Furazanopyrazine-based novel promising anticancer agents interfering with the eicosanoid biosynthesis pathways by dual mPGES-1 and sEH inhibition

Abstract

We report the identification of a new set of compounds based on the furazanopyrazine core interfering with eicosanoid biosynthesis and acting as potentially effective anti-inflammatory and anticancer agents. Based on our previous promising results on a set of furazanopyrazine-based compounds against the microsomal prostaglandin E₂ synthase-1 (mPGES-1) enzyme, we here identified derivatives with improved pharmacokinetic properties by replacing the ester moiety with a more stable ether group.A focused virtual library of 1 × 10⁴ molecules was built and screened against mPGES-1 through molecular docking experiments, leading to the selection of 10 candidates for synthesis and biological evaluation. Several molecules were found to inhibit mPGES-1 with IC₅₀ values in the low micromolar range. Additional computational studies on the collection of synthesized compounds demonstrated that compound 3b, previously emerged as an mPGES-1 inhibitor, interfered with soluble epoxide hydrolase (sEH) activity, thus emerging as a valuable dual mPGES-1/sEH inhibitor. The pharmacokinetic features of the most potent compounds were accurately estimated. Unfortunately, poor outcomes were obtained for 3b; on the other hand, compound 7e exhibited promising mPGES-1 inhibition and excellent pharmacokinetic profile, demonstrating that the novel furazanopyrazine-based items with ether functionalities possess improved pharmacokinetic properties compared to the ester-based compounds reported in our previous study. Additionally, the anticancer properties of 7e and 7d, the latter emerged as the most active mPGES-1 inhibitor, were evaluated and both compounds showed promising activities against HCT-116 human colorectal cancer (CRC) cells.These findings highlight the furazanopyrazine core as a promising scaffold for disclosing new anti-inflammatory drugs with the ability to inhibit targets belonging to arachidonic acid cascade.