title: Activity of β-lapachone derivatives against rifampicin-susceptible and -resistant strains of Mycobacterium tuberculosis.
abstract: The increase of incidence of tuberculosis (TB) with resistant strains and HIV co-infection has reinforced the necessity of developing new drugs for its treatment. The reaction of naphthoquinones with aromatic or aliphatic aldehydes in the presence of ammonium acetate led to the synthesis of the three β-lapachone derivatives (naphthoimidazoles) that were tested in this study. Phenazines were prepared by the reaction of the respective naphtoquinone with o-phenylenediamine in acetic acid under reflux. The antimicrobial activity of the derivatives was evaluated in vitro against Mycobacterium tuberculosis H37Rv (ATCC 27294) and the rifampicin-resistant strain (ATCC 35338) containing a His-526-Tir mutation in the rpoB gene. Using the Resazurin Microtiter Assay (REMA) method, bioactive molecules were observed in the susceptible and resistant strains with MICs ranging from 2.2 μM to 17 μM. The naphthoimidazoles with p-toluyl and indolyl group attached to the imidazole ring were more active against the H37Rv strain (MIC 9.12 μM and 4.2 μM, respectively) than the rifampicin-resistant strain (MIC 8.3 μM and 17 μM, respectively). The phenazine with the allyl-pyran group was most active among the two strains and had an MIC of 2.2 mM. These results show the potential of these molecules as prototypes for future drugs used in treating TB.
authors.affiliation: Universidade Federal do Rio Grande, Brazil.
authors.forename: Tatiane S
authors.initials: TS
authors.lastname: Coelho
authors.forename: Raphael S F
authors.initials: RS
authors.lastname: Silva
authors.forename: Antonio V
authors.initials: AV
authors.lastname: Pinto
authors.forename: Maria C F R
authors.initials: MC
authors.lastname: Pinto
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Scaini
authors.forename: Kelly C G
authors.initials: KC
authors.lastname: Moura
authors.forename: Pedro
authors.initials: P
authors.lastname: Almeida da Silva
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D002460:Cell Line; D004352:Drug Resistance, Microbial / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009285:Naphthoquinones / Q000494:pharmacology*; D010619:Phenazines / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D009285:Naphthoquinones; D010619:Phenazines; C014638:beta-lapachone; D012293:Rifampin