2. Academic Validation
  3. Design, synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: Preliminary data and computational analysis

Design, synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: Preliminary data and computational analysis

  • Bioorg Med Chem Lett. 2019 Sep 1;29(17):2468-2474. doi: 10.1016/j.bmcl.2019.07.025.
Daniele Zampieri 1,  Maria Grazia Mamolo 2,  Julia Filingeri 2,  Sara Fortuna 2,  Alessandro De Logu 3,  Adriana Sanna 4,  Davide Zanon 5
Affiliations

Affiliations

  • 1 Department of Chemistry and Pharmaceutical Sciences, University of Trieste, P.le Europa 1-Via Giorgeri 1, 34127 Trieste, Italy. Electronic address: dzampieri@units.it.
  • 2 Department of Chemistry and Pharmaceutical Sciences, University of Trieste, P.le Europa 1-Via Giorgeri 1, 34127 Trieste, Italy.
  • 3 Department of Life and Environmental Sciences, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy.
  • 4 Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy.
  • 5 Pharmacy and Clinical Pharmacology Department, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell'Istria 65/1, 34137 Trieste, Italy.
PMID: 31350124 DOI: 10.1016/j.bmcl.2019.07.025
Abstract

This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125-0.250 μg/mL (0.37-0.75 μM) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans.

Keywords

ADME; Antimycobacterial activity; Benzoxazinone; Molecular dynamics; Oxoacetamide.

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