New Chromone-Thiazolopyrimidine Hybrids as Potent TNF-α, IL-6 and PGE2 Inhibitors: Synthesis, Anti-Inflammatory Evaluation and Molecular Modeling Studies

Abstract

Inflammation is deemed to be a substantial and terrifying indicator of the advancement of diverse life‐threatening diseases. Regarding the preceding studies that assured the remarkable efficiency of chromone scaffolds and thiazolopyrimidine-based compounds as efficacious anti-inflammatory candidates, a new chromone-thiazolopyrimidine hybrid 3a–t was synthesized and investigated for their in vivo anti-inflammatory efficacy as well as their ulcerogenic effect. The majority of the examined candidates displayed a noticeable anti-inflammatory potency comparable to the standard drug (celecoxib), and interestingly, they exhibited no ulcerogenic effect. Moreover, the promising compounds 3a, 3c, 3i, and 3 l were assessed for their inhibitory properties against the production of various inflammatory mediators (TNF-α, IL-6, and PGE2). They demonstrated a noteworthy suppression efficiency on the emission of TNF-α, IL-6 and PGE2 (TNF-α level range 52.30-63.56 pg/mL, IL-6 level range 165.44–177.17 pg/mL, PGE2 level range 38.46–47.21 pg/mL) relative to celecoxib (49.77, 164.49, and 37.50 pg/mL, respectively). Additionally, the molecular docking studies for the bioactive derivatives 3a, 3c, 3i, and 3l were accomplished to determine the interaction forms inside the binding sites of the inflammatory mediators TNF-α, IL-6, and mPGES-1. The screened receptors exhibited essential binding interactions with the chromone and the 3-oxothiazolo[3,2-a]pyrimidine scaffolds. Finally, ADME investigations of the latter derivatives portended their significant oral bioavailability and GI absorption.