Antitrypanosomatid Pharmacomodulation at Position 3 of the 8‐Nitroquinolin‐2(1H)‐one Scaffold Using Palladium‐Catalysed Cross‐Coupling Reactions

• Published in: ChemMedChem Vol. 13; no. 20; pp. 2217 - 2228
• Main Authors: Pedron, Julien, Boudot, Clotilde, Bourgeade‐Delmas, Sandra, Sournia‐Saquet, Alix, Paloque, Lucie, Rastegari, Maryam, Abdoulaye, Mansour, El‐Kashef, Hussein, Bonduelle, Colin, Pratviel, Geneviève, Wyllie, Susan, Fairlamb, Alan H., Courtioux, Bertrand, Verhaeghe, Pierre, Valentin, Alexis
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 22.10.2018; Wiley Subscription Services, Inc; Wiley-VCH Verlag
• Subjects: 8-nitroquinolin-2(1H)-ones; Amastigotes; antikinetoplastid pharmacomodulation; Biocompatibility; Catalysis; Chemical reactions; Chemical synthesis; Chemistry, Medicinal; Coupling; Coupling (molecular); Cytotoxicity; Eflornithine; Hep G2 Cells; Humans; Leishmania donovani - drug effects; Leishmania infantum - drug effects; Life Sciences; Life Sciences & Biomedicine; Molecular Structure; Nitroquinolines - chemical synthesis; Nitroquinolines - chemistry; Nitroquinolines - pharmacology; Nitroquinolines - toxicity; Nitroreductase; Palladium; Palladium - chemistry; palladium-catalysed cross-coupling; parasitic nitroreductases; Parasitic Sensitivity Tests; Pharmacology; Pharmacology & Pharmacy; Protozoa; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; Quinolones - toxicity; Santé publique et épidémiologie; Scaffolds; Science & Technology; Toxicity; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanocidal Agents - toxicity; Trypanosoma brucei brucei - drug effects; trypanosomatids; Trypomastigotes; antikinetoplastid pharmacomodulation; trypanosomatids; DESIGN; TRYPANOSOMA-BRUCEI; ASSAY; ANALOGS; RHODESIENSE; COMPLEXES; parasitic nitroreductases; IDENTIFICATION; DISCOVERY; 8-nitroquinolin-2(1H)-ones; palladium-catalysed cross-coupling
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800456

An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3‐bromo‐8‐nitroquinolin‐2(1H)‐one was conducted. Twenty‐four derivatives were synthesised using the Suzuki–Miyaura cross‐coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para‐carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3‐(4‐carboxyphenyl)‐8‐nitroquinolin‐2(1H)‐one (21) with a lower reduction potential (−0.56 V) than the initial hit (−0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50=1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC50=120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action. Para‐sites against parasites: Antikinetoplastid pharmacomodulation at position 3 of an 8‐nitroquinolin‐2(1H)‐one scaffold was achieved using an optimised Suzuki–Miyaura cross‐coupling reaction. Among the 24 molecules synthesised, a para‐carboxyphenyl derivative was identified as a new selective antitrypanosomal hit with a lower reduction potential. Unlike the initial hit, this compound is not efficiently bioactivated by type I trypanosomal nitroreductase, which suggests an alternative mechanism of action.