2. Academic Validation
  3. 6-Fluorophenylbenzohydrazides inhibit Mycobacterium tuberculosis growth through alteration of tryptophan biosynthesis

6-Fluorophenylbenzohydrazides inhibit Mycobacterium tuberculosis growth through alteration of tryptophan biosynthesis

  • Eur J Med Chem. 2021 Dec 15:226:113843. doi: 10.1016/j.ejmech.2021.113843.
Sara Consalvi 1,  Giulia Venditti 1,  Junhao Zhu 2,  Helena I Boshoff 3,  Kriti Arora 3,  Alessandro De Logu 4,  Thomas R Ioerger 5,  Eric J Rubin 2,  Mariangela Biava 6,  Giovanna Poce 7
Affiliations

Affiliations

  • 1 Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy.
  • 2 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA.
  • 3 National Institute of Allergy and Infectious Diseases, Laboratory of Clinical Immunology and Microbiology, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
  • 4 Department of Life and Environmental Sciences, University of Cagliari, via Ospedale 72, 09124, Cagliari, Italy.
  • 5 Department of Computer Science, Texas A&M University, 3112 TAMU, College Station, TX, 77843, USA.
  • 6 Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy. Electronic address: mariangela.biava@uniroma1.it.
  • 7 Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy. Electronic address: giovanna.poce@uniroma1.it.
PMID: 34520959 DOI: 10.1016/j.ejmech.2021.113843
Abstract

A major constraint in reducing tuberculosis epidemic is the emergence of strains resistant to one or more of clinically approved Antibiotics, which emphasizes the need of novel drugs with novel targets. Genetic knockout strains of Mycobacterium tuberculosis (Mtb) have established that tryptophan (Trp) biosynthesis is essential for the bacterium to survive in vivo and cause disease in animal models. An anthranilate-like compound, 6-FABA, was previously shown to synergize with the host immune response to Mtb Infection in vivo. Herein, we present a class of anthranilate-like compounds endowed with good antimycobacterial activity and low cytotoxicity. We show how replacing the carboxylic moiety with a hydrazide led to a significant improvement in both activity and cytotoxicity relative to the parent compound 6-FABA. Several new benzohydrazides (compounds 20-31, 33, 34, 36, 38 and 39) showed good activities against Mtb (0.625 ≤ MIC≤6.25 μM) and demonstrated no detectable cytotoxicity against Vero cell assay (CC50 ≥ 1360 μM). The target preliminary studies confirmed the hypothesis that this new class of compounds inhibits Trp biosynthesis. Taken together, these findings indicate that fluorophenylbenzohydrazides represent good candidates to be assessed for drug discovery.

Keywords

6-Fluorophenylbenzohydrazides; Drug development; Tryptophan biosynthesis; Tuberculosis.

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