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Structure‐Based Design of Microsomal Prostaglandin E 2 Synthase‐1 (mPGES‐1) Inhibitors using a Virtual Fragment Growing Optimization Scheme
Author(s) -
Lauro Gianluigi,
Tortorella Paolo,
Bertamino Alessia,
Ostacolo Carmine,
Koeberle Andreas,
Fischer Katrin,
Bruno Ines,
Terracciano Stefania,
GomezMonterrey Isabel Maria,
Tauro Marilena,
Loiodice Fulvio,
Novellino Ettore,
Riccio Raffaele,
Werz Oliver,
Campiglia Pietro,
Bifulco Giuseppe
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500598
Subject(s) - moiety , chemistry , virtual screening , small molecule , stereochemistry , sulfonamide , microsome , combinatorial chemistry , active site , ic50 , atp synthase , prostaglandin , structure–activity relationship , molecule , enzyme , in vitro , biochemistry , pharmacophore , organic chemistry
A small library of 2,3‐dihydroxybenzamide‐ and N ‐(2,3‐dihydroxyphenyl)‐4‐sulfonamide‐based microsomal prostaglandin E 2 synthase‐1 (mPGES‐1) inhibitors was identified following a step‐by‐step optimization of small aromatic fragments selected to interact in focused regions in the active site of mPGES‐1. During the virtual optimization process, the 2,3‐dihydroxybenzamide moiety was first selected as a backbone of the proposed new chemical entities; the identified compounds were then synthesized and biologically evaluated, identifying derivatives with very promising inhibitory activities in the micromolar range. Subsequent structure‐guided replacement of the 2,3‐dihydroxybenzamide by the N ‐(2,3‐dihydroxyphenyl)sulfonamide moiety led to the identification of N ‐(2,3‐dihydroxyphenyl)‐4‐biphenylsulfonamide ( 6 ), the most potent small molecule of the series (IC 50 =0.53±0.04 μ m ). The simple synthetic procedure and the possibility of enhancing the potency of this class of inhibitors through additional structural modifications pave the way for further development of new molecules with mPGES‐1‐inhibitory activity, with potential application as anti‐inflammatory and anticancer agents.