Antimycobacterial and Anti-Inflammatory Activities of Substituted Chalcones Focusing on an Anti-Tuberculosis Dual Treatment Approach

Molecules

Thatiana Lopes Biá Ventura³  Sanderson Dias Calixto³  Bárbara de Azevedo Abrahim-Vieira⁴  Alessandra Mendon๺ Teles de Souza⁴  Marcos Vinໜius Palmeira Mello²  Carlos Rangel Rodrigues⁴  Leandro Soter de Mariz e Miranda⁵  Rodrigo Octavio Mendon๺ Alves de Souza⁵  Ivana Correa Ramos Leal⁴  Elena B. Lasunskaia³  Michelle Frazão Muzitano¹ 

[1] Laboratório de Produtos Bioativos, Curso de Farmácia, Universidade Federal do Rio de Janeiro, Campus Macaé, Pólo Novo Cavaleiro—IMMT, Macaé 27933-378, RJ, Brazil;Instituto de Química, Universidade Federal Fluminense, Niterói, Rio de Janeiro 24020141, RJ, Brazil; E-Mail:;Laboratório de Biologia do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, RJ, Brazil; E-Mails:;Faculdade de Farmácia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil; E-Mails:;Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, RJ, Brazil; E-Mails:

关键词: tuberculosis;    Mycobacterium;    inflammation;    chalcone;   

DOI  :  10.3390/molecules20058072

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.