Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation

Abstract

A hybrid pharmacophore model, based on structural motifs previously identified by our team, was employed to generate ligands that simultaneously target COX-2, 15-LOX, and PPARγ in the context of metabolic dysfunction-associated fatty liver disease (MAFLD). Notable COX-2 inhibitory activities (IC 50 = 0.065–0.24 μM) were observed relative to celecoxib (IC 50 = 0.049 μM). The two most effective 15-LOX inhibitors, 2a and 2b , exhibited 69 % and 57 % of quercetin's action, respectively. Utilizing the rat hemi-diaphragm model to assess in vitro glucose uptake capacity, compounds 2a and 2b demonstrated significant glucose uptake potential in the absence of insulin, surpassing that of pioglitazone. Compound 2a activated PPARγ with an EC 50 value of 3.4 μM in a Gal4-hybrid reporter gene assay, indicating partial agonistic action. Interesting binding interactions with targets of interest were identified by molecular docking studies. As well, the expression levels of 20-HETE, Il-1β and TNF-α were decreased in LPS-challenged RAW264.7 macrophages upon treatment with compound 2a . The pharmacokinetic analysis of 2a and assessment of its in vivo efficacy in addressing hepatic impairment in rat models of diabetes and pre-diabetes were carried out. Together, these findings may offer preliminary insights into the potential of these compounds for further refinement in the existing therapeutic arsenals for metabolic diseases. • Design of propargylated thiazolones as MTDLs to manage metabolic diseases-associated systemic/hepatic inflammation. • The most active compounds showcased significant COX-2 and 15-LOX inhibitory activities in comparison to the reference drugs. • They demonstrated noticeable glucose uptake capability as well as PPARγ partial agonistic activity. • Favorable in vivo pharmacokinetic parameters of 2a warranted its testing in rat models of metabolic dysfunction. • Treatment with 2a resulted in reduction of pro-inflammatory cytokines and hepatic lipid peroxidation markers in vivo .