YENİ PİRİMİDO[1,2-a]PİRİMİDİN BİLEŞİKLERİNİN ANTİOKSİDAN VE ANTİBAKTERİYAL ÖZELLİKLERİNİN KARŞILAŞTIRILMASI

Abstract

Amaç: Pirimidopirimidin yapı iskeletine sahip heterohalkalı bileşikler, sahip oldukları çok çeşitli biyolojik özellikleri sayesinde tıbbi kimya alanındaki araştırmacıların ilgi odağı olmuştur. Bu çalışma ile, bir seri yeni pirimido[1,2-a]pirimidin türevlerinin antioksidan kapasitesi ve antibakteriyel aktivitesi araştırılmıştır.

Gereç ve Yöntem: Sentezlenen tüm bileşiklerin in vitro antioksidan aktiviteleri 2,2-difenil-1-pikrilhidrazil (DPPH) radikal süpürme testi kullanılarak gerçekleştirilmiştir. Antibakteriyel aktivite çalışmaları, bazı Gram-pozitif ve negatif ATCC suşlarına karşı minimum inhibisyon konsantrasyonu (MİK) olarak Avrupa Antimikrobiyal Duyarlılık Testi standartlarına göre sıvı mikrodilüsyon yöntemi kullanılarak belirlenmiştir.

Sonuç ve Tartışma: Yeni pirimidoprimidin türevleri için DPPH serbest radikal süpürme aktivitesinin genel aralığının 0.1 mM'de %3.86-6.90 ve 1 mM'de %6.28-16.59 olduğu bulunmuştur. Tüm bileşiklerin serbest radikal süpürme aktiviteleri %20'nin altında bulunduğundan, pirimidin halkasında enolize olabilen bir amit grubunun bulunmamasından kaynaklı olarak bileşiklerin aktivitesinin zayıf olduğu düşünülmüştür. Buna ek olarak, seçilen bileşiklerin bazıları zayıf antioksidan aktivite göstermiştir.. Tüm bileşiklerin MİK değerleri, Staphylococcus aureus ATCC 29213, metisiline dirençli Staphylococcus aureus ATCC 43300, Enterococcus faecalis 29212, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 13883, Pseudomonas 27853 ATCC'ye karşı > 100 µg/ml bulunmuştur. Bu çalışmadan elde edilen veriler, ileriki çalışmalarda daha kapsamlı değerlendirme ve yorumlama yapabilmek amacıyla pirimidin halkasının farklı konumlarında çeşitli sübstitüentlerin bulunduğu türevlerin sentezini gerektirmektedir.

Keywords

• Antibakteriyel etki
• antioksidan etki
• MİK
• pirimidopirimidin
• radikal süpürücü

THE COMPARISON OF ANTIOXIDANT AND ANTIBACTERIAL ACTIVITY OF NOVEL PYRIMIDO[1,2-a]PYRIMIDINE COMPOUNDS

Abstract

Objective: Heterocycles with a pyrimidopyrimidine scaffold have been the focus of interest of researchers in the field of medicinal chemistry as they have a wide range of biological properties. In the current study antioxidant capacity and antibacterial activity of a series of new pyrimido[1,2-a]pyrimidines were investigated

Material and Method: All these novel compounds were screened for their in vitro antioxidant effectiveness using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging test and the antibacterial activity was determined using the broth microdilution method according to The European Committee on Antimicrobial Susceptibility Testing standards (EUCAST) as a minimal inhibition concentration (MIK) against some Gram- positive and negative ATCC strains.

Result and Discussion: The overall range of DPPH free radical scavenging activity was found to be 3.86-6.90% at 0.1mM and 6.28–16.59% at 1mM for the novel pyrimidopyrimidine derivates. Since the free radical scavenging activities of all the compounds were below 20%, it was considered that the weak activity of compounds might be due to the absence of an enolizable amide group in the pyrimidine ring. In addition to that, some of the selected compounds showed weak antioxidant activity. MIC values of all compounds were found as > 100 µg/ml against Staphylococcus aureus ATCC 29213, methicillin resistant Staphylococcus aureus ATCC 43300, Enterococcus faecalis 29212, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 13883, Pseudomonas aeruginosa ATCC 27853. The data obtained from present study require the synthesis of derivatives with various substituents in different positions of the pyrimidine ring in order to be able to evaluate and interpret more comprehensively in future studies.

Keywords

• Antibacterial activity
• antioxidant activity
• MIC
• pyrimidopyrimidine
• radical scavenging

References

1. 1. Sahu, M., Siddiqui, N. (2016). A review on biological importance of pyrimidines in the new era. International Journal of Pharmaceutical Sciences Research, 8(5), 8-21.
2. 2. Lagoja, I.M. (2005). Pyrimidine as constituent of natural biologically active compounds. Chemistry & Biodiversity, 2(1), 1-50. [CrossRef]
3. 3. Baumann, M., Baxendale, I.R. (2013). An overview of the synthetic routes to the best-selling drugs containing 6-membered heterocycles. Beilstein Journal of Organic Chemistry, 9(1), 2265-2319. [CrossRef]
4. 4. Abbas, S.E., Gawad, N.M.A., George, R.F., Akar, Y.A. (2013). Synthesis, antitumor and antibacterial activities of some novel tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine derivatives. European Journal of Medicinal Chemistry, 65, 195-204. [CrossRef]
5. 5. Buron, F., Mérour, J.Y., Akssira, M., Guillaumet, G., Routier, S. (2015). Recent advances in the chemistry and biology of pyridopyrimidines. European Journal of Medicinal Chemistry, 95, 76-95. [Crossref]
6. 6. Hossan, A.S., Abu-Melha, H.M., Al-Omar, M.A., Amr, A.E.G.E. (2012). Synthesis and antimicrobial activity of some new pyrimidinone and oxazinone derivatives fused with thiophene rings using 2-chloro-6-ethoxy-4-acetylpyridine as starting material. Molecules, 17(11), 13642-13655. [CrossRef]
7. 7. Asmat, U., Abad, K., Ismail, K. (2016). Diabetes mellitus and oxidative stress—A concise review. Saudi Pharmaceutical Journal, 24(5), 547-553. [CrossRef]
8. 8. Rodrigo, R., Fernandez-Gajardo, R., Gutierrez, R., Manuel Matamala, J., Carrasco, R., Miranda-Merchak, A., Feuerhake, W. (2013). Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 12(5), 698-714. [CrossRef]

9. 9. Biswas, S.K. (2016). Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox? Oxidative Medicine and Cellular Longevity, 2016. [CrossRef]
10. 10. Naeem, A., Badshah, S.L., Muska, M., Ahmad, N., Khan, K. (2016). The current case of quinolones: synthetic approaches and antibacterial activity. Molecules, 21(4), 268. [CrossRef]
11. 11. Andersson, M.I., MacGowan, A.P. (2003). Development of the quinolones. Journal of Antimicrobial Chemotherapy, 51(1), 1-11. [CrossRef]
12. 12. Hurd, C.D., Hayao, S. (1955). Reaction of propiolactone with heterocyclic amines. Journal of the American Chemical Society, 77(1), 117-121. [CrossRef]
13. 13. Kappe, T. (1967). Synthesen von Heterocyclen, 95. Mitt.: Chinolizine und Indolizine I: Eine Synthese von 2-Hydroxychinolizinonen-(4). Monatshefte für Chemie-Chemical Monthly, 98(3), 874-886. [CrossRef]
14. 14. Güllü, M., Dinçsönmez, A., Özyavaş, Ö. (2010). Facile Synthesis of Novel Pyrimido[1, 2‐a]pyrimidin‐4‐ones from Highly Reactive Malonates. European Journal of Organic Chemistry, 11, 2113-2120. [CrossRef]
15. 15. Bayramoğlu, D., Güllü, M. (2021). An Efficient Synthetic Method for the Synthesis of Novel Pyrimido [1,2-a] pyrimidine-3-carboxylates: Comparison of Microwave and Conventional Heating. Polycyclic Aromatic Compounds, 42(8), 4948-4964. [CrossRef]
16. 16. The European Committee on Antimicrobial Susceptibility Testing Web site. (2022). From https://www.eucast.org. Erişim tarihi: 01.01.2022.
17. 17. Alam, M.N., Bristi, N.J., Rafiquzzaman, M. (2013). Review on in vivo and in vitro methods evaluation of antioxidant activity. Saudi Pharmaceutical Journal, 21(2), 143-152. [CrossRef]
18. 18. Blois, M.S. (1958). Antioxidant determinations by the use of a stable free radical. Nature, 181(4617), 1199-1200. [CrossRef]
19. 19. Leyva-Ramos, S., de Loera, D., Cardoso-Ortiz, J. (2017). In vitro antibacterial activity of 7-substituted-6-fluoroquinolone and 7-substituted-6,8-difluoroquinolone derivatives. Chemotherapy, 62, 194-198. [CrossRef]
20. 20. Smith, A., Pennefather, P.M., Kaye, S.B., Hart, C.A. (2001). Fluoroquinolones. Drugs, 61(6), 747-761. [CrossRef]
21. 21. The European Committee on Antimicrobial Susceptibility Testing Web site. (2022). From https://www.eucast.org Erişim tarihi: 01.01.2022.
22. 22. Solca, F.F., Baum, A., Langkopf, E., Dahmann, G., Heider, K.H., Himmelsbach, F., Meel, J.C.A. (2004). Inhibition of epidermal growth factor receptor activity by two pyrimidopyrimidine derivatives. The journal of Pharmacaology and Experimental Therapeutics, 311(2), 502-509. [CrossRef]
23. 23. Cruz, J.P., Carrasco, T., Ortega, G., Cuesta, F.S. (1992). Inhibition of ferrous-induced lipid peroxidation by pyrimido-pyrimidine derivatives in human liver membranes. Lipids, 27(3), 192-194. [CrossRef]
24. 24. Sharma, P., Rane, N., Pandey, P. (2006). Synthesis and evaluation of antimicrobial activity of novel hydrazino and N-benzylidinehydrazino-substituted 4,8-dihydro-1H,3H-pyrimido[4,5-d]pyrimidin-2,7-dithiones. Archiv de Pharmazie. 339(10), 572-578. [CrossRef]
25. 25. Krueger, A.C., Madigan, D.L., Beno, D.W., Betebenner, D.A., Carrick, R., Green, B.E., He, W., Liu, D., Maring, C.J., Daniel, K.F., Mo, H., Molla, A., Motter, C.E., Pilot-Matias, T.J., Tufano, M.D., Kempf, D.J. (2012). Novel hepatitis C virus replicon inhibitors: synthesis and structure-activity relationships of fused pyrimidine derivatives. Bioorganic & Medicinal Chemistry Letters. 22(6), 2212-2215. [CrossRef]
26. 26. Ellatar, K.M., Mert B.D., Monier, M., El-Mekabaty, A. (2020). Advances in the chemical and biological diversity of heterocyclic systems incorporating pyrimido[1,6-a]pyrimidine and pyrimido[1,6-c]pyrimidine scaffolds. RSC Advances, 10(26), 15461-15492. [CrossRef]
27. 27. Saundane, A.R., Vjaykumar, K., Vaijinath, A.V., Walmik, P. (2013) Synthesis, antimicrobial and antioxidant activities of some new indole derivatives containing pyridopyrimidine and pyrazolopyridine moieties. Medicinal Chemistry Research, 22, 806-817. [CrossRef]