Al-Slami and A. Jabbar Radhi “Synthesis and Studying Antibacterial Activity of New Nitrogen Rich Polymers,” Egypt. J. Chem., vol. 65, no. 2, pp. 29–33, 2022DOIoi: DOI: 10.21608/EJCHEM.2021 .34931.2727.
27. D. Neumann,The Design and Synthesis of Novel Barbiturates of Pharmaceutical Interest by, ” “ScholarWorks @ UNO University of New Orleans Theses, pp 1-314, 2004.
28. J. T. Bojarski, J. L. Mokrosz, H. J. Bartoń, and M. H. Paluchowska, “Recent Progress in Barbituric Acid Chemistry,” Advances in Heterocyclic Chemistry, vol. 38, no. C. pp. 229–297, 1985, doi: 10.1016/S0065-2725(08)60921-6.
29. D. A. Cozanitis et al, “One hundred years of barbiturates and their saint,” Journal Of The Royal Society Of Medicine, vol. 97, pp. 594–597, 2004.
30. K A Savage and D Wielbo, “Pharmacology Of Legal And Illicit Drugs,” Natl. Forensic Sci. Technol. Cent., pp. 435–446, 2005.
31. E. J. Almulla, A. J. Radhi and E. H. Zimam, “New Barbiturate Derivatives as Potent in vitro α-Glucosidase Inhibitors,” Egypt. J. Chem., vol. 64, no. 1, pp. 117–123, 2021DOIoi: DOI: 10.21608/EJCHEM.2019.16210.1991.
32. Ling, R. Hashim, and K. J. Sabah, “Sugar thiacrown-ether appended calix[4]arene as a selective chemosensor for Fe2+ and Fe3+ ions,” RSC Adv., vol. 5, no. 107, pp. 88038–88044, 2015DOIoi: 10.1039/c5ra15448k.
33. M. Szyma´nska et al., “Synthesis and Spectroscopic Investigations of Schiff Base Ligand and Its Bimetallic Ag(I) Complex as DNA and BSA Binders,” Biomol. Artic., vol. 11, p. 1449, 2021DOIoi: doi.org/10.3390/biom11101449.
34. QI H-zhen, MO S-yan and XU Jia-xi, “Highly Stereoselective Synthesis of trans-3-Chloro-b-lactams from Imines and Mixed Chloroacetyl and Nitroacetyl Chlorides,” CHEM. RES. CHINESE Univ., vol. 27, no. 6, p. 958—962 Highly, 2011DOIoi: DOI : 1005-9040(2011)-06-958-05.
35. ß. Beltr, B. Eleuterio ßlvarez, P. J. M. Mar and a.Requejo, “Direct Synthesis of Hemiaminal Ethers via aThree-Component Reaction,” Adv.Synth. Catal., vol. 357, pp. 2821 –2826, 2015, doi: 10.1002/adsc .201500588.
36. A.Aziz Abu-Yamin , M. Siddiq Abduh , S. Ayesh Mohammed and N. Al-Gabri, “ Synthesis, Characterization and Biological Activities of New Schiff Base Compound and Its Lanthanide Complexes“ Pharmaceuticals 2022, 15, 454, doi.org/10.3390/ph15040454
37. M. Gil, J. L. Núñez, M. A. Palafox, and N. Iza, “FTIR study of five complex β-lactam molecules,” Biopolymers - Biospectroscopy Section, vol. 62, no. 5. pp. 278–294, 2001, DOI: 10.1002/bip.1023.
2. J. A. Joule and K. Mills, Heterocyclic Chemistry, Fifth Edit. A John Wiley & Sons, Ltd., Publication, pp. 588-592, 2010.
3. S. Alfei and A. Maria Schito, “β-Lactam Antibiotics and β-Lactamase Enzymes Inhibitors, Part 2: Our Limited Resources,” pharmaceuticals, vol. 15, no. 476, 2022DOIoi: doi.org/10.3390/ph15040476.
4. K. Busha, “Past and Present Perspectives on b-Lactamases,” Antimicrob. Agents Chemother., vol. 62, no. 10 e01076-18, 2018DOIoi: DOI : .org/10.1128/AAC.01076-18.
5. Y. Sik Park et al., “Structural Study of Metal Binding and Coordination in Ancient Metallo-β-Lactamase PNGM-1 Variants,” Int. J. Mol. Sci., vol. 21, no. 14, 2020DOIoi: doi.org/10.3390/ijms21144926.
6. V. Güner, S. Yildirir, B. Özçelik, and U. Abbasoglu, “Synthesis and antimicrobial activity of 1,4-diaryl-2-azetidinones,” Farmaco, vol. 55, no. 2. pp. 147–150, 2000DOIoi: 10.1016/S0014-827X(99)00126-3.
7. M. Peng et al., “In vitro Combined Inhibitory Activities of β- Lactam Antibiotics and Clavulanic Acid Against blaKPC-2-Positive Klebsiella pneumoniae,” Infect. Drug Resist., vol. 14, pp. 361–368, 2021DOIoi: DOI: 10.2147/IDR.S292612.
8. M. Babic, A. M. Hujer, and R. A. Bonomo, “What’s new in antibiotic resistance? Focus on beta-lactamases,” Drug Resistance Updates, vol. 9, no. 3. pp. 142–156, 2006DOIoi: 10.1016/j.drup.2006.05.005.
9. Karaiskos, I. Galani, V. Papoutsaki, L. Galani, and H. Giamarellou, “Carbapenemase producing Klebsiella pneumoniae: implication on future therapeutic strategies,” Expert Review of Anti-Infective Therapy, vol. 20, no. 1. pp. 53–69, 2022DOIoi: 10.1080/14787210.2021.1935237.
10. Y. K. and M. Y. Shinichiro Yamachika, Chika Sugihara, “Correlation between penicillin-binding protein 2 mutations and carbapenem resistance in Escherichia coli,” J. Med.
Microbiol., vol. 62, pp. 429–463, 2013DOIoi: DOI 10.1099/jmm.0.051631-0.
11. M. Malebari et al., “β-Lactam analogues of combretastatin A-4 prevent metabolic inactivation by glucuronidation in chemoresistant HT-29 colon cancer cells,” European Journal of Medicinal Chemistry, vol. 130. pp. 261–285, 2017DOIoi: 10.1016/j.ejmech.2017.02.049.
12. D. Kuhn, C. Coates, K. Daniel, D. Chen, and Mohammad Bhuiyan, “Beta-lactams and their potential use as novel anticancer chemotherapeutics drugs,” Front. Biosci., vol. 9, no. 4, pp. 2605–2617, 2004DOIoi: doi.org/10.2741/1420.
13. C. A. Hobson et al., “impact of anticancer chemotherapy on the extension of beta-lactamase spectrum: an example with Kpc- type carbapenemase activity towards ceftazidime-avibactam,” Sci. Rep., vol. 10, p. 589, 2020DOIoi: doi.org/10.1038/s41598-020-57505-w.
14. J. L. Dong-Jun Fu, Y. F. Zhang, An-Qi Chang, “β-Lactams as promising anticancer agents: molecular hybrids, structure activity relationships and potential targets Dong-Jun,” Eur. J. Med. Chem., vol. 201, no. 1, 2020DOIoi: doi.org/10.1016/j.ejmech.2020.112510.
15. E. P. Luigino Troisi and C. Granito, “Novel and Recent Synthesis and Applications of b-Lactams,” Top Heterocycl Chem, vol. 22, pp. 101–209, 2010, doi: DOI 10.1007/7081_2009_12.
16. B. Mohan Sahoo and B. K. Banik, Therapeutic Potentials of β-Lactam : A Scaffold for New Drug Development. Synthetic Approaches to Nonaromatic Nitrogen Heterocycles- John Wiley & Sons Ltd, 2021.
17. Gupta and A. K. Halve, “Synthesis & Antifungal Screening of Novel Azetidin-2-ones,” Open Chemistry Journal, vol. 2, no. 1. pp. 1–6, 2015DOIoi: 10.2174/1874842201502010001.
18. Jarrahpour, P. Shirvani, V. Sin,ou and C. Latour “Synthesis and biological evaluation of some new b-lactam-triazole hybrids,” Med. Chem. Res., vol. 8, 2015DOIoi: DOI 10.1007/s00044-015-1474-x ORIGINAL.
19. S. S. Chhajed and C. D. Upasani, “Synthesis and in-silico molecular docking simulation of 3-chloro-4-substituted-1-(2- (1H-benzimidazol-2-yl)phenyl))-azetidin-2-ones as novel analgesic anti-inflammatory agent,” Arab. J. Chem., vol. 9, no. 2, pp. 1779–1785, 2016DOIoi: doi.org/10.1016/j.arabjc.2012.04.038.
20. J. W. Skiles and D. McNeil, “Spiro indolinone beta-lactams, inhibitors of poliovirus and rhinovlrus 3C-proteinases,” Tetrahedron Letters, vol. 31, no. 50. pp. 7277–7280, 1990DOIoi: 10.1016/S0040-4039(00)88543-3.
21. M. Ali et al., “Enamine barbiturates and thiobarbiturates as a new class of bacterial urease inhibitors,” Applied Sciences (Switzerland), vol. 10, no. 10. 2020DOIoi: 10.3390/app10103523.
22. J. Figueiredo et al., “Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents,” European Journal of Medicinal Chemistry, vol. 143. pp. 829–842, 2018DOIoi: 10.1016/j.ejmech.2017.11.070.
23. J. N. Suzana Apostolov1, Đ. Vaštag1, B. Matijević1and G. Mrđan, “Study Of The Biological Activity Descriptors Of The Barbituric Acid Derivatives,” Contemp. Mater., Vol. 11, No. 2, 2020DOIOI: Doi 10.7251/Comen2002077a.
24. Jabbar Radhi, E. Hussein Zimam and A. J. Almulla “New Barbiturate Derivatives as Potent in vitro α-Glucosidase Inhibitors,” Egypt. J. Chem., vol. 64, no. 1, pp. 117–123, 2021DOIoi: DOI: 10.21608/EJCHEM.2019.16210.1991.
25. B. Sokmen, S. Ugras, H. Y. Sarikaya, H. I. Ugras, and R. Yanardag, “Antibacterial, antiurease, and antioxidant activities of some arylidene barbiturates,” Applied Biochemistry and Biotechnology, vol. 171, no. 8. pp. 2030–2039, 2013DOIoi: 10.1007/s12010-013-0486-6.
26. W. Mohammed Najem, M. Zuheir, Sami E. Al-Slami and A. Jabbar Radhi “Synthesis and Studying Antibacterial Activity of New Nitrogen Rich Polymers,” Egypt. J. Chem., vol. 65, no. 2, pp. 29–33, 2022DOIoi: DOI: 10.21608/EJCHEM.2021 .34931.2727.
27. D. Neumann,The Design and Synthesis of Novel Barbiturates of Pharmaceutical Interest by, ” “ScholarWorks @ UNO University of New Orleans Theses, pp 1-314, 2004.
28. J. T. Bojarski, J. L. Mokrosz, H. J. Bartoń, and M. H. Paluchowska, “Recent Progress in Barbituric Acid Chemistry,” Advances in Heterocyclic Chemistry, vol. 38, no. C. pp. 229–297, 1985, doi: 10.1016/S0065-2725(08)60921-6.
29. D. A. Cozanitis et al, “One hundred years of barbiturates and their saint,” Journal Of The Royal Society Of Medicine, vol. 97, pp. 594–597, 2004.
30. K A Savage and D Wielbo, “Pharmacology Of Legal And Illicit Drugs,” Natl. Forensic Sci. Technol. Cent., pp. 435–446, 2005.
31. E. J. Almulla, A. J. Radhi and E. H. Zimam, “New Barbiturate Derivatives as Potent in vitro α-Glucosidase Inhibitors,” Egypt. J. Chem., vol. 64, no. 1, pp. 117–123, 2021DOIoi: DOI: 10.21608/EJCHEM.2019.16210.1991.
32. Ling, R. Hashim, and K. J. Sabah, “Sugar thiacrown-ether appended calix[4]arene as a selective chemosensor for Fe2+ and Fe3+ ions,” RSC Adv., vol. 5, no. 107, pp. 88038–88044, 2015DOIoi: 10.1039/c5ra15448k.
33. M. Szyma´nska et al., “Synthesis and Spectroscopic Investigations of Schiff Base Ligand and Its Bimetallic Ag(I) Complex as DNA and BSA Binders,” Biomol. Artic., vol. 11, p. 1449, 2021DOIoi: doi.org/10.3390/biom11101449.
34. QI H-zhen, MO S-yan and XU Jia-xi, “Highly Stereoselective Synthesis of trans-3-Chloro-b-lactams from Imines and Mixed Chloroacetyl and Nitroacetyl Chlorides,” CHEM. RES. CHINESE Univ., vol. 27, no. 6, p. 958—962 Highly, 2011DOIoi: DOI : 1005-9040(2011)-06-958-05.
35. ß. Beltr, B. Eleuterio ßlvarez, P. J. M. Mar and a.Requejo, “Direct Synthesis of Hemiaminal Ethers via aThree-Component Reaction,” Adv.Synth. Catal., vol. 357, pp. 2821 –2826, 2015, doi: 10.1002/adsc .201500588.
36. A.Aziz Abu-Yamin , M. Siddiq Abduh , S. Ayesh Mohammed and N. Al-Gabri, “ Synthesis, Characterization and Biological Activities of New Schiff Base Compound and Its Lanthanide Complexes“ Pharmaceuticals 2022, 15, 454, doi.org/10.3390/ph15040454
37. M. Gil, J. L. Núñez, M. A. Palafox, and N. Iza, “FTIR study of five complex β-lactam molecules,” Biopolymers - Biospectroscopy Section, vol. 62, no. 5. pp. 278–294, 2001, DOI: 10.1002/bip.1023.
Article Sidebar
Published
Apr 15, 2023
Article Details
How to Cite
Dhurgham Aziz, Mohauman Mohammed Majeed, & Ahmed Thamer Salim. (2023). Synthesis, Characterization, and Study the Biological Activity of New Di-azetidinone Derivatives. Journal of Population Therapeutics and Clinical Pharmacology, 30(7), 349–359. https://doi.org/10.47750/jptcp.2023.30.07.041
Issue
Section
Articles
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.