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

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Marcos Lorca
Mario Faundez
C. David Pessoa-Mahana
Benjamin Diethelm-Varela
Gonzalo Recabarren-Gajardo
Daniela Millan
Ismail Celik
Marco Mellado
Ileana Araque
Jaime Mella
Javier Romero-Parra


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,
r2ncv = 0.891 and r2test = 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.


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How to Cite
M. Lorca, “Design of benzimidazoles, benzoxazoles, benzothiazoles and thiazolopyridines as leukotriene A4 hydrolase inhibitors through 3D-QSAR, docking and molecular dynamics: Scientific paper”, J. Serb. Chem. Soc., vol. 88, no. 1, pp. 25–39, Dec. 2022.
Theoretical Chemistry
Author Biography

Javier Romero-Parra, Department of Organic Chemistry and Physical Chemistry, Faculty of Chemistry and Pharmaceutical Sciences, University of Chile, Santiago 8380544, Chile



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