Nuclease activity and ultrastructural effects of new sulfonamides with anti-leishmanial and trypanocidal activities

Bilbao-Ramos, Pablo; Galiana‐Roselló, Cristina; Dea-Ayuela, María Auxiliadora; González‐Álvarez, Marta; Vega, Celeste; Rolón, Míriam; Pérez-Serrano, Jorge; Bolás‐Fernández, F.; González‐Rosende, M. Eugenia

doi:10.1016/j.parint.2012.05.015

Cited by 27 publications

(17 citation statements)

References 48 publications

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“…Recent research shows that some synthetic compounds promote cellular disorganization in L. infantum affecting mainly the nucleus, mitochondria, and kinetoplast, with frequent disruption of the nuclear membrane, loss of cellular integrity, and accumulation of bodies lipids [54]. In T. cruzi , ultrastructural changes as the formation of myelin figures, autophagosomes-like vacuoles, disruption of the Golgi complex, and mitochondria enlargement were observed in response to treatment with inhibitors of sterol biosynthesis [55, 56].…”

Section: Discussionmentioning

confidence: 99%

Effects of (1E,4E)-2-Methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one onTrypanosoma cruziand Its Combinational Effect with Benznidazole, Ketoconazole, or Fluconazole

Peron

Lazarin‐Bidóia

Din

et al. 2017

BioMed Research International

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This study reports the activity induced by (1E,4E)-2-methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one (A3K2A3) against Trypanosoma cruzi. This compound showed trypanocidal activity against the multiplicative epimastigote and amastigote forms of this protozoan, with IC50 values of 1.99 ± 0.17 and 1.20 ± 0.16 μM, respectively, and EC50 value of 15.57 ± 0.34 μM against trypomastigotes. The combination of A3K2A3 with benznidazole or ketoconazole demonstrated strong synergism, increasing effectiveness against trypomastigotes or epimastigotes of T. cruzi. In addition, the drug combination of A3K2A3 with benznidazole or ketoconazole on LLCMK2 cells demonstrated an antagonist effect, which resulted in greater protection of the cells from drug damage. The combination of the compound with fluconazole was not effective. Transmission and scanning electron micrographs showed changes on parasites, mainly in the cytoplasmatic membrane, nucleus, mitochondrion, and Golgi complex, and a large increase in the number of autophagosome-like structures and lipid-storage bodies, accompanied by volume reduction and rounding of the parasite. A3K2A3 might be a promising compound against T. cruzi.

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Section: Discussionmentioning

confidence: 99%

Effects of (1E,4E)-2-Methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one onTrypanosoma cruziand Its Combinational Effect with Benznidazole, Ketoconazole, or Fluconazole

Peron

Lazarin‐Bidóia

Din

et al. 2017

BioMed Research International

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“…Toxicity cell assays were carried out as described elsewhere [17]. To test the oxoisoaporphine compounds, the J774.2 cells (EACC 80011428) were seeded (5×10 4 cells/well) in 96-well flat bottomed microplates and allowed to adhere for 24 h at 37°C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Synthetic Oxoisoaporphine Alkaloids: In Vitro, In Vivo and In Silico Assessment of Antileishmanial Activities

et al. 2013

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Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candidates. In this study, 18 novel oxoisoaporphine derivatives were synthesized and their possible antileishmanial activity was evaluated. The in vitro activity of these derivatives against Leishmania amazonensis axenic amastigotes was first evaluated, and the selected compounds were then tested in an inhibition assay with promastigotes of L. infantum, L. braziliensis, L. amazonensis and L. guyanensis, and with intracellular amastigotes of L. infantum and L. amazonensis. Finally, the most active compounds, OXO 1 (2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one) and OXO 13 (2,3,8,9,10,11-hexahydro-7H-dibenzo[de,h]quinolin-7-one), were tested in BALB/c mice infected with L. infantum. Treatment of mice at a dose of 10 mg/kg with OXO 1 yielded significant reductions (p<0.05) in parasite burden in liver and spleen (99% and 78%, respectively) whereas with OXO 13 were not significant. Although previous reports suggest that this family of molecules displays inhibitory activity against monoamine oxidase A and acetylcholinesterase, these enzymes were not confirmed as targets for antileishmanial activity on the basis of the present results. However, after development of a new bioinformatics model to analyze the Leishmania proteome, we were able to identify other putative targets for these molecules. The most promising candidates were four proteins: two putative pteridine reductase 2 (1MXF and 1MXH), one N-myristoyltransferase (2WUU) and one type I topoisomerase (2B9S).

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“…The assay was performed as previously described [50]. Briefly, log-phase promastigotes (2.5 × 10 5 parasites/well) were cultured in 96-well plastic plates.…”

Section: In Vitro Promastigote Susceptibility Assaymentioning

confidence: 99%

Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis

et al. 2020

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Leishmaniasis affects around 12 million people worldwide and is estimated to cause the ninth-largest disease burden. There are three main forms of the disease, visceral (VL), cutaneous (CL), and mucocutaneous (MCL), leading to more than one million new cases every year and several thousand deaths. Current treatments based on chemically synthesized molecules are far from ideal. In this study, we have tested the in vitro and in vivo efficacy of ursolic acid (UA), a multifunctional triterpenoid with well-known antitumoral, antioxidant, and antimicrobial effects on different Leishmania strains. The in vitro antileishmanial activity against the intracellular forms was six and three-fold higher compared to extracellular forms of L. amazonensis and L. infantum, respectively. UA also showed to be a potent antileishmanial drug against both VL and CL manifestations of the disease in experimental models. UA parenterally administered at 5 mg/kg for seven days significantly reduced the parasite burden in liver and spleen not only in murine acute infection but also in a chronic-infection model against L. infantum. In addition, UA ointment (0.2%) topically administered for four weeks diminished (50%) lesion size progression in a chronic infection model of CL caused by L. amazonensis, which was much greater than the effect of UA formulated as an O/W emulsion. UA played a key role in the immunological response modulating the Th1 response. The exposure of Leishmania-infected macrophages to UA led to a significant different production in the cytokine levels depending on the Leishmania strain causing the infection. In conclusion, UA can be a promising therapy against both CL and VL.

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Nuclease activity and ultrastructural effects of new sulfonamides with anti-leishmanial and trypanocidal activities

Cited by 27 publications

References 48 publications

Effects of (1E,4E)-2-Methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one onTrypanosoma cruziand Its Combinational Effect with Benznidazole, Ketoconazole, or Fluconazole

Effects of (1E,4E)-2-Methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one onTrypanosoma cruziand Its Combinational Effect with Benznidazole, Ketoconazole, or Fluconazole

Synthetic Oxoisoaporphine Alkaloids: In Vitro, In Vivo and In Silico Assessment of Antileishmanial Activities

Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis

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