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

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 mu M. In molecular docking studies, full compatibility (- 3016.93 FF), binding affinities (Delta G = - 8.58 kcal/mol), LUMO-HOMO energy gap (Delta E = 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.

Automated summary

This study investigated the activation of pyruvate kinase enzyme in vitro by different urea substituents in 1,4-dihydropyridine derivatives synthesized via the Hantzsch reaction method. The synthesized compounds successfully activated pyruvate kinase, with the compound 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)) showing the strongest activation effect.