Yeni kumarin ve oksihalohidrin türevlerinin sentezi, biyolojik ve fotofiziksel özelliklerinin incelenmesi
Synthesis of new coumarin and oxyhalohydrine derivatives and investigation of their biological and photophysical properties
- Tez No: 989295
- Danışmanlar: PROF. DR. MUSTAFA ZENGİN, DOÇ. DR. ARLİNDA BYTYQİ DAMONİ
- Tez Türü: Doktora
- Konular: Kimya, Chemistry
- Anahtar Kelimeler: Biyolojik özellikler, Fotofiziksel özellikler, Sentez, Biological properties, Photophysical properties, Synthesis
- Yıl: 2026
- Dil: Türkçe
- Üniversite: Sakarya Üniversitesi
- Enstitü: Fen Bilimleri Enstitüsü
- Ana Bilim Dalı: Kimya Ana Bilim Dalı
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: Belirtilmemiş.
Özet
Bu çalışmada, kumarin çekirdeğinin kimyasal çeşitlendirilebilirliği ve biyolojik açıdan önem taşıyan heterosiklik sistemlerle olan uyumu değerlendirilerek yeni kumarin-pirazin türevleri sentezlenmiş ve bu türevlerin fotofiziksel ile biyolojik aktiviteleri araştırılmıştır. Çalışmanın ilk bölümünde, 2-hidroksi benzaldehit türevleri kullanılarak kumarin halkasının farklı pozisyonlarına türevlendirme olarak -H, -OH ve -NO2 gruplarının yerleştirilmesiyle çeşitli yapısal varyasyonlar elde edilmiştir. Bu sübstitüentlerin elektronik özellikleri ve konumları, pirazin halkasının oluşumu, reaksiyon verimi ve ürünlerin floresans özellikleri üzerinde belirleyici bir rol oynamıştır. Sentezlenen bileşiklerin floresans davranışları UV-vis spektroskopisi ve floresans spektroskopisi kullanımıyla karakterizasyon çalışmaları yapılmış; kuantum verimleri, emisyon dalga boyları değerlendirilmiştir. UV-vis ölçümlerinde türevlerin yaklaşık 350-400 nm civarında güçlü absorpsiyon bantları verdiği belirlendi. Böylece sübstitüent etkisinin fotofiziksel özellikler üzerindeki yapısal-fonksiyonel ilişkisi ortaya konmuştur. Bileşiklerin biyolojik potansiyelini belirlemek amacıyla AChE, BChE, hCA I ve hCA II enzimlerindeki inhibitör aktiviteleri incelenmiştir. Yapılan biyolojik testler, kumarin ve pirazin halkalarının birleşik yapısının enzim bağlama bölgeleriyle güçlü etkileşimler oluşturduğunu, belirli sübstitüentlerin ise inhibisyon potansiyelini anlamlı düzeyde artırdığını göstermiştir. Özellikle 2d türevli yapı AChE üzerinde Takrin'den daha güçlü inhibisyon gösterdi. 2a türevi ise Takrin benzeri özellik göstermiştir. 2a ve 2c türevleri ise hCA II enzimi üzerinde en güçlü inhibisyonu gösterdi. 2e türevi ise hCA II üzerinde daha güçlü inhibisyon göstermiştir. Bu sonuçlar, kumarin-pirazin türevlerinin enzim seçiciliği üzerinde belirgin etkiler yarattığını ve gelecekteki tasarım stratejileri için değerli bilgiler sunduğunu göstermektedir. Tezin ikinci bölümünde, kumarin türevinin yanı sıra eugenol, timol, karvakrol ve (S)-(-)perililalkol gibi bileşiklerden türetilen halo hidrin ve halo tiyol yapıları sentezlenmiştir. Bu sentezler yapılırken öncelikle fenolik veya alifatik -OH grubundan epiklorohidrin ile oksiran yapısı sentezlenmiştir. Bu oksiran türevlerinden ise β-halo hidrin yapıları (halojen: -Cl, -Br, -I) elde edilmiştir. Daha sonra oksiran türevleri tiyoüre kullanılarak tiran türevlerine dönüştürülmüştür. Tiran türevleri de tekrardan halojenleme ve halka açılma mekanizmaları üzerinden elde edilen yapılar NMR ve MS teknikleriyle doğrulanmıştır. Oksihalohidrin ve halo tiyol yapıların antimikrobiyal aktiviteleri için beş standart bakteri suşu (K. pneumoniae-ATTC 700603 E. coli-ATCC 25922, S. aureus-ATCC 29213, P. aeruginosa-ATCC 27853, Enterococcus feacalis-ATTC 29212) kullanılmıştır. β-halo hidrin ve β-halo tiyol türevlerin senteziyle literatüre yeni katkılar sağlanmıştır. Elde edilen bulgular, sentezlenen bileşiklerin ilaç tasarımı, biyosensör geliştirme ve fotonik malzemeler gibi çeşitli uygulama alanlarında kullanılabilirliğine işaret etmektedir.
Özet (Çeviri)
In this study, novel coumarin-pyrazine derivatives were synthesized, utilizing the coumarin core for its highly functionalizable chemical structure and its wide recognition in the literature as a versatile pharmacophore compatible with biological systems. The photophysical and biological properties of these compounds were investigated through a comprehensive and holistic approach. The extensive π-conjugation system of the coumarin skeleton provides significant advantages in photophysical processes and offers suitable electronic distribution and steric properties for interaction with biological targets. Consequently, the coumarin core is among the heterocyclic systems with high potential for pharmaceutical and biomedical applications and serves as the primary building block in this research. The coupling of the coumarin core with the pyrazine ring was performed to impart a distinct electron-accepting character to the structure and to enhance its intramolecular charge transfer (ICT) properties. The electron-withdrawing nature of the pyrazine ring facilitated the redistribution of electron density in the excited state, thereby increasing the tunability of the optical properties. In this context, one of the primary objectives of the study was to systematically elucidate structure-function relationships from both photophysical and biological perspectives. In the initial stage of the study, substituents with varying electronic characteristics, such as hydrogen (-H), hydroxyl (-OH), and nitro (-NO₂), were positioned at different sites on the coumarin ring using 2-hydroxybenzaldehyde derivatives, yielding a series of intermediates with significantly different electronic properties. It was observed that the electron-donating or electron-withdrawing nature of these substituents and their positions on the coumarin ring had significant effects on the formation mechanism of the pyrazine ring, the reaction kinetics, and the synthesis yields of the final products. Furthermore, it was determined that these structural differences were not limited to the synthesis steps but also directly affected the excited-state behavior and fluorescence properties of the final compounds. It was concluded that electron-donating groups contributed to the stabilization of the excited state by increasing the π-electron density, whereas electron-withdrawing groups enhanced the ICT character by promoting intramolecular charge transfer. The photophysical properties of the synthesized coumarin-pyrazine derivatives were characterized in detail using UV-vis absorption and fluorescence spectroscopy techniques. In this context, absorption maxima, emission wavelengths, Stokes shifts, and solvent-dependent spectral changes were systematically evaluated. UV-vis absorption measurements revealed that all derivatives exhibited strong absorption bands in the approximately 350–400 nm range. These bands are thought to primarily originate from π-π* electronic transitions of the coumarin core, while the pyrazine ring modulates the absorption properties by contributing to the conjugation system. The 2a derivative compound showed excitation bands in the 368–378 nm range and emission maxima in the 400–450 nm range in DMSO, THF, DMF, and CHCl₃ solvents. The calculated Stokes shift values were found to be sensitive to solvent polarity, varying from 63 nm in CHCl₃ to 81 nm in THF. These results clearly indicate that the compound undergoes a specific geometric relaxation and electronic rearrangement process in the excited state. In the 2b derivative compound, excitation maxima were obtained in the 370–378 nm range and emission maxima in the 406–468 nm range across different solvents. The 96 nm Stokes shift calculated in THF, in particular, indicates that this compound exhibits a distinct intramolecular charge-transfer character. The efficient positioning of electron donor and acceptor units within the same molecule facilitates charge separation in the excited state and significantly affects fluorescence properties. The high sensitivity of the 2c derivative compound to solvent polarity reveals that the π-π* and n-π* transitions are stabilized to varying degrees by the solvent environment, indicating that the compound exhibits distinct solvatochromic properties. The absorption bands observed in the 402–410 nm range indicate that this derivative is excited at longer wavelengths than other compounds in the series. The Stokes shifts, calculated as 78–83 nm in CHCl₃ and THF and 106 nm in DMSO, clearly revealed the decisive effect of solvent-molecule interactions on the excited state. The 2d derivative compound was the structure excited at the lowest wavelength in the series, with absorption bands observed in the 325–355 nm range. While emission maxima were observed around 405–407 nm in DMSO, DMF, and THF, the maximum shifted to 513 nm in CHCl₃. This significant redshift indicates that the excited state is strongly stabilized depending on the solvent polarity. In parallel, it was observed that the Stokes shifts varied widely, with the highest recorded at 161 nm in CHCl₃. These results reveal that the 2d derivative exhibits a strong ICT character and undergoes significant geometric and electronic rearrangement in the excited state. The differences in the appearance of compound 2e under 365 nm UV light in different solvents were attributed to the strong electron-withdrawing effect of the nitro group. The presence of the nitro group significantly altered the molecule-solvent interactions, leading to an increase in absorption intensity. Absorption maxima were observed in the 403–409 nm range and emission maxima in the 479–491 nm range, with Stokes shift values calculated as 70 nm for CHCl₃ and DMSO, and 87 nm for THF. In recent years, the design and synthesis of compounds with intramolecular charge-transfer properties have attracted significant interest due to their potential applications in advanced technologies, including nonlinear optical devices, organic photovoltaic systems, OLEDs, memory devices, and field-effect transistors. In this context, the UV-vis and fluorescence results suggest that the 2a–e derivatives are promising candidates for fluorescent probes, solvatochromic dyes, and biological imaging applications. In biological activity studies, the inhibitory effects of the synthesized 2a–e compounds on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), human carbonic anhydrase I (hCA I), and human carbonic anhydrase II (hCA II) enzymes were investigated, and the results were compared with standard inhibitors. For AChE, tacrine had an IC₅₀ of 81.60 µM, while the 2d derivative was a powerful inhibitor with an IC₅₀ of 1.08 µM. Similarly, for BChE, tacrine had an IC₅₀ of 8.80 µM, while the 2d derivative was the most potent inhibitor in the series, with an IC₅₀ of 2.10 µM. Furthermore, it was determined that the 2a derivative compound exhibited a higher inhibitory effect than tacrine, with IC₅₀ values of 71.14 µM for AChE and 1.10 µM for BChE. Regarding carbonic anhydrase inhibition, some derivatives exhibited more potent inhibition than the acetazolamide (AZA) standard. While AZA was determined to have an IC₅₀ of 2.51 µM on hCA I and 76.10 µM on hCA II, the 2c derivative compound was more effective than AZA, with an IC₅₀ of 1.75 µM for hCA I and 8.20 µM for hCA II. Additionally, the 2e derivative exhibited selective inhibition on hCA II with an IC₅₀ of 7.50 µM. These results demonstrate that the synthesized derivatives exhibit significant enzyme-inhibition activity. In the second part of this research, the antibacterial activities of β-halo alcohol and β-halo thiol structures derived from natural compounds were investigated in detail. Natural products are preferred as starting materials in pharmaceutical chemistry because they are compatible with biological systems, have low toxicity profiles, and are amenable to structural modifications. Phenolic and terpenic structures such as eugenol, thymol, carvacrol, and (S)-(–)-perillyl alcohol are known for their antimicrobial activity, and this study aimed to functionalize these structures chemically. Oxirane intermediates were first obtained using epichlorohydrin, then β-halo alcohol derivatives were synthesized from these intermediates, and finally, β-halo thiol derivatives were converted from thiirane derivatives. β-halo alcohol derivatives were synthesized in two steps, and β-halo thiol derivatives in three steps, achieving high yields ranging from 79–82% and 66–71%, respectively. The structures of all synthesized compounds were confirmed by ¹H-NMR, ¹³C-NMR, and mass spectrometry (MS) techniques. In total, 27 new compounds were synthesized and subjected to biological evaluation, including 15 new β-halo alcohols and 12 new β-halo thiol derivatives. Antibacterial activity was assessed in vitro using the microdilution method to determine minimum inhibitory concentration (MIC) values. The study utilized five standard bacterial strains: Klebsiella pneumoniae (ATCC 700603), Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 29213), Pseudomonas aeruginosa (ATCC 27853), and Enterococcus faecalis (ATCC 29212). For activation, inoculation was performed in Mueller-Hinton broth, followed by plating on Mueller-Hinton agar. After 18 hours of incubation at 37°C, colonies were standardized to 0.5 McFarland and inoculated into sterile microplate wells. Chloramphenicol and Streptomycin were used as standard antibiotics for comparison. Generally, β-halo alcohol derivatives exhibited higher antibacterial activity than β-halo thiol derivatives. This is due to the higher hydrogen-bonding capacity and cell membrane interaction of the oxygen atom compared to the sulfur atom. Furthermore, the higher polarity of β-halo alcohols facilitates their passage through the bacterial cell wall and membrane. Except for carvacrol and compound 6a, all β-halo alcohol derivatives showed similar inhibitory activity against Staphylococcus aureus. The results indicate that β-halo alcohol derivatives can exhibit specific activity against this Gram-positive bacterium despite its thick peptidoglycan layer. The compounds coded 8a–c, derived from perillyl alcohol, suggests that the main skeleton, rather than the halogen species, is the determining factor in the antibacterial effect for Staphylococcus aureus. However, the iodinated derivative 8c showed the lowest activity against Enterococcus faecalis and Pseudomonas aeruginosa, while the brominated derivative 8b had the weakest effect against Escherichia coli. In contrast, the iodinated derivative 8c exhibited the highest inhibitory activity against Klebsiella pneumoniae, potentially due to interactions between the halogen atom's size and polarizability and specific cell wall structures. When comparing carvacrol (6a–c) and thymol (5a–c) isomers, both groups exhibited similar inhibitory profiles, suggesting the position of the phenolic hydroxyl group is not a determining factor for Staphylococcus aureus. Significant differences in activity against Gram-negative bacteria like Escherichia coli and Klebsiella pneumoniae were observed depending on the halogen type, as their outer membrane structures are more selective. Eugenol derivatives (7a–c) exhibited the lowest antibacterial activity overall. While the brominated derivative 7b performed better against Enterococcus faecalis and Escherichia coli, the chlorinated derivative 7a showed the lowest activity against Klebsiella pneumoniae and Pseudomonas aeruginosa. β-halo thiol derivatives generally had lower inhibitory effects than β-halo alcohols, which may be explained by the lower stability of the thiol group in biological systems. Among perillyl alcohol derivatives, the iodinated compound 12c performed best against Staphylococcus aureus. In carvacrol and thymol derivatives, chlorinated versions were more effective against Enterococcus faecalis. Overall, β-halo alcohol derivatives are more effective antibacterial agents, as the presence of an oxygen atom enhances the synergistic effect with the halogen atom. These findings show that β-halo alcohol derivatives are promising starting compounds for the development of new antibacterial agents.
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KimyaMarmara ÜniversitesiKimya Ana Bilim Dalı
PROF. DR. BAHATTİN YALÇIN
DR. ÖĞR. ÜYESİ BAYBARS KÖKSOY