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

[Display omitted] •Synthesis of thiourea derivatives exhibiting antimycobacterial and anti-inflammatory activities.•Five thioureas derivatives showed notable antimycobacterial activity with low cytotoxicity.•Fifteen are novel thioureas derivatives.•Five thioureas derivatives were further active when...

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Published in:Bioorganic & medicinal chemistry 2022-01, Vol.53, p.116506-116506, Article 116506
Main Authors: Calixto, Sanderson Dias, Simão, Thatiana Lopes Biá Ventura, Palmeira-Mello, Marcos Vinicius, Viana, Gil Mendes, Assumpção, Paloma Wetler Meireles Carreiros, Rezende, Marianne Grilo, do Espirito Santo, Camila Couto, de Oliveira Mussi, Vinicius, Rodrigues, Carlos Rangel, Lasunskaia, Elena, de Souza, Alessandra Mendonça Teles, Cabral, Lúcio Mendes, Muzitano, Michelle Frazão
Format: Article
Language:English
Subjects:
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - chemistry
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Antitubercular Agents - chemical synthesis
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Dose-Response Relationship, Drug
Humans
Inflammation
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium
Mycobacterium tuberculosis - drug effects
Severity of Illness Index
Structure-Activity Relationship
Thiourea
Thiourea - chemical synthesis
Thiourea - chemistry
Thiourea - pharmacology
Tuberculosis
Tuberculosis, Pulmonary - drug therapy
Tuberculosis, Pulmonary - microbiology
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Summary:[Display omitted] •Synthesis of thiourea derivatives exhibiting antimycobacterial and anti-inflammatory activities.•Five thioureas derivatives showed notable antimycobacterial activity with low cytotoxicity.•Fifteen are novel thioureas derivatives.•Five thioureas derivatives were further active when evaluated in infected macrophages in vitro and in hypervirulent extracellular aggregates of Mtb.•Thiourea derivatives 16, 28 and 29 are promising candidates for further in vivo studies. 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2021.116506