5-methyl-2-carboxamidepyrrole-based novel dual mPGES-1/sEH inhibitors as promising anticancer candidates

Abstract

Inhibiting microsomal prostaglandin E₂ synthase-1 (mPGES-1), an inducible enzyme involved in prostaglandin E₂ (PGE₂) biosynthesis and tumor microenvironment (TME) homeostasis, is a valuable strategy for treating inflammation and cancer. In this work, 5-methylcarboxamidepyrrole-based molecules were designed and synthesized as new compounds targeting mPGES-1. Remarkably, compounds 1f, 2b, 2c, and 2d were able to significantly reduce the activity of the isolated enzyme, showing IC₅₀ values in the low micromolar range. With the aim of further profiling the synthesized molecules, their ability to interfere with the activity of soluble epoxide hydrolase (sEH), whose inhibition blocks the loss of the anti-inflammatory mediators epoxyeicosatrienoic acids (EETs or epoxyicosatrienoic acids), was investigated in silico and by employing specific biological assays. Among the set of tested compounds, 1f, 2b, 2c, and 2d emerged as mPGES-1/sEH dual inhibitors. Moreover, given that overexpression of mPGES-1 has been observed in many human tumors, we finally explored the biological effect of our compounds in an in vitro model of human colorectal cancer (CRC). The obtained outcomes pave the way for future investigation to optimize and further characterize anticancer pharmacological profile of the carboxamidepyrrole-based molecules.