Thiazolidin-4-one-based compounds interfere with the eicosanoid biosynthesis pathways by mPGES-1/sEH/5-LO multi-target inhibition

• Main Authors: Ester Colarusso (Author), Marianna Potenza (Author), Gianluigi Lauro (Author), Maria Giovanna Chini (Author), Valentina Sepe (Author), Angela Zampella (Author), Katrin Fischer (Author), Robert K. Hofstetter (Author), Oliver Werz (Author), Giuseppe Bifulco (Author)
• Format: Book
• Published: Elsevier, 2022-08-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2772-4174; 10.1016/j.ejmcr.2022.100046
• Keywords: Thiazolidin-4-one; Virtual screening; Drug-repurposing; Inflammation; mPGES-1; sEH; Pharmacy and materia medica; RS1-441; Other systems of medicine; RZ201-999
• Source: European Journal of Medicinal Chemistry Reports, Vol 5, Iss , Pp 100046- (2022)

Here we report the application of a multi-disciplinary protocol for investigating thiazolidin-4-one-based compounds as new promising anti-inflammatory agents interfering with the eicosanoid biosynthesis pathways. The workflow foresaw the generation of a focused virtual library of ∼4.2 ​× ​104 molecules featuring the thiazolidin-4-one core based on the related one-pot synthetical combinatorial route. The built library was initially screened in silico against the microsomal prostaglandin E2 synthase-1 (mPGES-1) enzyme and, afterwards, 23 selected chemical items were synthesized for the subsequent biological screening, applying the one-pot multicomponent synthetic strategy. Preliminary results highlighted the moderate ability of several tested thiazolidin-4-one-based compounds in inhibiting mPGES-1. On the other hand, further computational repurposing investigations were performed on a set of synthesized compounds, highlighting the promising binding of a several items against the soluble epoxide hydrolase (sEH) enzyme, whose inhibition leads to an increase of epoxyeicosatrienoic acids (EETs) that are anti-inflammatory mediators. Three molecules (3, 9 and 21) were able to inhibit sEH featuring IC50 values in the low micromolar range. In order to further profile their anti-inflammatory properties, additional investigations of the three identified hits highlighted their ability to inhibit 5-lipoxygenase (5-LO) and thus to interfere with leukotriene biosynthesis in neutrophils, devoid of activity against cyclooxygenases (COXs) and cytotoxic effects on human monocytes. Our results, obtained by applying a multidisciplinary approach, highlight the thiazolidin-4-one-core as a valuable template for developing novel anti-inflammatory compounds able to synergistically inhibit different targets involved in the arachidonic acid cascade.