2. Academic Validation
  3. Antimycobacterial and anti-inflammatory activities of thiourea derivatives focusing on treatment approaches for severe pulmonary tuberculosis

Antimycobacterial and anti-inflammatory activities of thiourea derivatives focusing on treatment approaches for severe pulmonary tuberculosis

  • Bioorg Med Chem. 2022 Jan 1;53:116506. doi: 10.1016/j.bmc.2021.116506.
Sanderson Dias Calixto 1,  Thatiana Lopes Biá Ventura Simão 1,  Marcos Vinicius Palmeira-Mello 2,  Gil Mendes Viana 3,  Paloma Wetler Meireles Carreiros Assumpção 3,  Marianne Grilo Rezende 3,  Camila Couto do Espirito Santo 4,  Vinicius de Oliveira Mussi 4,  Carlos Rangel Rodrigues 5,  Elena Lasunskaia 4,  Alessandra Mendonça Teles de Souza 5,  Lúcio Mendes Cabral 6,  Michelle Frazão Muzitano 7
Affiliations

Affiliations

  • 1 Universidade Federal do Rio de Janeiro, Campus Macaé, Pólo Novo Cavaleiro, Laboratório de Produtos Bioativos, Curso de Farmácia, Macaé, RJ, Brazil; Universidade Estadual do Norte Fluminense Darcy Ribeiro, Laboratório de Biologia do Reconhecer, Centro de Biociências e Biotecnologia, Campos dos Goytacazes, RJ, Brazil.
  • 2 Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Laboratório de Modelagem Molecular & QSAR (ModMolQSAR), Rio de Janeiro, RJ, Brazil; Universidade Federal Fluminense, Instituto de Química, Valonguinho, Niteroi, RJ, Brazil.
  • 3 Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Laboratório de Tecnologia Industrial Farmacêutica, Rio de Janeiro, RJ, Brazil.
  • 4 Universidade Estadual do Norte Fluminense Darcy Ribeiro, Laboratório de Biologia do Reconhecer, Centro de Biociências e Biotecnologia, Campos dos Goytacazes, RJ, Brazil.
  • 5 Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Laboratório de Modelagem Molecular & QSAR (ModMolQSAR), Rio de Janeiro, RJ, Brazil.
  • 6 Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Laboratório de Tecnologia Industrial Farmacêutica, Rio de Janeiro, RJ, Brazil. Electronic address: lmcabral@pharma.ufrj.br.
  • 7 Universidade Federal do Rio de Janeiro, Campus Macaé, Pólo Novo Cavaleiro, Laboratório de Produtos Bioativos, Curso de Farmácia, Macaé, RJ, Brazil. Electronic address: mfmuzitano@macae.ufrj.br.
PMID: 34890996 DOI: 10.1016/j.bmc.2021.116506
Abstract

Tuberculosis (TB) remains a serious public health problem and one of the main concern is the emergence of multidrug-resistant and extensively resistant TB. Hyper-reactive patients develop inflammatory necrotic lung lesions that aggravate the pathology and facilitate transmission of mycobacteria. Treatment of severe TB is a major clinical challenge that has few effective solutions and patients face a poor prognosis, years of treatment and different adverse drug reactions. In this work, fifteen novel and thirty-one unusual thiourea derivatives were synthesized and evaluated in vitro for their antimycobacterial and anti-inflammatory potential and, in silico for ADMET parameters and for structure-activity relationship (SAR). Thioureas derivatives 10, 15, 16, 28 and 29 that had shown low cytotoxicity and high activities were selected for further investigation, after SAR study. These five thioureas derivatives inhibited Mtb H37Rv growth in Bacterial culture and in infected macrophages, highlighting thiourea derivative 28 (MIC50 2.0 ± 1.1 and 2.3 ± 1.1 µM, respectively). Moreover, these compounds were active against the hypervirulent clinical Mtb strain M299, in Bacterial culture, especially 16, 28 and 29, and in extracellular clumps, highlighting 29, with MIC50 5.6 ± 1.2 µM. Regarding inflammation, they inhibited NO through the suppression of iNOS expression, and also inhibited the production of TNF-α and IL-1β. In silico studies were carried out suggesting that these five compounds could be administered by oral route and have low toxicological effects when compared to rifampicin. In conclusion, our data show that, at least, thiourea derivatives 16, 28 and 29 are promising antimycobacterial and anti-inflammatory agents, and candidates for further prospective studies aiming new anti-TB drugs, that can be used on a dual approach for the treatment of severe TB cases associated with exacerbated inflammation.

Keywords

Inflammation; Mycobacterium; Structure-activity relationship; Thiourea; Tuberculosis.

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