Funct. Mater. 2023; 30 (4): 486-493.

doi:https://doi.org/10.15407/fm30.04.486

Imidazole derivatives as potent inhibitors of sirtuin-1

V.V. Lipson1-3, F.G. Yaremenko2, V.M. Vakula1,2, S.V. Kovalenko1, A.V. Kyrychenko1,3, S.M. Desenko1,V.I. Musatov1, P.O. Borysko4, S.O. Zozulya+

1Division of Chemistry of Functional Materials, State Scientific Institution "Institute for Single Crystals "NAS of Ukraine, 60 Nauky Ave., Kharkiv, 61072
2State Institution "V. Ya. Danilevsky Institute for Endocrine Pathology Problems", NationalAcademy of Medical Sciences of Ukraine, Kharkiv, Ukraine, Alchevsky St.,10, Kharkiv, 61002
3V.N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv, 61022, Ukraine
4ENAMINE Ltd., Chervonotkatska str., 67, Kyiv, 02094, Ukraine

Abstract: 

Developing of small molecule modulators of SIRT1 activity opens up opportunities for delaying age-related diseases. Therefore, the design of novel modulators is a promising therapeutic approach. Here, we synthesized a series of imidazole derivatives and studied their modulatory activity of against SIRT1 using high-throughput fluorescent assay screening and molecular docking calculations. We found that despite some structural similarity with the known imidazothiazole-based activators, such as SRT1460 and SRT1720, our synthesized derivatives demonstrated an essentially different modulating behavior. In particular, all synthesized derivatives revealed significant inhibiting activity, so that compounds 7a and 8b were characterized by the almost complete inhibition (up to 98-100 %) of SIRT1 enzymatic activity. Molecular docking calculations suggest that all studied imidazole derivatives favor a strong binding to the catalytic domain of SITR1, similar to the known inhibitors, such as (S)-selisistat. On the opposite, SRT1460 and SRT1720 activators occupied allosteric sites terminal to the catalytic domain of SIRT1. These findings demonstrate the essentially different molecular mechanisms of modulating SIRT1 enzyme activity by these two groups of imidazothiazole derivatives and help further understand SIRT1 action.

Keywords: 
Sirtuin-1, inhibitor, organic synthesis, imidazole derivatives, molecular docking, high-throughput screening.<pta:>

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