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Benzoylthioureas: Design, Synthesis and Antimycobacterial Evaluation

Author(s):

Tiago O. Brito, Lethícia O. Abreu, Karen M. Gomes, Maria C. S. Lourenço, Patricia M. L. Pereira, Sueli F. Yamada-Ogatta, Ângelo de Fàtima, Cesar A. Tisher, Fernando Macedo and Marcelle L. F. Bispo*   Pages 1 - 11 ( 11 )

Abstract:


Background: New drugs and strategies to treat tuberculosis (TB) are urgently needed. In this context, thiourea derivatives have a wide range of biological activities, including anti-TB. This fact can be illustrated with the structure of isoxyl, an old anti-TB drug, which have a thiourea as pharmacophore group.

Objective: The aim of this study is to describe the synthesis and the antimycobacterial activity of fifty-nine benzoylthioureas derivatives.

Method: Benzoylthiourea derivatives have been synthesized and evaluated for their activity against Mycobacterium tuberculosis using the MABA assay. After that, a structure-activity relationship study of this series of compounds has been performed.

Results and Discussion: Nineteen compounds exhibited antimycobacterial activity between 423.1 and 9.6 µM. In general, we observed that the presence of bromine, chlorine and t-Bu group at the para-position in benzene ring plays an important role in the antitubercular activity of Series A. These substituents were fixed at this position in benzene ring and other groups such as Cl, Br, NO2 and OMe were introduced in the benzoyl ring, leading to the derivatives of Series B. In general, Series B was less cytotoxic than Series A, which indicates that the presence of a substituent at benzoyl ring contributes to an improvement in both antimycobacterial activity and toxicity profiles.

Conclusion: The compound 4c could be considered a good prototype to be submitted to further structural modifications in the search for new anti-TB drugs, since it is 1.8 times more active than the first line anti-TB drug ethambutol and 0.65 times less active than isoxyl.

Keywords:

antimycobacterial activity, tuberculosis, thioureas, benzoylthioureas, structure-activity relationship, drugs.

Affiliation:

Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid (PR 445), Km 380, Campus Universitário, Londrina – PR, 86057-970, Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid (PR 445), Km 380, Campus Universitário, Londrina – PR, 86057-970, Laboratório de Bacteriologia e Bioensaios, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Av Brasil, 4365, Manguinhos, Rio de Janeiro – RJ, 21040-360, Laboratório de Bacteriologia e Bioensaios, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Av Brasil, 4365, Manguinhos, Rio de Janeiro – RJ, 21040-360, Departamento de Microbiologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid (PR 445), Km 380, Campus Universitário, Londrina – PR, 86057-970, Departamento de Microbiologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid (PR 445), Km 380, Campus Universitário, Londrina – PR, 86057-970, Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Av Antônio Carlos, 6627, Pampulha, Belo Horizonte – MG, 31270-901, Departamento de Bioquímica e Biotecnologia, Centro de Ciências Exatas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid (PR 445), Km 380, Campus Universitário, Londrina – PR, 86057-970, Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid (PR 445), Km 380, Campus Universitário, Londrina – PR, 86057-970, Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid (PR 445), Km 380, Campus Universitário, Londrina – PR, 86057-970



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