N-Myristoyltransferases as antileishmanial targets: a piggyback approach with benzoheterocyclic analogues

Leishmaniasis is one of the neglected diseases that remain in need for pharmacological alternatives. In this context, N-Myristoyltransferases (NMT) arise as interesting targets to explore since they are involved in the co/post-translational processing of peptides which are responsible for host cell invasion. Studies that consider these enzymes as targets point out the potential of benzoheterocyclic compounds as inhibitors of Candida albicans's N-myristoyltransferase. Here we applied a combination of comparative binding site analysis and molecular docking studies based on a Piggyback approach in the search for new Leishmania major NMT ligands. Our results revealed that NMT enzymes from both pathogens present enough structural similarity to allow extrapolation of the knowledge available from C. albicans studies to develop new L. major NMT inhibitors. Molecular docking studies with benzoheterocyclic analogues indicate the potential of benzothiazole derivatives as L. major NMT ligands, giving rise to a completely new class of chemical compounds to be explored in the development of antileishmanial drugs.

4-Phenyl-1, 3-thiazole-2-amines as scaffolds for new antileishmanial agents

There is still a need for new alternatives in pharmacological therapy for neglected diseases, as the drugs available show high toxicity and parenteral administration. That is the case for the treatment of leishmaniasis, particularly to the cutaneous clinical form of the disease. In this study, we present the synthesis and biological screening of eight 4-phenyl-1,3-thiazol-2-amines assayed against Leishmania amazonensis. Herein we propose that these compounds are good starting points for the search of new antileishmanial drugs by demonstrating some of the structural aspects which could interfere with the observed activity, as well as suggesting potential macromolecular targets. Methods: The compounds were easily synthesized by the methodology of Hantzsch and Weber, had their purities determined by Gas Chromatography-Mass spectrometry and assayed against the promastigote forms of Leishmania amazonensis as well as against two white cell lines (L929 and THP-1) and the monkey's kidney Vero cells. PrestoBlue® and MTT viability assays were the methodologies applied to measure the antileishmanial and cytotoxic activities, respectively. A molecular modeling target fishing study was performed aiming to propose potential macromolecular targets which could explain the observed biological behavior. Results: Four out of the eight compounds tested exhibited important anti-promastigote activity associated with good selectivity indexes when considering Vero cells. For the most promising compound, compound 6, IC50 against promastigotes was 20.78 while SI was 5.69. Compounds 3 (IC50: 46.63 µM; SI: 26.11) and 4 (IC50: 53.12 µM; SI: 4.80) also presented important biological behavior. A target fishing study suggested that S-methyl-5-thioadenosine phosphorylase is a potential target to these compounds, which could be explored to enhance activity and decrease the potential toxic side effects. Conclusions: This study shows that 4-phenyl-1,3-thiazol-2-amines could be good scaffolds to the development of new antileishmanial agents. The S-methyl-5-thioadenosine phosphorylase could be one of the macromolecular targets involved in the action.(AU)

Antiproliferative and antimetastatic activity of DM-1, sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate, in B16F10 melanoma

Melanoma causes 75% of skin cancer deaths mainly due to its high potential to progress to metastasis and by its recognized resistance to conventional therapies. Compound DM-1, sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate, presents structural and biological similarity to curcumin, exhibiting properties such as potent antitumoral and antioxidant activities. In this work, the antitumoral and antiproliferative effects of this compound in in vitro assays with tumor and normal cell lines have been evaluated. Also evaluated was the in vivo antitumoral potential against B16F10 melanoma-bearing mice. Normal and tumor cells were treated with different concentrations of compound DM-1 and the cellular viability was determined by MTT colorimeter assay. The half maximal inhibitory concentration (IC50) found was 30 ìg/mL in B16F10 melanoma cells, while no toxic activity was verified against normal human fibroblastic cells. When DM-1 was administrated by intraperitoneal and endovenous routes to melanoma-bearing animals the survival rate increased by 40% when compared to the control group. Tumor load was reduced by 84% when administered via endovenous and by 54% via intraperitoneal. In conclusion, compound DM-1 acts as selective antitumoral agent inducing cytotoxicity in B16F10 melanoma cells, reducing the tumor load in the treated animals, as well as increasing the survival rate of the animal bearing this neoplasia.

Quimioterápicos potencialmente ativos em endemias tropicais e tuberculose: estudos de QSAR na série de 5-nitroderivados benzidrazídicos e o planejamento de pró-fármacos de ação prolongada / Chemotherapeutic agents potentially active in tropical endemic and tuberculosis: QSAR studies in the series of 5-nitro-benzhydrazide derivatives and the design of prolonged action prodrugs

Malária, doença de Chagas e leishmaniose, consideradas doenças negligenciadas, e tuberculose, infecção bacteriana reemergente, que grassa em diversas regiões do mundo, constituem-se grandes desafios médico-sociais para os países acometidos. Nitroderivados são substâncias utilizadas na terapêutica como antimicrobianos de amplo espectro. O mecanismo de ação proposto para estes compostos engloba a redução do grupo nitro por nitrorredutases inespecíficas, levando à produção de radicais livres. Estes, altamente reativos, reagiriam, por sua vez, com macromoléculas, organelas, membranas e mesmo ácidos nucléicos danificando-os irreversivelmente e levando o microrganismo bactérias e parasitos - à morte. No caso particular da doença de Chagas, a redutase envolvida na redução seria a tripanotiona redutase, que poderia ser inibida por estes compostos...

Use of N-methylene phosphonic chitosan to obtain an isoniazid prodrug

Tuberculosis (TB) is one of the most neglected health problems and has out of control in many areas of the world. Since new antituberculous alternatives, including controlled classical drug delivery systems, are urgently needed to face this serious situation, the purpose of the present work was the sysnthesis and characterization of a prolonged action prodrug of isoniazid. The N-methylene phosphonic chitosan (NMPC), a hydrosoluble derivative of chitosan was the synthesis and characterization of a prolonged action prodrug of isoniazid. The N-methylene phosphonic chitosan (NMPC), a hydrosoluble derivative of chitosan was used as drug carrier. This analog, as well as its precursor, exhibits simulatory activity on macrophages, host cells of Mycobacterium tuberculosis...