Synthesis and Antimycobacterial Activity of 3-Phenyl-1 H-indoles

  • Molecules. 2021 Aug 25;26(17):5148. doi: 10.3390/molecules26175148.
Renata Jardim Etchart  1  2 ,  Raoní S Rambo  1 ,  Bruno Lopes Abbadi  1 ,  Nathalia Sperotto  1 ,  Christiano Ev Neves  1  2 ,  Fernanda Fries Silva  1  2 ,  Maiele Dornelles  1 ,  Lovaine Duarte  1 ,  Fernanda Souza Macchi  1  2 ,  Marcia Alberton Perelló  1 ,  Rogério Vescia Lourega  3 ,  Cristiano Valim Bizarro  1  2 ,  Luiz Augusto Basso  1  2  4 ,  Pablo Machado  1  2  4
Affiliations
  • 1. Centro de Pesquisas em Biologia Molecular e Funcional, Instituto Nacional de Ciência e Tecnologia em Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681-Prédio 92A, Porto Alegre 90616-900, RS, Brazil.
  • 2. Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre 90616-900, RS, Brazil.
  • 3. Instituto de Química, Departamento de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, RS, Brazil.
  • 4. Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre 90616-900, RS, Brazil.
PMID: 34500579 DOI: 10.3390/molecules26175148
Abstract

Tuberculosis has been described as a global health crisis since the 1990s, with an estimated 1.4 million deaths in the last year. Herein, a series of 20 1H-indoles were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Furthermore, the top hit compounds were active against multidrug-resistant strains, without cross-resistance with first-line drugs. Exposing HepG2 and Vero cells to the molecules for 72 h showed that one of the evaluated structures was devoid of apparent toxicity. In addition, this 3-phenyl-1H-indole showed no genotoxicity signals. Finally, time-kill and pharmacodynamic model analyses demonstrated that this compound has bactericidal activity at concentrations close to the Minimum Inhibitory Concentration, coupled with a strong time-dependent behavior. To the best of our knowledge, this study describes the activity of 3-phenyl-1H-indole against Mtb for the first time.

Keywords
1H-indoles; Mycobacterium tuberculosis; genotoxicity; mammalian cellular viability; pharmacodynamic model; time-kill.
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