Structure-Based Discovery of Inhibitors of Microsomal Prostaglandin E₂ Synthase−1, 5-Lipoxygenase and 5-Lipoxygenase-Activating Protein: Promising Hits for the Development of New Anti-inflammatory Agents

Abstract

Microsomal prostaglandin E(2) synthase (mPGES)-1 catalyzes the transformation of PGH(2) to PGE(2) that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC(50) value of 3.2 μM, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC(50) = 0.4 μM).

1-(Cyclohex-1-en-1-yl)-3-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-1H-benzimidazol-2(3H)-one

“…1,2,3-Triazoles display a wide range of interesting biological activities, and are used as anti-inflammatory (De Simone et al, 2011), anti-allergic (Buckle et al, 1986) and anti-HIV agents (Giffin et al, 2008;Whiting et al, 2006). They are also effective in the inhibition of histidine biosynthesis (Ventura et al, 1997).…”

Identification and Development of Mpges-1 Inhibitors: Where We are At?

“…As another example, 50 (IC 50 = 3.2 μM) was identified by molecular docking studies on 26 triazole-based compounds. This small set of compounds was designed by taking into account the binding requirements to the active site of MGST-1, which shares significant homology with mPGES-1 [113]. As revealed by molecular modeling, the carboxy group of 50 forms a hydrogen bond with the highly conserved Arg131 in MGST-1 (corresponding to Arg110 in mPGES-1), which is critical for PGH 2 binding.…”

Microwave dielectric heating in modern organic synthesis and drug discovery

“…The microwave irradiation technique was introduced in the two steps to provide a faster way to obtain the desired final compounds in satisfactory yields. Biological evaluation of these compounds disclosed three new potential anti-inflammatory drugs (Simone, R. D. et al, 2011).…”