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. 2018 Dec 31;24(1):134.
doi: 10.3390/molecules24010134.

Effective Tetradentate Compound Complexes against Leishmania spp. that Act on Critical Enzymatic Pathways of These Parasites

Kristína Urbanová  1 , Inmaculada Ramírez-Macías  2 , Rubén Martín-Escolano  3 , María José Rosales  4 , Olaf Cussó  5 , Joan Serrano  6 , Anna Company  7 , Manuel Sánchez-Moreno  8 , Miquel Costas  9 , Xavi Ribas  10 , Clotilde Marín  11
Affiliations

Effective Tetradentate Compound Complexes against Leishmania spp. that Act on Critical Enzymatic Pathways of These Parasites

Kristína Urbanová et al. Molecules. .

Abstract

The spectrum and efficacy of available antileishmanial drugs is limited. In the present work we evaluated in vitro the antiproliferative activity of 11 compounds based on tetradentate polyamines compounds against three Leishmania species (L. braziliensis, L. donovani and L. infantum) and the possible mechanism of action. We identified six compounds (3, 5, 6, 7, 8 and 10) effective against all three Leishmania spp both on extracellular and intracellular forms. These six most active leishmanicidal compounds also prevent the infection of host cells. Nevertheless, only compound 7 is targeted against the Leishmania SOD. Meanwhile, on the glucose metabolism the tested compounds have a species-specific effect on Leishmania spp.: L. braziliensis was affected mainly by 10 and 8, L. donovani by 7, and L. infantum by 5 and 3. Finally, the cellular ultrastructure was mainly damaged by 11 in the three Leishmania spp. studied. These identified antileishmania candidates constitute a good alternative treatment and will be further studied.

Keywords: Leishmania spp.; SOD; amastigote; antileishmania; antiproliferative; promastigote; tetradentate polyaminic compounds; ultrastructure.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results

Figures

Figure 1
Figure 1
Chemical structure of the tested polyaminic compound complexes.
Figure 2
Figure 2
Leishmania braziliensis infectivity assay. (A,B) Infection rate percentage and (C,D) amastigote count per macrophage cell. In brackets: percentage of decrease in infection rate/number of amastigotes per macrophage cell in comparison to the control measured on the last day of the experiment (peak of infection). (E) Effects of the compounds on the endocytic and infection indexes. Each drug at IC25 concentration was tested in triplicate. Values are the means of four separate determinations ± standard deviation.
Figure 3
Figure 3
Leishmania donovani infectivity assay. (A,B) Infection rate percentage and (C,D) amastigote count per macrophage cell. In brackets: percentage of decrease in infection rate/number of amastigotes per macrophage cell in comparison to the control measured on the last day of the experiment (peak of infection). (E) Effects of the compounds on the endocytic and infection indexes. Each drug at IC25 concentration was tested in triplicate. Values are the means of four separate determinations ± standard deviation.
Figure 4
Figure 4
Leishmania infantum infectivity assay. (A,B) Infection rate percentage and (C,D) amastigote count per macrophage cell. In brackets: percentage of decrease in infection rate/number of amastigotes per macrophage cell in comparison to the control measured on the last day of the experiment (peak of infection). (E) Effects of the compounds on the endocytic and infection indexes. Each drug at IC25 concentration was tested in triplicate. Values are the means of four separate determinations ± standard deviation.
Figure 5
Figure 5
SOD inhibition assay. Representation of the inhibition of 3, 5–8 and 10 against: (A,B) L. braziliensis Fe-SOD (C,D) L. donovani Fe-SOD (E,F) L. infantum Fe-SOD and (G,H) human CuZn-SOD. Each drug concentration was tested in triplicate. Values are the means of four separate determinations ± standard deviation. In brackets: IC50 value, calculated by non-linear regression analysis.
Figure 6
Figure 6
Variation in metabolic excretion in L. braziliensis, L. donovani and L. infantum exposed to compounds at IC25 concentrations in comparison to untreated incubated 72 h, and determined by 1H-NMR.
Figure 7
Figure 7
Ultrastructural images of L. braziliensis promastigotes treated for 72 h at IC25 concentrations with: (A) untreated control, (B) 3, (C) 7, (D) 8, (E,F) 10. (N) nucleus, (Nu) nucleolus, (R) ribosomes, (K) kinetoplast, (M) mitochondrion, (G) glycosome, (V) vacuole, (arrow) electron-dense precipitates of unassimilated compounds, (dashed arrow) irregular morphologies. In all cases scale bar corresponds to 1 μm.
Figure 8
Figure 8
Ultrastructural images of L. donovani promastigotes treated for 72 h at IC25 concentrations with: (A) untreated control, (B) 6, (C) 7, (D) 8, (E) 10, (F) 5. (N) nucleus, (NM) nuclear membrane, (M) mitochondrion, (F) flagellum, (R) ribosomes, (MT) microtubule, (GA) Golgi apparatus, (G) glycosome, (CR) cellular rest, (V) vacuole, (LV) lipid vacuole, (VR) vacuole full of rests, (arrow) dead promastigote. In all cases scale bar corresponds to 1 μm.
Figure 9
Figure 9
Ultrastructural images of L. infantum promastigotes treated for 72 h at IC25 concentrations with: (A) untreated control, (B,C) 3, (D,E) 5, (F) 7, (G,H) 8, (I) 10. (N) nucleus, (M) mitochondrion, (F) flagellum, (R) ribosomes, (MT) microtubule, (GA) Golgi apparatus, (G) glycosome, (K) kinetoplast, (CR) cellular rest, (V) vacuole, (LV) lipid vacuole, (VE) vesicle, (FP) flagellar pocket, (arrow) dead promastigote, (dashed arrow) nuclear membrane separation, (dotted arrow) lysed promastigote. In all cases scale bar corresponds to 1 μm.
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