title: Antimycobacterial and anti-inflammatory activities of substituted chalcones focusing on an anti-tuberculosis dual treatment approach.
abstract: 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.
authors.affiliation: Laboratório de Biologia do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, RJ, Brazil. thativentura@yahoo.com.br.|Laboratório de Produtos Bioativos, Curso de Farmácia, Universidade Federal do Rio de Janeiro, Campus Macaé, Pólo Novo Cavaleiro-IMMT, Macaé 27933-378, RJ, Brazil. thativentura@yahoo.com.br.
authors.forename: Thatiana Lopes Biá
authors.initials: TL
authors.lastname: Ventura
authors.affiliation: Laboratório de Biologia do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, RJ, Brazil. sandersoncalixto@yahoo.com.br.
authors.forename: Sanderson Dias
authors.initials: SD
authors.lastname: Calixto
authors.affiliation: Faculdade de Farmácia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil. babi_abrahim@hotmail.com.
authors.forename: Bárbara
authors.initials: B
authors.lastname: de Azevedo Abrahim-Vieira
authors.affiliation: Faculdade de Farmácia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil. amtsouza2@yahoo.com.br.
authors.forename: Alessandra Mendonça Teles
authors.initials: AM
authors.lastname: de Souza
authors.affiliation: Instituto de Química, Universidade Federal Fluminense, Niterói, Rio de Janeiro 24020141, RJ, Brazil. mvpmello@id.uff.br.
authors.forename: Marcos Vinícius Palmeira
authors.initials: MV
authors.lastname: Mello
authors.affiliation: Faculdade de Farmácia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil. rangelfarmacia@gmail.com.
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
authors.affiliation: Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, RJ, Brazil. leandrosoter@iq.ufrj.br.
authors.forename: Leandro
authors.initials: L
authors.lastname: Soter de Mariz e Miranda
authors.affiliation: Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, RJ, Brazil. souzarod21@gmail.com.
authors.forename: Rodrigo Octavio Mendonça
authors.initials: RO
authors.lastname: Alves de Souza
authors.affiliation: Faculdade de Farmácia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil. ivanafarma@yahoo.com.br.
authors.forename: Ivana Correa Ramos
authors.initials: IC
authors.lastname: Leal
authors.affiliation: Laboratório de Biologia do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, RJ, Brazil. elassounskaia@gmail.com.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Lasunskaia
authors.affiliation: Laboratório de Produtos Bioativos, Curso de Farmácia, Universidade Federal do Rio de Janeiro, Campus Macaé, Pólo Novo Cavaleiro-IMMT, Macaé 27933-378, RJ, Brazil. mfmuzitano@gmail.com.
authors.forename: Michelle Frazão
authors.initials: MF
authors.lastname: Muzitano
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D002460:Cell Line; D047188:Chalcones / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000995:Antitubercular Agents; D047188:Chalcones; D053583:Interleukin-1beta; D009589:Nitrogen Oxides; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone