The Anti-Leishmania amazonensis and Anti-Leishmania chagasi Action of Copper(II) and Silver(I) 1,10-Phenanthroline-5,6-dione Coordination Compounds

Abstract

Leishmaniasis is a neglected disease caused by protozoa belonging to the Leishmania genus. Notably, the search for new, promising and potent anti-Leishmania compounds remains a major goal due to the inefficacy of the available drugs used nowadays. In the present work, we evaluated the effects of 1,10-phenanthroline-5,6-dione (phendione) coordinated to silver(I), [Ag(phendione)2]ClO4 (Ag-phendione), and copper(II), [Cu(phendione)3](ClO4)2·4H2O (Cu-phendione), as potential drugs to be used in the chemotherapy against Leishmania amazonensis and Leishmania chagasi. The results showed that promastigotes treated with Ag-phendione and Cu-phendione presented a significant reduction in the proliferation rate. The IC50 values calculated to Ag-phendione and Cu-phendione, respectively, were 7.8 nM and 7.5 nM for L. amazonensis and 24.5 nM and 20.0 nM for L. chagasi. Microscopical analyses revealed several relevant morphological changes in promastigotes, such as a rounding of the cell body and a shortening/loss of the single flagellum. Moreover, the treatment promoted alterations in the unique mitochondrion of these parasites, inducing significant reductions on both metabolic activity and membrane potential parameters. All these cellular perturbations induced the triggering of apoptosis-like death in these parasites, as judged by the (i) increased percentage of annexin-positive/propidium iodide negative cells, (ii) augmentation in the proportion of parasites in the sub-G0/G1 phase and (iii) DNA fragmentation. Finally, the test compounds showed potent effects against intracellular amastigotes; contrarily, these molecules were well tolerated by THP-1 macrophages, which resulted in excellent selective index values. Overall, the results highlight new selective and effective drugs against Leishmania species, which are important etiological agents of both cutaneous (L. amazonensis) and visceral (L. chagasi) leishmaniasis in a global perspective.

Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin)

“…In this set of experiments, L. amazonensis promastigotes (1 × 10 6 cells) were cultured for 24 h at 26 °C in the absence (control) or presence of either IC 50 or 2 × IC 50 values of both Ag-phendione (IC 50 for 72 h = 7.8 nM) and Cu-phendione (IC 50 for 72 h = 7.5 nM) as previously reported by our group [ 25 ]. After that, promastigotes were washed and processed to evaluate both gp63 activity and gp63 protein levels.…”

“…The Leishmania gp63 is a member of the metzincin family of zinc-metallopeptidases, and its hydrolytic activity is efficiently inhibited by 1,10-phenanthroline (phen) [ 16 , 18 ]. Our research group demonstrated that treating L. amazonensis , L. braziliensis and L. infantum with phen resulted in various biological alterations, such as irreversible morphological, morphometric, ultrastructural and physiological changes, leading to parasite death via apoptosis [ 23 , 24 , 25 ]. Additionally, phen decreased the infection rate of promastigotes in murine macrophages, with a clear involvement of gp63 in this crucial step of the infectious process.…”

Peptidases Are Potential Targets of Copper(II)-1,10-Phenanthroline-5,6-dione Complex, a Promising and Potent New Drug against Trichomonas vaginalis

“…Moreover, MP from Leishmania spp. proved to be a target of Cu-phendione, reducing both membrane-associated and secreted MP activities, with direct impacts on the establishment and maintenance of infection [ 19 ]. These results demonstrate an imperative effect of Cu-phendione on cellular homeostasis considering the different functions and MPs enrolled in the protozoal metabolism, leading to in-depth investigation of peptidases targeted by this compound.…”

“…The antibacterial effects of phendione and its silver and copper derivatives have been reported against the widespread multidrug-resistant gram-negative bacterium Pseudomonas aeruginosa , revealing that elastase B (a metallo-type peptidase that is a well-known virulence factor of this pathogen) is a target of these metal-based complexes [ 14 , 17 ]. In addition, these complexes have displayed antiparasitic activity against protozoa such as Leishmania amazonensis , Leishmania braziliensis , Leishmania chagasi , and T. vaginalis [ 16 , 18 , 19 ]. Interestingly, the interaction of copper(II) and silver(I)-phendione compounds with MPs have been described as key target in its antiparasitic activity [ 16 ].…”

“…In this context, phendione-based compounds were able to inhibit the main metallopeptidase activity (gp63) produced by L. brasiliensis promastigotes, affecting either the infection establishment or infection maintenance processes between parasites and macrophages [ 16 ]. Moreover, Cu-phendione induced several impacts on metabolic activity and membrane potential parameters of these Leishmania species [ 19 ]. Similarly, our group previously demonstrated the potent action of phendione and its silver and copper complexes against T. vaginalis, especially the copper derivative (Cu-phendione), which presented values of minimum inhibitory concentration comparable to metronidazole, a common drug used in clinical therapy [ 18 ].…”