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

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Abstract

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.

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Authors and Affiliations

  1. Faculty of Arts and Science, Chemistry Department, Kocaeli University, Umuttepe Campus, Kocaeli, Turkey

    Mustafa Oğuzhan Kaya

  2. Scientific and Technological Research Laboratory, Duzce University, Konuralp Campus, Duzce, Turkey

    Tuna Demirci

  3. Science and Technology Application and Research Center, Siirt University, Kezer Campus, Siirt, Turkey

    Ümit Çalışır

  4. Technical Sciences Vocational School, Veterinary Science Department, Batman University, Raman Campus, Batman, Turkey

    Oğuzhan Özdemir

  5. Institute of Science, Chemistry Department, Kocaeli University, Umuttepe Campus, Kocaeli, Turkey

    Yeşim Kaya

  6. Faculty of Sciences, Chemistry Department, Sakarya University, Esentepe Campus, Serdivan, Sakarya, Turkey

    Mustafa Arslan

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Contributions

In this study, both M.O.K. and M.A. designed the study. M.O.K., T.D., O.Ö., Y.K. and Ü.Ç. and performed all experiments/analysis, enzymatic and computational studies. All authors evaluated the results and prepared the manuscript.

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Kaya, M.O., Demirci, T., Çalışır, Ü. et al. Synthesis, activatory effects, molecular docking and ADME studies as rabbit muscle pyruvate kinase activators of ureido phenyl substituted 1,4-dihydropyridine derivatives. Res Chem Intermed 50, 437–463 (2024). https://doi.org/10.1007/s11164-023-05149-6

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