2. Academic Validation
  3. Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

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

  • ACS Omega. 2022 Oct 3;7(40):35635-35655. doi: 10.1021/acsomega.2c03421.
Christina L Koumpoura 1,  Michel Nguyen 1,  Christian Bijani 1,  Laure Vendier 1,  Elena G Salina 2,  Silvia Buroni 3,  Giulia Degiacomi 3,  Sandrine Cojean 4,  Philippe M Loiseau 4,  Françoise Benoit-Vical 1,  Alfonso T García-Sosa 5,  Anne Robert 1,  Michel Baltas 1
Affiliations

Affiliations

  • 1 Laboratoire de Chimie de Coordination du CNRS-UPR8241, Inserm ERL 1289 Team "New antiplasmodial molecules and pharmacological approaches", 205 route de Narbonne, BP 44099, Toulouse Cedex 31077, France.
  • 2 Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia.
  • 3 Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia 27100, Italy.
  • 4 Antiparasite Chemotherapy, UMR 8076 CNRS BioCIS, Faculty of Pharmacy, University Paris-Saclay, Châtenay-Malabry 92290, France.
  • 5 Department of Molecular Technology, Institute of Chemistry, University of Tartu, Ravila 14a, Tartu 50411, Estonia.
PMID: 36249398 DOI: 10.1021/acsomega.2c03421
Abstract

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.

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