Nitro-Heterocyclic compounds induce apoptosis-like effects in Leishmania (L). amazonensis promastigotes

Mendonca, Daiane Barros Dias; Silva, Renata Ellen Costa; Palace-Berl, Fanny; Takakura, C F H; Soares, Sandra Regina; Braz, Lúcia Maria Almeida; Tavares, Leoberto Costa; Lindoso, José Ângelo Lauletta

doi:10.1590/1678-9199-jvatitd-1444-18

Cited by 10 publications

(3 citation statements)

References 24 publications

(36 reference statements)

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“…Our results showed no statistically significant effect of guanidine derivatives on cell death in promastigotes. In contrast, the AmB demonstrated an apparent apoptotic impact similar to that observed in previous studies [ 40 , 41 ]. However, the LQOFG-2 and LQOFG-6 treatments resulted in a gradual increase in late-apoptotic axenic amastigotes cells.…”

Section: Discussionsupporting

confidence: 86%

Leishmanicidal Activity of Guanidine Derivatives against Leishmania infantum

et al. 2023

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Leishmaniasis is a neglected tropical infectious disease with thousands of cases annually; it is of great concern to global health, particularly the most severe form, visceral leishmaniasis. Visceral leishmaniasis treatments are minimal and have severe adverse effects. As guanidine-bearing compounds have shown antimicrobial activity, we analyzed the cytotoxic effects of several guanidine-bearing compounds on Leishmania infantum in their promastigote and amastigote forms in vitro, their cytotoxicity in human cells, and their impact on reactive nitrogen species production. LQOFG-2, LQOFG-6, and LQOFG-7 had IC50 values of 12.7, 24.4, and 23.6 µM, respectively, in promastigotes. These compounds exhibited cytotoxicity in axenic amastigotes at 26.1, 21.1, and 18.6 µM, respectively. The compounds showed no apparent cytotoxicity in cells from healthy donors. To identify mechanisms of action, we evaluated cell death processes by annexin V and propidium iodide staining and nitrite production. Guanidine-containing compounds caused a significant percentage of death by apoptosis in amastigotes. Independent of L. infantum infection, LQOFG-7 increased nitrite production in peripheral blood mononuclear cells, which suggests a potential mechanism of action for this compound. Therefore, these data suggest that guanidine derivatives are potential anti-microbial molecules, and further research is needed to fully understand their mechanism of action, especially in anti-leishmanial studies.

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Section: Discussionsupporting

confidence: 86%

Leishmanicidal Activity of Guanidine Derivatives against Leishmania infantum

et al. 2023

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“…Among the compounds with significant pharmacological activities, compounds containing a nitro group are highlighted because they have an important pharmacophoric functionality in their molecules, which facilitates their use in medicinal and therapeutic applications. Nitro‐derivatives are associated with several biological activities including anti‐inflammatory, [ 39 ] antitumor, [ 40 ] antimicrobial, [ 41 ] and antileishmanial [ 42 ] activities. To ascertain the effect of the nitro group at position 3, we planned to synthesize nitro product 3 by nitration of compound 2 with a mixture of fuming nitric acid and sulfuric acid in acetic acid (Scheme 3).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, anticancer evaluation, and molecular docking study of novel 4‐hydroxybenzo[h][1,6]naphthyridine‐2,5‐dione derivatives

Mostafa

2022

J of Physical Organic Chem

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An operationally efficient and affordable lactone-to-lactam transformation was designed from pyrano [3,2-c]quinolinone 1 to obtain 4-hydroxybenzo [h][1,6] naphthyridine-2,5-dione 2 utilizing ammonium acetate. The newly synthesized compound 2 was subjected to different electrophilic substitution reactions such as nitration, chlorination, bromination, and N-acylation to obtain novel benzo [h][1,6]naphthyridine derivatives with different substituents at C-3, C-4, and NH. Structures of novel products were achieved by elemental analyses and spectroscopic techniques. The benzonapthyridine derivatives were screened for their antitumor activities against some cancer cell lines including HepG-2, HCT-116, and MCF-7. All the examined compounds revealed strong, good, moderate to weak anticancer activity compared with 5-fluorouracil as a reference standard. Compound (3, -3NO 2 ) was the most cytotoxic one and exhibited a higher inhibitory activity than the standard drug against HCT-116 and MCF-7 with IC 50 values of 20.7 ± 1.9 and 22.5 ± 2.1 μg/ml, respectively, and strong activity against HepG-2 with IC 50 = 15.3 ± 0.7 μg/ml. Moreover, a molecular docking study was carried out for the tested compounds against the crystallographic structure of the Topo II enzyme as a potential target to investigate their binding modes. Docking results showed that compound 6b fitted well into the active site of topoisomerase II (PDB ID: 1ZXM) with hydrogen bond interactions.

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“…In addition, the nitro heterocyclics are considered unsatisfactory because the long-lasting treatment (60 to 90 days) do not clear the parasite from the host´s body [62][63][64][65][66][67][68][69]. Moreover, the nitro heterocyclic free-anion radicals bind to DNA and the resulting DNA adducts associate severe genotoxicity [70][71][72][73][74].…”

Section: Introductionmentioning

confidence: 99%

The Trypanosoma cruzi kinetoplast DNA minicircle sequences transfer biomarker of the multidrug treatment of Chagas disease

Teixeira

Sousa

Gomes

et al. 2021

Preprint

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BackgroundThe Trypanosoma cruzi infection renders the transfer of the mitochondrion kinetoplast DNA minicircle sequences into the host’s genome. The Aves are refractory to the infection, but chicks hatched from the T. cruzi inoculated eggs integrate the DNA minicircle sequences into the germ line cells. Rabbits, mice and chickens with the minicircle sequences mutations develop the Chagas cardiomyopathy and the DNA transfer underpins the heart disease.MethodologyThe PCR with the specific primer sets revealed the Protist nuclear DNA and the kinetoplast DNA in the agarose gels bands probed with the radiolabel specific sequences from tissues of the T. cruzi-infected rabbits and of the mice. A target- primer TAIL-PCR amplification employing primer sets from the chickens, rabbits and mice, in combination with primer sets from the the T. cruzi kinetoplast minicircle sequences was used. This approach led us to disclose the integration sites of the kinetoplast DNA biomarker, then, used to monitor the effect of multidrug treatment of the T. cruzi infected mice.Principal findingsThe Southern hybridization, clone and sequence of the amplification products revealed the DNA minicircle sequences integrations sites in the LINE transposable elements. An array of inhibitors of eukaryote cells division was used to arrest the DNA transfer. It was shown that nine out of 12 inhibitors prevented the kinetoplast DNA integration into the macrophage genome. The multidrug treatment of the acutely T. cruzi-infected mice with Benznidazole, Azidothymidine and Ofloxacin lessened circa 2.5-fold the rate of the minicircle sequences integrations in the mouse genome and inhibited the rejection of the target heart cells.Conclusion and significanceThe T. cruzi mitochondrion kinetoplast minicircle sequences transfer driven pathogenesis of Chagas disease is an ancient Cross-Kingdom DNA phenomenon of evolution and, therefore, paradigm research with effective purposing inhibitors is needed.Authors summaryChagas disease is considered the main cause of human heart failure in the Western Hemisphere. The treatment of the clinically manifested Chagas heart disease is considered unsatisfactory. Perhaps the most important problem in the field of Chagas disease is determination of the pathogenesis of the target heart cells lysis. We showed the transfer of the T. cruzi kDNA minicircle sequences into the genome of rabbits and mice, and to Bird refractory to the infections. The inoculation of a few T. cruzi in the fertile chicken eggs renders the kDNA sequences integration in the stem cells. Interestingly, the chicks that hatched retain the kDNA and develop the Chagas-like cardiomyopathy indistinguishable to that in the rabbits and mice. This result prompted the multidrug treatment of the Chagas heart disease with inhibitors of the eukaryotic cells division. We showed that nine out of 12 inhibitors prevented the transfer of the kDNA mutations into the macrophage genome, and that the treatment of the acutely T. cruzi-infected mice with Benznidazole + Ofloxacin + Azidothymidine lowered circa 2.5-fold the rate of the mutations in the chromosomes. These findings translated to the pathology showing inhibition of the heart lesions in the treated T. cruzi-infected mice. We suggest purposing new inhibitors should be tested to overturning the Chagas heart disease.

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Nitro-Heterocyclic compounds induce apoptosis-like effects in Leishmania (L). amazonensis promastigotes

Cited by 10 publications

References 24 publications

Leishmanicidal Activity of Guanidine Derivatives against Leishmania infantum

Leishmanicidal Activity of Guanidine Derivatives against Leishmania infantum

Synthesis, anticancer evaluation, and molecular docking study of novel 4‐hydroxybenzo[h][1,6]naphthyridine‐2,5‐dione derivatives

The Trypanosoma cruzi kinetoplast DNA minicircle sequences transfer biomarker of the multidrug treatment of Chagas disease

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