Synthesis, activatory effects, molecular docking and ADME studies as rabbit muscle pyruvate kinase activators of ureido phenyl substituted 1,4-dihydropyridine derivatives

KAYA M. O., Demirci T., Çalışır Ü., Özdemir O., Kaya Y., Arslan M.

Research on Chemical Intermediates, cilt.50, sa.1, ss.437-463, 2024 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 50 Sayı: 1
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1007/s11164-023-05149-6
  • Dergi Adı: Research on Chemical Intermediates
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, Chimica, Compendex, Environment Index
  • Sayfa Sayıları: ss.437-463
  • Anahtar Kelimeler: 1,4-dihydropyridine, Cancer, Hantzsch reaction, Pyruvate kinase, Urea
  • Kocaeli Üniversitesi Adresli: Evet

Özet

In this study, the activation of pyruvate kinase enzyme in vitro via different urea substituents in the para position as functional groups of 1,4-dihydropyridine derivatives synthesized by Hantzsch reaction method was investigated. Elemental analysis, 1H-NMR, 13C-NMR and FT-IR spectroscopy were used to identify the ureido phenyl substituted 1,4-dihydropyridine derivatives. Virtual screening based on molecular docking supported the results of possible in vitro pyruvate kinase (PK) activators among the synthesized substances. The results showed that all compounds successfully activated PK. The strongest activator effect was shown by ethyl-4-(4-(4-(3-(3-methoxyphenyl)thioureido)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,7,8-hexahydroquinolin-3 (7) with an AC50 value of 87.70 µM. In molecular docking studies, full compatibility (− 3016.93 FF), binding affinities (ΔG = − 8.58 kcal/mol), LUMO–HOMO energy gap (ΔE = 7.85 eV) in Density functional theory (DFT) studies and drug similarity score of the compounds were found to be 0.69. These results shed light on the therapeutic potential of the produced compounds to treat PK-related diseases.