Antimycobacterial and anti-inflammatory activities of thiourea derivatives focusing on treatment approaches for severe pulmonary tuberculosis
| Autor: | Thatiana Lopes Biá Ventura Simão, Sanderson Dias Calixto, Vinicius de Oliveira Mussi, Elena B. Lasunskaia, Marcos V. Palmeira-Mello, Alessandra Mendonça Teles de Souza, Lucio Mendes Cabral, Paloma Wetler Meireles Carreiros Assumpção, Marianne Grilo Rezende, Carlos Rangel Rodrigues, Gil Mendes Viana, Michelle Frazão Muzitano, Camila Santo |
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| Rok vydání: | 2021 |
| Předmět: |
Tuberculosis
medicine.drug_class Clinical Biochemistry Antitubercular Agents Pharmaceutical Science Inflammation Microbial Sensitivity Tests Pharmacology Antimycobacterial Biochemistry Severity of Illness Index Anti-inflammatory chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Humans Cytotoxicity Molecular Biology Tuberculosis Pulmonary Dose-Response Relationship Drug Molecular Structure Organic Chemistry Anti-Inflammatory Agents Non-Steroidal Thiourea Mycobacterium tuberculosis medicine.disease In vitro chemistry Molecular Medicine medicine.symptom Rifampicin medicine.drug |
| Zdroj: | Bioorganicmedicinal chemistry. 53 |
| ISSN: | 1464-3391 |
| Popis: | Tuberculosis (TB) remains a serious public health problem and one of the main concerns 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±1.1µM, 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. |
| Databáze: | OpenAIRE |
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