Antimycobacterial and Anti-Inflammatory Activities of Substituted Chalcones Focusing on an Anti-Tuberculosis Dual Treatment Approach
Thatiana Lopes Biá Ventura,
Sanderson Dias Calixto,
Bárbara de Azevedo Abrahim-Vieira,
Alessandra Mendonça Teles de Souza,
Marcos Vinícius Palmeira Mello,
Carlos Rangel Rodrigues,
Leandro Soter de Mariz e Miranda,
Rodrigo Octavio Mendonça Alves de Souza,
Ivana Correa Ramos Leal,
Elena B. Lasunskaia,
Michelle Frazão Muzitano
Affiliations
Thatiana Lopes Biá Ventura
Laboratório de Biologia do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, RJ, Brazil
Sanderson Dias Calixto
Laboratório de Biologia do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, RJ, Brazil
Bárbara de Azevedo Abrahim-Vieira
Faculdade de Farmácia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil
Alessandra Mendonça Teles de Souza
Faculdade de Farmácia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil
Marcos Vinícius Palmeira Mello
Instituto de Química, Universidade Federal Fluminense, Niterói, Rio de Janeiro 24020141, RJ, Brazil
Carlos Rangel Rodrigues
Faculdade de Farmácia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil
Leandro Soter de Mariz e Miranda
Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, RJ, Brazil
Rodrigo Octavio Mendonça Alves de Souza
Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, RJ, Brazil
Ivana Correa Ramos Leal
Faculdade de Farmácia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil
Elena B. Lasunskaia
Laboratório de Biologia do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, RJ, Brazil
Michelle Frazão Muzitano
Laboratório de Produtos Bioativos, Curso de Farmácia, Universidade Federal do Rio de Janeiro, Campus Macaé, Pólo Novo Cavaleiro—IMMT, Macaé 27933-378, RJ, Brazil
Tuberculosis (TB) remains a serious public health problem aggravated by the emergence of M. tuberculosis (Mtb) strains resistant to multiple drugs (MDR). Delay in TB treatment, common in the MDR-TB cases, can lead to deleterious life-threatening inflammation in susceptible hyper-reactive individuals, encouraging the discovery of new anti-Mtb drugs and the use of adjunctive therapy based on anti-inflammatory interventions. In this study, a series of forty synthetic chalcones was evaluated in vitro for their anti-inflammatory and antimycobacterial properties and in silico for pharmacokinetic parameters. Seven compounds strongly inhibited NO and PGE2 production by LPS-stimulated macrophages through the specific inhibition of iNOS and COX-2 expression, respectively, with compounds 4 and 5 standing out in this respect. Four of the seven most active compounds were able to inhibit production of TNF-α and IL-1β. Chalcones that were not toxic to cultured macrophages were tested for antimycobacterial activity. Eight compounds were able to inhibit growth of the M. bovis BCG and Mtb H37Rv strains in bacterial cultures and in infected macrophages. Four of them, including compounds 4 and 5, were active against a hypervirulent clinical Mtb isolate as well. In silico analysis of ADMET properties showed that the evaluated chalcones displayed satisfactory pharmacokinetic parameters. In conclusion, the obtained data demonstrate that at least two of the studied chalcones, compounds 4 and 5, are promising antimycobacterial and anti-inflammatory agents, especially focusing on an anti-tuberculosis dual treatment approach.
