Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis.

Alveolar echinococcosis (AE) is caused by infection with the fox tapeworm E. multilocularis. The disease affects humans, dogs, captive monkeys, and other mammals, and it is caused by the metacestode stage of the parasite growing invasively in the liver. The current drug treatment is based on non-parasiticidal benzimidazoles. Thus, they are only limitedly curative and can cause severe side effects. Therefore, novel and improved treatment options for AE are needed. Mefloquine (MEF), an antimalarial agent, was previously shown to be effective against E. multilocularis in vitro and in experimentally infected mice. However, MEF is not parasiticidal and needs improvement for successful treatment of patients, and it can induce strong neuropsychiatric side-effects. In this study, the structure-activity relationship and mode of action of MEF was investigated by comparative analysis of 14 MEF derivatives. None of them showed higher activity against E. multilocularis metacestodes compared to MEF, but four compounds caused limited damage. In order to identify molecular targets of MEF and effective derivatives, differential affinity chromatography combined with mass spectrometry was performed with two effective compounds (MEF, MEF-3) and two ineffective compounds (MEF-13, MEF-22). 1'681 proteins were identified that bound specifically to MEF or derivatives. 216 proteins were identified as binding only to MEF and MEF-3. GO term enrichment analysis of these proteins and functional grouping of the 25 most abundant MEF and MEF-3 specific binding proteins revealed the key processes energy metabolism and cellular transport and structure, as well as stress responses and nucleic acid binding to be involved. The previously described ferritin was confirmed as an exclusively MEF-binding protein that could be relevant for its efficacy against E. multilocularis. The here identified potential targets of MEF will be further investigated in the future for a clear understanding of the pleiotropic effects of MEF, and improved therapeutic options against AE.

Camphor nitroimine: a key building block in unusual transformations and its applications in the synthesis of bioactive compounds.

The development of new drugs requires a lot of time and high financial investments. It involves a research network in which there is the participation of several researchers from different areas. For a new drug to reach the market, thousands of substances must be evaluated. There are several tools for this and the use of suitable building blocks can facilitate the process by allowing a lead compound to have suitable parameters. These compounds are key structures containing special functional groups that also permit adequate synthetic transformations, leading to several structures of interest in a short period of time. In this review, the use of camphor nitroimine as a potential key building block is explored. Derived from camphor, an abundant natural product present in various plant species, this nitroimine has proved to be quite versatile, allowing the access to substances with miscellaneous biological activities, ligands to asymmetric catalysis, asymmetric oxidants, O-N transfer agents and other applications. Its easy conversion to camphecene and other derivatives is described, as well as their applications in medicinal chemistry. Druglikeness analyses were performed on these studied agents as well as on their bioactive derivatives in order to assess their use in the development of potential drugs.

Antibacterial activity of new substituted 4-N-alkylated-2-trifluoromethyl-quinoline analogues against sensitive and resistant Mycobacterium tuberculosis strains.

OBJECTIVES: The emergence of resistant strain has aggravated the tuberculosis situation in the world, running out of control and hard to fight. We evaluate forty new quinoline analogues against sensitive and resistant Mycobacterium tuberculosis (Mtb). METHODS: The compounds were obtained via synthesis and evaluated against sensitive strain ATCC 27294. Selected compounds were evaluated against resistant strains SR 2571/0215 and T113/09, using the MABA method. The more active compounds were selected for their potential cytotoxic activity against human macrophage cells. RESULTS: Twenty-nine compounds displayed activity against sensitive strain, and thirteen were active against resistant strains. Against sensitive strain, the most promising compounds were 4c and 4d (MIC = 9 and 12 µM, respectively). Against resistant strains, the compounds 4a, 4d displayed the best results (MIC = 4 and 5 µM, respectively). The active compounds 4a, 4d, 6d, 7c, 8d, and 10d were non-cytotoxic to the host cells at concentrations near to the MIC. The non-cytotoxic compound 4d was the most potent against resistant and sensitive Mtb. CONCLUSION: These findings contribute to relevant information and perspectives in search of new bioactive compounds against sensitive and resistant TB. Resistant strains have turned tuberculosis a severe disease in the world.

In vitro Assessment of Camphor Hydrazone Derivatives as an Agent Against Leishmania amazonensis.

PURPOSE: Due to serious problems with the treatment of leishmaniasis all around the world, here is an urgent need in the search for new drugs that are more effective and safer for the treatment of the various forms of leishmaniasis. Actual therapy is limited and lacks sufficient efficacy due to incomplete elimination of the parasites form of patients. In this sense, we decided to evaluate, by first-time, a series of seventeen camphor hydrazone derivatives (2a-2p) against Leishmania amazonensis. METHODS: The compounds previously synthesized from camphor, an abundant natural compound, were evaluated in vitro against the extra and intracellular forms of Leishmania amazonensis, and murine macrophages. RESULTS: The majority of compounds, fourteen, displayed activity against the intracellular form of the parasite (amastigote) with IC50 values ranging from 21.78 to 58.23 µM, being six compounds active for both forms of the parasite. The compound 2i exhibited higher activity against the amastigote form with the value of IC50 (21.78 µM) close to standard utilized miltefosine (12.74 µM) and selectivity index of at least 6.9. Six compounds displayed activity against promastigote form of Leishmania amazonensis 2g, 2j-2n (41.17-69.59 µM), with the compound 2m being the more active with IC50 = 41.17 µM, 1.9 times less active than the reference drug (IC50 = 21.39 µM). The compound 2m was the more selective to this form, with a selectivity index of at least 3.6. All the compounds were non-cytotoxic to macrophages. CONCLUSIONS: Most compounds showed activity against amastigote form of Leishmania amazonensis, being that they were not cytotoxic to macrophage at the maximum tested concentration, showing the selective property of these compounds. Since amastigotes are the parasite stages that cause the disease in humans, these results highlight the antileishmanial effect of the compounds. This study indicates the possible development of candidates to leishmanicidal drugs from an abundant natural compound of easy access.