Anti-Mycobacterium tuberculosis activity of naphthoimidazoles combined with isoniazid and rifampicin.

Tuberculosis (TB) is the cause of more than one million deaths worldwide, and despite being a curable disease, some factors can make therapy difficult, emphasizing the need for the development of new drugs that may potentiate the action of the classic anti-TB antimicrobials. Naphthoimidazoles show a broad spectrum of biological activities, including antimycobacterial activity. The aim of this study was to evaluate the anti-Mycobacterium tuberculosis activity of nine naphthoimidazoles, alone and combined with isoniazid (INH) and rifampicin (RIF). We evaluated the minimum inhibitory concentration (MIC) of the compounds, the fractional inhibitory concentration of the combinations of the naphthoimidazoles with INH or RIF, and the cytotoxicity of these compounds. Eight compounds showed MICs ranging from 1.56 to 25 µg/mL and the presence of substituents on phenyl groups shown to be essential for antimycobacterial activity. Four compounds showed additivity with both INH and RIF and showed SI values higher than 10, indicating safety. Thus, considering the antimycobacterial activity and the absence of antagonism between naphthoimidazoles and the two main drugs for TB treatment, these compounds could be scaffolds for the development of new anti-TB drugs.

Differential Gel Electrophoresis (DIGE) Evaluation of Naphthoimidazoles Mode of Action: A Study in Trypanosoma cruzi Bloodstream Trypomastigotes.

BACKGROUND: The obligate intracellular protozoan Trypanosoma cruzi is the causative agent of Chagas disease, a neglected illness affecting millions of people in Latin America that recently entered non-endemic countries through immigration, as a consequence of globalization. The chemotherapy for this disease is based mainly on benznidazole and nifurtimox, which are very efficient nitroderivatives against the acute stage but present limited efficacy during the chronic phase. Our group has been studying the trypanocidal effects of naturally occurring quinones and their derivatives, and naphthoimidazoles derived from ß-lapachone N1, N2 and N3 were the most active. To assess the molecular mechanisms of action of these compounds, we applied proteomic techniques to analyze treated bloodstream trypomastigotes, which are the clinically relevant stage of the parasite. METHODOLOGY/PRINCIPAL FINDINGS: The approach consisted of quantification by 2D-DIGE followed by MALDI-TOF/TOF protein identification. A total of 61 differentially abundant protein spots were detected when comparing the control with each N1, N2 or N3 treatment, for 34 identified spots. Among the differentially abundant proteins were activated protein kinase C receptor, tubulin isoforms, asparagine synthetase, arginine kinase, elongation factor 2, enolase, guanine deaminase, heat shock proteins, hypothetical proteins, paraflagellar rod components, RAB GDP dissociation inhibitor, succinyl-CoA ligase, ATP synthase subunit B and methionine sulfoxide reductase. CONCLUSION/SIGNIFICANCE: Our results point to different modes of action for N1, N2 and N3, which indicate a great variety of metabolic pathways involved and allow for novel perspectives on the development of trypanocidal agents.