Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

Christina L Koumpoura (1, 2) , Michel Nguyen (1, 2) , Christian Bijani (1) , Laure Vendier (1) , Elena G Salina (3) , Silvia Buroni (4) , Giulia Degiacomi (4) , Sandrine Cojean (5) , Philippe M Loiseau (5) , Françoise Benoit-Vical (1, 2) , Alfonso T García-Sosa (6) , Anne Robert (1, 2) , Michel Baltas (1, 2)

1 LCC - Laboratoire de chimie de coordination
2 ERL1289 - New Antimalarial Molecules and Pharmacological Approaches
3 RAS - Russian Academy of Sciences [Moscow]
4 DBB UNIPV - Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani" = Department of Biology and Biotechnology [Univ di Pavia]
5 BioCIS - Biomolécules : Conception, Isolement, Synthèse
6 University of Tartu

The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC50 = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC50 = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions.

Mots clés: Aldehydes; Carbon; Inorganic carbon compounds; Multicomponent reactions; Reaction products

Domaines: Biochimie, Biologie Moléculaire

Christina L Koumpoura, Michel Nguyen, Christian Bijani, Laure Vendier, Elena G Salina, et al.. Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides. ACS Omega, 2022, 7 (40), pp.35635-35655. ⟨10.1021/acsomega.2c03421⟩. ⟨hal-03818601⟩