2. Academic Validation
  3. Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

  • J Med Chem. 2021 May 13;64(9):6397-6409. doi: 10.1021/acs.jmedchem.1c00483.
Jan-Frederik Uth 1,  Frederik Börgel 1,  Kirstin Lehmkuhl 1,  Dirk Schepmann 1,  Marcel Kaiser 2,  Valquiria A P Jabor 3,  Maria Cristina Nonato 3,  R Luise Krauth-Siegel 4,  Thomas J Schmidt 5,  Bernhard Wünsch 1 6
Affiliations

Affiliations

  • 1 Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
  • 2 Swiss Tropical and Public Health Institute (Swiss TPH), Socinstraße 57, CH-4002 Basel, Switzerland.
  • 3 Laboratório de Cristalografia de Proteínas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. Café, s/n, 14040-903 Ribeirão Preto, SP, Brazil.
  • 4 Biochemie-Zentrum der Universität Heidelberg (BZH), Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.
  • 5 Institut für Pharmazeutische Biologie und Phytochemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
  • 6 GRK 2515, Chemical Biology of Ion Channels (Chembion), Westfälische Wilhelms-Universität, 48149 Münster, Germany.
PMID: 33901399 DOI: 10.1021/acs.jmedchem.1c00483
Abstract

Herein, relationships between the structures of 1-aminoethyl-substituted chromenes and their antimalarial activities were thoroughly investigated. At first, the methyl moiety in the side chain was removed to eliminate chirality. The hydrogenation state of the benzopyran system, the position of the phenolic OH moiety, and the distance of the basic amino moiety toward both aromatic rings were varied systematically. 1-Benzopyran-5-ol 8b (IC50 = 10 nM), 1-benzopyran-7-ol 9c (IC50 = 38 nM), and the aminoalcohol 19c (IC50 = 17 nM) displayed antiplasmodial activity with IC50 values below 50 nM. To identify the mechanism of action, inhibition of three key Enzymes by 9c was investigated. 9c was not able to reduce the number of Plasmodia in erythrocytes of mice. This low in vivo activity was explained by fast clearance from blood plasma combined with rapid biotransformation of 9c. Three main metabolites of 9c were identified by liquid chromatography-mass spectrometry (LC-MS) methods.

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