Synthesis, Theoretical Studies, Cytotoxicity of 2-((4-(Dimethylamino)Benzylidene)Amino)-5-Methylphenol with Potential JNK1 Inhibitory Activity

Year 2023, Volume: 14 Issue: 2, 253 - 272, 15.08.2023

Oğuzhan Karaosmanoğlu Halil Berber Ülkü Dilek Uysal

https://doi.org/10.22312/sdusbed.1310094

Abstract

Cisplatin, doxorubicin, hydroxycamptothecin, leucovorin, vincristine and 5-fluorouracil resistance of cancer cells are associated with the activities of C-Jun N-Terminal Kinase 1 (JNK1). Inhibition of the JNK1 by pharmacological agents could be a beneficial attempt for reversing the chemoresistance of various cancer cells. However, there is no FDA-approved JNK inhibitor for safe use in clinics in today’s clinics. In this study, a Schiff base 2-((4-(dimethylamino)benzylidene)amino)-5-methylphenol, (7S4) has been synthesized and characterized by 1H, 13C-NMR, FT-IR and elemental analysis. The stable geometry of 7S4 has been determined by DFT method with Gaussian09 program (B3LYP/6-311g++(d,p))). The Gibbs Free energies, stable tautomer forms, H-bond, Mulliken charges, dipole moment, natural bond orbital (NBO), HOMO, LUMO and band gap energy (EGAP), molecular electrostatic potential (MEP) and solvent accessibility surface areas (SASA) have been calculated. Drug-likeness, anticancer and JNK1 inhibitory activities of 7S4 have been evaluated. Enol tautomer form of trans 7S4 was characterized as the most stable structure. 7S4 was observed to be a reactive compound in chemical reactions with a low EGAP value. In addition, high and low electron density regions of 7S4 are responsible for the establishment of chemical bonds in biological systems. 7S4 exhibited strong druggability with the agreement on Lipinski, Ghose, Veber, Egan, and Muegge rules. Cytotoxicity tests and molecular docking revealed that 7S4 poses a potential JNK1 inhibitor activity.

Keywords

Schiff bases, DFT method, JNK1 inhibitors, antitumor agents, druglikeness, molecular docking

Supporting Institution

Anadolu University Scientific Research Projects (Project No. ) for financial support. The authors also grateful to Anadolu University Scientific Research commission for supporting Gaussian 09 (Project No:1102F027) and Gauss View 5.0 (Project No:

Project Number

1509F633, 20ADP182 and 1102F027, 1304F064

Thanks

Authors are also grateful to Prof. Dr. Hülya Sivas, Ayşe Aydoğdu Erdönmez and Dila Ercengiz for their valuable contributions and suggestions. The authors are thankful to the Anadolu University Scientific Research Projects (Project No. 1509F633 and 20ADP182) for financial support. The authors also grateful to Anadolu University Scientific Research commission for supporting Gaussian 09 (Project No:1102F027) and Gauss View 5.0 (Project No: 1304F064) programs with the projects. We would like to thank to Anadolu University for providing the opportunity to use the CS ChemBioDraw Ultra 16.0.1.4 for Microsoft Windows program.

Potansiyel JNK1 İnhibe Edici Aktiviteye Sahip 2-((4-(dimetilamino)benziliden)amino)-5-metilfenol’ün Sentezi, Teorik Çalışmaları, Sitotoksisitesi

Abstract

Kanser hücrelerinin sisplatin, doksorubisin, hidroksikamptotesin, lökovorin, vinkristin ve 5-fluorourasil direnci, C-Jun N-Terminal Kinaz 1 (JNK1) aktiviteleri ile ilişkilidir. JNK1'in farmakolojik ajanlar tarafından inhibisyonu, çeşitli kanser hücrelerinin kemodirencini tersine çevirmek için yararlı bir yaklaşım olabilir. Ancak günümüz kliniklerinde güvenli kullanım için FDA onaylı bir JNK inhibitörü bulunmamaktadır. Bu çalışmada, bir Schiff bazı 2-((4-(dimetilamino)benziliden)amino)-5-metilfenol, (7S4) sentezlenmiş ve 1H, 13C-NMR, FT-IR ve element analizi ile karakterize edilmiştir. 7S4'ün kararlı geometrisi Gaussian09 programı (B3LYP/6-311g++(d,p)) ile DFT yöntemi ile belirlenmiştir. Gibbs Serbest enerjileri, kararlı tautomer formları, H-bağı, Mulliken yükleri, dipol momenti, doğal bağ orbital (NBO), HOMO, LUMO ve bant boşluk enerjisi (EGAP), moleküler elektrostatik potansiyel (MEP) ve çözücü erişilebilirlik yüzey alanları (SASA) hesaplanmıştır. 7S4'ün ilaca benzerliği, antikanser ve JNK1 inhibitör aktiviteleri değerlendirilmiştir. Trans 7S4'ün enol tautomer formu en kararlı yapı olarak nitelendirildi. 7S4'ün düşük EGAP değeri ile kimyasal reaksiyonlarda reaktif bir bileşik olduğu gözlendi. Ayrıca 7S4'ün yüksek ve düşük elektron yoğunluklu bölgeleri biyolojik sistemlerde kimyasal bağların kurulmasından sorumludur. 7S4, Lipinski, Ghose, Veber, Egan ve Muegge kurallarına ilişkin anlaşma ile güçlü uyuşturulabilirlik sergiledi. Sitotoksisite testleri ve moleküler kenetlenme, 7S4'ün potansiyel bir JNK1 inhibitör aktivitesi oluşturduğunu ortaya çıkardı.

Keywords

Schiff bazları, DFT yöntemi, JNK1 inhibitörleri, antitümör ajanlar, ilaca benzerlik, moleküler kenetlenme

Project Number

1509F633, 20ADP182 and 1102F027, 1304F064

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