1. Academic Validation
  2. Expanding the knowledge around antitubercular 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides: Hit-to-lead optimization and release of a novel antitubercular chemotype via scaffold derivatization

Expanding the knowledge around antitubercular 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides: Hit-to-lead optimization and release of a novel antitubercular chemotype via scaffold derivatization

  • Eur J Med Chem. 2023 Jan 5;245(Pt 2):114916. doi: 10.1016/j.ejmech.2022.114916.
Miriam Girardini 1 Francesca Ferlenghi 2 Giannamaria Annunziato 1 Giulia Degiacomi 3 Bianca Papotti 4 Cinzia Marchi 4 José Camilla Sammartino 3 Sari S Rasheed 5 Anna Contini 1 Maria Rosalia Pasca 3 Federica Vacondio 2 Joanna C Evans 6 Thomas Dick 7 Rolf Müller 5 Gabriele Costantino 8 Marco Pieroni 9
Affiliations

Affiliations

  • 1 P4T Group, Italy; Department of Food and Drug, University of Parma, 43124, Parma, Italy.
  • 2 Department of Food and Drug, University of Parma, 43124, Parma, Italy; Centro Interdipartimentale "Biopharmanet-tec", Università degli Studi di Parma, Parma, Italy.
  • 3 Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, 27100, Pavia, Italy.
  • 4 Department of Food and Drug, University of Parma, 43124, Parma, Italy.
  • 5 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123, Saarbrücken, Germany; German Centre for Infection Research, partner site Hannover-Braunschweig, Germany.
  • 6 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
  • 7 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ, USA; Department of Microbiology and Immunology, Georgetown University, Washington DC, USA.
  • 8 P4T Group, Italy; Department of Food and Drug, University of Parma, 43124, Parma, Italy; Centro Interdipartimentale "Biopharmanet-tec", Università degli Studi di Parma, Parma, Italy; Centro Interdipartimentale Misure (CIM) 'G. Casnati', University of Parma, Parma, Italy.
  • 9 P4T Group, Italy; Department of Food and Drug, University of Parma, 43124, Parma, Italy; Centro Interdipartimentale "Biopharmanet-tec", Università degli Studi di Parma, Parma, Italy. Electronic address: [email protected].
Abstract

Tuberculosis is one of the deadliest infectious diseases in the world, and the increased number of multidrug-resistant and extensively drug-resistant strains is a reason for concern. We have previously reported a series of substituted 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides with growth inhibitory activity against Mycobacterium tuberculosis strains and low propensity to be substrate of efflux pumps. Encouraged by these preliminary results, we have undertaken a medicinal chemistry campaign to determine the metabolic fate of these compounds and to delineate a reliable body of Structure-Activity Relationships. Keeping intact the (thiazol-4-yl)isoxazole-3-carboxamide core, as it is deemed to be the pharmacophore of the molecule, we have extensively explored the structural modifications able to confer good activity and avoid rapid clearance. Also, a small set of analogues based on isostere manipulation of the 2-aminothiazole were prepared and tested, with the aim to disclose novel antitubercular chemotypes. These studies, combined, were instrumental in designing improved compounds such as 42g and 42l, escaping metabolic degradation by human liver microsomes and, at the same time, maintaining good antitubercular activity against both drug-susceptible and drug-resistant strains.

Keywords

2-Aminothiazoles; Drug discovery; Drug metabolism; Isoxazole-3-carboxyamides; Structure–activity relationships; Tuberculosis.

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