TY - JOUR
T1 - Synthesis and evaluation of a new class of MIF-inhibitors in activated macrophage cells and in experimental septic shock in mice
AU - Garai, János
AU - Radnai, Balázs
AU - Vámos, Eszter
AU - Kovács, Dominika
AU - Vántus, Viola Bagóné
AU - Rumbus, Zoltán
AU - Pákai, Eszter
AU - Garami, András
AU - Gulyás-Fekete, Gergely
AU - Agócs, Attila
AU - Krekó, Marcell
AU - Zaman, Khadiza
AU - Prókai, László
AU - Őrfi, László
AU - Jakus, Péter B.
AU - Lóránd, Tamás
N1 - Funding Information:
This work was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences [ BO/00855/18/5 to BR]; the New National Excellence Program of the Ministry for Innovation and Technology through the National Research, Development and Innovation Office [ UNKP-19-4-PTE-405 and UNKP-20-5-PTE-762 to BR; UNKP-21-3-II-PTE-1317 to ZR]; the Hungarian National Research, Development and Innovation Office [ FK 138722 to AG]; the European Union , co-financed by the European Social Fund [ EFOP-3.6.1-16-2016-00004 ]; the Ministry of Finance, Hungary [ GINOP-2.3.3-15-2016-00025 , GINOP-2.3.2-15-2016-00049G ]; and by the Robert A. Welch Foundation [endowment BK-0031 to LP].
Publisher Copyright:
© 2022 The Authors
PY - 2023/2/5
Y1 - 2023/2/5
N2 - Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with enzymatic activities. Anti-inflammatory effects of MIF enzyme inhibitors indicate a link between its cytokine- and catalytic activities. Herein the synthesis, docking, and bioactivity of substituted benzylidene-1-indanone and -1-tetralone derivatives as MIF-tautomerase inhibitors is reported. Many of these substituted benzylidene-1-tetralones and -indan-1-ones were potent MIF-tautomerase inhibitors (IC50 < 10 μmol/L), and the most potent inhibitors were the 1-indanone derivatives 16 and 20. Some of these compounds acted as selective enolase or ketonase inhibitors. In addition, compounds 16, 20, 26, 37 and 61 efficiently inhibited NO, TNFα and IL-6 production in lipopolysaccharide-induced macrophages. Compound 20, 37 and 61 also inhibited ROS generation, and compound 26 and 37 abolished activation of NF-κB. Compound 37 significantly augmented hypothermia induced by high dose of lipopolysaccharide in mice. The possible mechanisms of action were explored using molecular modelling and docking, as well as molecular dynamics simulations.
AB - Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with enzymatic activities. Anti-inflammatory effects of MIF enzyme inhibitors indicate a link between its cytokine- and catalytic activities. Herein the synthesis, docking, and bioactivity of substituted benzylidene-1-indanone and -1-tetralone derivatives as MIF-tautomerase inhibitors is reported. Many of these substituted benzylidene-1-tetralones and -indan-1-ones were potent MIF-tautomerase inhibitors (IC50 < 10 μmol/L), and the most potent inhibitors were the 1-indanone derivatives 16 and 20. Some of these compounds acted as selective enolase or ketonase inhibitors. In addition, compounds 16, 20, 26, 37 and 61 efficiently inhibited NO, TNFα and IL-6 production in lipopolysaccharide-induced macrophages. Compound 20, 37 and 61 also inhibited ROS generation, and compound 26 and 37 abolished activation of NF-κB. Compound 37 significantly augmented hypothermia induced by high dose of lipopolysaccharide in mice. The possible mechanisms of action were explored using molecular modelling and docking, as well as molecular dynamics simulations.
KW - Inflammation
KW - Macrophage migration inhibitory factor inhibitor
KW - Molecular modelling
KW - Substituted benzylidene-1-tetralones and -indan-1-ones
KW - Thermophysiology
UR - http://www.scopus.com/inward/record.url?scp=85145181885&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2022.115050
DO - 10.1016/j.ejmech.2022.115050
M3 - Article
C2 - 36587420
AN - SCOPUS:85145181885
SN - 0223-5234
VL - 247
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 115050
ER -