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

Human leukotriene A₄ hydrolase enzyme (LTA₄H) catalyses the bio-transformation 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.