1. Aminobenzosuberone derivatives as PfA-M1 inhibitors: Molecular recognition and antiplasmodial evaluation.
- Author
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Salomon E, Schmitt M, Mouray E, McEwen AG, Bounaadja L, Torchy M, Poussin-Courmontagne P, Alavi S, Tarnus C, Cavarelli J, Florent I, and Albrecht S
- Subjects
- Aminopeptidases metabolism, Anisoles chemical synthesis, Anisoles chemistry, Antimalarials chemical synthesis, Antimalarials chemistry, Cycloheptanes chemical synthesis, Cycloheptanes chemistry, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Molecular Structure, Parasitic Sensitivity Tests, Plasmodium falciparum enzymology, Structure-Activity Relationship, Aminopeptidases antagonists & inhibitors, Anisoles pharmacology, Antimalarials pharmacology, Cycloheptanes pharmacology, Enzyme Inhibitors pharmacology, Plasmodium falciparum drug effects
- Abstract
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 IC
50 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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