Aminobenzosuberone derivatives as PfA-M1 inhibitors: Molecular recognition and antiplasmodial evaluation

Emmanuel Salomon (1) , Marjorie Schmitt (1) , Elisabeth Mouray (2) , Alastair G Mcewen (3) , Lotfi Bounaadja (2) , Morgan Torchy (3) , Pierre Poussin-Courmontagne (3) , Sarah Alavi (4) , Céline Tarnus (5) , Jean Cavarelli (3) , Isabelle Florent (2) , Sebastien Albrecht (1)

1 LIMA - Laboratoire d'innovation moléculaire et applications
2 MCAM - Molécules de Communication et Adaptation des Micro-organismes
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
4 COB - Laboratoire de Chimie organique et bioorganique
5 Université de Haute-Alsace (UHA) - Université de Haute-Alsace (UHA) Mulhouse - Colmar

Aminobenzosuberone-based PfA-M1 inhibitors were explored as novel antimalarial agents against two different Plasmodium falciparum strains. The 4-phenyl derivative 7c exhibited the most encouraging growth inhibitory activity with IC50 values of 6.5-11.2 µM. X-ray crystal structures and early assessment of DMPK/ADME-Tox parameters allowed us to initiate structure-based drug design approach and understand the liabilities (such as potential metabolic and aqueous solubility issues) as well as identify the opportunities for improvement of this aminobenzosuberone series. It also suggested that compound 7c should be regarded as an attractive chemical tool to investigate the different biological roles of this multifunctional PfA-M1 protein.

Mots clés: protein crystallization; aminobenzosuberone inhibitors; antiplasmodial activity; PfA-M1 aminopeptidase

Domaines: Chimie thérapeutique; Biologie structurale [q-bio.BM]

Emmanuel Salomon, Marjorie Schmitt, Elisabeth Mouray, Alastair G Mcewen, Lotfi Bounaadja, et al.. Aminobenzosuberone derivatives as PfA-M1 inhibitors: Molecular recognition and antiplasmodial evaluation. Bioorganic Chemistry, 2020, 98, pp.103750. ⟨10.1016/j.bioorg.2020.103750⟩. ⟨hal-02530528⟩