Yeni Kinolin-4-karboksilik Asit Türevlerinin Pfitzinger Sentezi, Tautomerik Davranışı ve in Silico ADMET Değerlendirmesi

Abstract

Bu çalışmada, iki farklı yapısal özelliğe sahip β-dikarbonil bileşiğinin klasik Pfitzinger reaksiyonu ile tepkimesi sonucunda iki yeni kinolin-4-karboksilik asit türevi sentezlendi. Sentezlenen bileşiklerin yapıları, 1H NMR, 13C NMR, FT-IR ve HR-ESI-MS spektroskopik teknikleri kullanılarak doğrulanmıştır. Spektroskopik veriler, Bileşik 1'in açık zincirli kinolin-4-karboksilik asit formu (%74) ile buna karşılık gelen halkalı lakton formu (%26) arasında tautomerik dengede bulunduğunu, Bileşik 2'nin ise yalnızca kaynaşık lakton yapısı olarak elde edildiğini gösterdi. Tautomerizmin öngörülen farmakokinetik özellikler üzerindeki etkisini değerlendirmek amacıyla, Bileşik 1'in her iki tautomerik formu ile Bileşik 2, in silico ADMET analizi kullanılarak incelendi. İncelenen tüm yapılar, Lipinski'nin Beş Kuralı'nı herhangi bir ihlal olmaksızın sağlayarak uygun ilaç benzeri özellikler sergiledi. İncelenen yapılar arasında Bileşik 2, en yüksek öngörülen bağırsak emilimi ve Caco-2 geçirgenliğini gösterirken, Bileşik 1'in açık zincirli tautomerik formunun AMES negatif olarak tahmin edilmesi, en uygun toksisite profiline sahip olduğunu ortaya koydu. Elde edilen sonuçlar, tautomerik yapının kinolin türevlerinin öngörülen ADMET özelliklerini etkilediğini göstermekte ve biyolojik olarak aktif kinolin türevlerinin gelecekteki tasarımına katkı sağlayabilecek önemli bilgiler sunmaktadır.

Keywords

• Pfitzinger reaksiyonu
• Kinolin
• Tautomerlik
• Yapısal karakterizasyon
• ADMET

Supporting Institution

Kütahya Dumlupınar Üniversitesi, Bilimsel Araştırmalar Projesi (BAP)

Project Number

2015/24

Ethical Statement

Bu çalışma, insan katılımcılar veya deney hayvanları üzerinde gerçekleştirilen herhangi bir araştırma içermemektedir. Bu nedenle etik kurul onayı gerekmemektedir. Yazar, araştırma ve yayın etiği kurallarına uyduğunu, makalenin özgün olduğunu, daha önce herhangi bir yerde yayımlanmadığını ve eş zamanlı olarak başka bir dergide değerlendirme sürecinde olmadığını beyan eder.

Thanks

Yazar, Kütahya Dumlupınar Üniversitesi, Bilimsel Araştırma Projeleri Koordinasyon Birimi (BAP) tarafından 2015/24 numaralı proje kapsamında sağlanan mali desteği için teşekkür eder.

Pfitzinger Synthesis, Tautomeric Behavior, and in Silico ADMET Evaluation of Novel Quinoline-4-carboxylic Acid Derivatives

Abstract

Two new quinoline-4-carboxylic acid derivatives were obtained through the classical Pfitzinger reaction using two structurally different β-dicarbonyl compounds. The molecular structures of the obtained compounds were verified using 1H NMR, 13C NMR, FT-IR, and HR-ESI-MS spectroscopic techniques. Spectroscopic data showed that Compound 1 existed as a tautomeric equilibrium between the open-chain quinoline-4-carboxylic acid form (74%) and the corresponding cyclic lactone form (26%), whereas Compound 2 was obtained exclusively as the fused lactone structure. To investigate the influence of tautomerism on the predicted pharmacokinetic properties, the individual tautomeric forms together with Compound 2 were subjected to in silico ADMET analysis. All investigated structures fulfilled Lipinski's Rule of Five without any violations, supporting their favorable drug-likeness. Among the investigated structures, Compound 2 showed the highest predicted intestinal absorption and Caco-2 permeability, while the open-chain tautomer of Compound 1 was predicted to be AMES negative, suggesting the most favorable toxicity profile. These results indicate that tautomeric structure influences the predicted ADMET properties of quinoline derivatives and provide useful information for the future design of biologically active quinoline-based compounds.

Keywords

• Pfitzinger reaction
• Quinoline
• Tautomerism
• Structural characterization
• ADMET

Supporting Institution

Kütahya Dumlupınar University, The Scientific Research Projects Coordination Unit (BAP)

Project Number

2015/24

Ethical Statement

This study does not involve human participants or experimental animals; therefore, ethical approval was not required. The author declares that this manuscript complies with the principles of research and publication ethics, is original, has not been published previously, and is not under consideration for publication elsewhere.

Thanks

The author gratefully acknowledges the financial support provided by the Scientific Research Projects Coordination Unit (BAP) of Kütahya Dumlupınar University under Project No. 2015/24.

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