Design of benzimidazoles, benzoxazoles, benzothiazoles and thiazolopyridines as leukotriene A4 hydrolase inhibitors through 3D-QSAR, docking and molecular dynamics Scientific paper

Abstract

Human leukotriene A₄ hydrolase enzyme (LTA₄H) catalyses the bio­transformation of the inactive precursor leukotriene A₄ (LTA₄) to the bioactive Leukotriene B₄ (LTB₄), which causes many inflammatory responses in the human body. Therefore, the selective inhibition of this enzyme becomes a use­ful strategy for the treatment of several illnesses such as asthma, allergic rhin­itis, cardio­vas­cular diseases, and cancer. Herein we report a 3D-QSAR/CoMFA and CoMSIA study on a series of 47 benzimidazoles, benzo­xazoles, benzothiazoles and thiazolo­pyridines reported as potent LTA4H inhibitors. Good statistical parameters were obtained for the best model (q² = 0.568,
r²_ncv = 0.891 and r²_test = 0.851). A new series of 10 compounds capable of inhibiting leukotriene A₄ hydrolase with high potency was presented. All designed inhi­b­itors showed low IC50 in nano- and sub-nanomolar ranges, when they were evaluated in 3D-QSAR models. Sub­sequently, the designed mole­cules, as well as the least and most active compounds were subjected to dock­ing and mole­cular dynamics studies into LTA₄H. In conclusion, we summar­ised a thorough structure–activity relationship (SAR) of LTA₄H inhibitors of heterocyclic structure. These models can be used for the rational proposal of new inhibitors.