New Benzophenone-Derived Bisphosphonium Salts as Leishmanicidal Leads Targeting Mitochondria through Inhibition of Respiratory Complex II

Luque‐Ortega, Juan Román; Reuther, Peter; Rivas, Luís; Dardonville, Christophe

doi:10.1021/jm901677h

Cited by 121 publications

(80 citation statements)

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“…Indeed, ROS production by inhibition of complex II is increasingly considered an objective for anticancer drugs that target mitochondria (10), thereby triggering apoptosis in these cells. Complex II has also been demonstrated to be a good target in Leishmania for phenyl-phenalenones (19), benzophenone-derived biphosphonium surrogates (20), and thenoyltrifluoroacetone (24).…”

Section: Discussionmentioning

confidence: 99%

The 8-Aminoquinoline Analogue Sitamaquine Causes Oxidative Stress in Leishmania donovani Promastigotes by Targeting Succinate Dehydrogenase

Carvalho

Luque‐Ortega

López-Martín

et al. 2011

Antimicrob Agents Chemother

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The 8-aminoquinoline analogue sitamaquine (SQ) is an oral antileishmanial drug currently undergoing phase 2b clinical trials for the treatment of visceral leishmaniasis. In the present study, we investigated the mechanism of action of this drug in Leishmania donovani promastigotes. SQ causes a dose-dependent inhibition of complex II (succinate dehydrogenase) of the respiratory chain in digitonin-permeabilized promastigotes, together with a drop in intracellular ATP levels and a decrease of the mitochondrial electrochemical potential. This is associated with increases of reactive oxygen species and intracellular Ca 2؉ levels, a higher percentage of the population with sub-G 1 DNA content, and exposure of phosphatidylserine. Taken together, these results support a lethal mechanism for SQ that involves inhibition of the respiratory chain complex II, which in turn triggers oxidative stress and finally leads to an apoptosis-like death of Leishmania parasites.Leishmaniasis, a protozoal infectious disease caused by a set of 17 species of the genus Leishmania, shows a wide spectrum of clinical manifestations, including, in order of increasing severity, cutaneous (CL), mucocutaneous (MCL), and visceral (VL) leishmaniasis (3). Although chemotherapy is the only current treatment option for leishmaniasis, its efficacy is increasingly limited by growing resistance to first-line drugs, especially antimonials, by the frequent side effects associated with their use, and by the high cost of treatment (30). The paucity of new drugs in the pipeline, together with the poor definition of Leishmania targets for the drugs in current clinical use, represents an additional concern for current chemotherapy. Solutions to curb this pessimistic scenario rely on combination therapy (40) and the rescue of old drugs, such as paromomycin (17, 36) and sitamaquine (SQ) (39), that were previously discarded.8-Aminoquinolines are an important class of antiparasitic agents (37) with broad application and excellent efficacy but with limitations due to their hematological toxicity (primarily metahemoglobinemia and hemolysis). SQ, formerly known as WR6026, is an 8-aminoquinoline that was initially developed by the Walter Reed Army Institute (46). The results of phase 2b clinical trials of this drug against VL in India (16) and Kenya (45) by GlaxoSmithKline were encouraging. These results, together with its oral administration, represent a substantial advantage in terms of its future widespread implementation.The targets for SQ remain elusive. Entry of SQ into the parasite starts with an electrostatic interaction with anionic phospholipids of the plasma membrane (11). In a seminal work, Vercesi and Docampo (43) observed a loss of mitochondrial electrochemical potential in digitonin-permeabilized parasites after SQ addition, together with alkalinization of acidocalcisomes (44), which also underwent a privileged SQ accumulation, although no correlation was found with its toxicity (18).Herein we provide further insight into the leishmanicidal mechanism of S...

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Section: Discussionmentioning

confidence: 99%

The 8-Aminoquinoline Analogue Sitamaquine Causes Oxidative Stress in Leishmania donovani Promastigotes by Targeting Succinate Dehydrogenase

Carvalho

Luque‐Ortega

López-Martín

et al. 2011

Antimicrob Agents Chemother

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“…The variation of Δ⌿ m caused by AS-48 was monitored by the intracellular accumulation of Rho123. After parasite incubation with AS-48 under the standard conditions, cells were diluted to 10 6 cells/ml in HBSS-Glc, loaded with Rho123 (0.3 g/ml, 10 min, 26°C), and analyzed by cytofluorometry as described previously (73). Parasites with a fully depolarized mitochondrion were obtained by incubation with KCN (10 mM, 30 min) prior to Rho123 loading.…”

Section: Methodsmentioning

confidence: 99%

“…Oxygen consumption rates were measured using a Clark oxygen electrode (Hansatech, King's Lynn, UK) as described previously (73). Briefly, promastigotes were resuspended at 10 8 cells/ml in respiration buffer containing 2 mM succinate and 10 mM glucose.…”

Section: Methodsmentioning

confidence: 99%

Enterocin AS-48 as Evidence for the Use of Bacteriocins as New Leishmanicidal Agents

Abengózar

Cebrián

Saugar

et al. 2017

Antimicrob Agents Chemother

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We report the feasibility of enterocin AS-48, a circular cationic peptide produced by Enterococcus faecalis, as a new leishmanicidal agent. AS-48 is lethal to Leishmania promastigotes as well as to axenic and intracellular amastigotes at low micromolar concentrations, with scarce cytotoxicity to macrophages. AS-48 induced a fast bioenergetic collapse of L. donovani promastigotes but only a partial permeation of their plasma membrane with limited entrance of vital dyes, even at concentrations beyond its full lethality. Fluoresceinated AS-48 was visualized inside parasites by confocal microscopy and seen to cause mitochondrial depolarization and reactive oxygen species production. Altogether, AS-48 appeared to have a mixed leishmanicidal mechanism that includes both plasma membrane permeabilization and additional intracellular targets, with mitochondrial dysfunctionality being of special relevance. This complex leishmanicidal mechanism of AS-48 persisted even for the killing of intracellular amastigotes, as evidenced by transmission electron microscopy. We demonstrated the potentiality of AS-48 as a new and safe leishmanicidal agent, expanding the growing repertoire of eukaryotic targets for bacteriocins, and our results provide a proof of mechanism for the search of new leishmanicidal bacteriocins, whose diversity constitutes an almost endless source for new structures at moderate production cost and whose safe use on food preservation is well established.

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“…However, it is likely that the lipophilic ammonium and phosphonium compounds would have to pass both the plasma membrane and the mitochondrial membrane, as such compounds are generally believed to accumulate, and act, in the mitochondria (De Koning, manuscript in preparation). 7 In summary, modulation of the cationic center (from phosphorus to nitrogen) of the diphenylether and benzophenone class of trypanocides resulted in 2-to 5-times lower activities against wild type and resistant T. b. brucei lines. Nevertheless, two new potent and selective trypanocidal compounds were obtained, 1c and 3c, which displayed nanomolar EC 50 and SI > 100.…”

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confidence: 96%

SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts

Dardonville

Alkhaldi

Koning

2014

ACS Med. Chem. Lett.

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ABSTRACT:In previous studies, we have shown that phosphonium salt diphenyl derivatives are attractive antitrypanosomal hit compounds with EC 50 values against Trypanosoma brucei in the nanomolar range. To evaluate the role of the cationic center on the trypanocidal activity and extend the structure−activity relationship (SAR) of this series, trialkylammonium, pyridinium, and quinolinium salt analogues were synthesized and evaluated in vitro against T. b. brucei. Similar SARs were observed with ammonium and phosphonium salts showing that charge dispersion and lipophilic groups around the cationic center are crucial to obtain submicromolar activities. The new compounds were equally effective against wild type (T. b. brucei s427) and resistant strains (TbAT1-KO and TbB48) of trypanosomes indicating that the P2 and high affinity pentamidine transporters (HAPT) are not essential to their trypanocidal action. Similarly to phosphonium salt derivatives, diffusion seems to be the main route of entry into trypanosomes. KEYWORDS: Trypanosoma brucei, ammonium salt, quinolinium salt, pyridinium salt, P2-transporter, high affinity pentamidine transporter (HAPT) P arasitic protozoa of the genus Trypanosoma cause human and animal trypanosomiases in Africa. Two subspecies of T. brucei (T. b. gambiense and T. b. rhodesiense) are pathogenic to man and cause human African trypanosomiasis (HAT) in sub-Saharan Africa. In contrast, T. b. brucei, T. congolense, and T. vivax cause veterinary diseases in domestic and wild animals. 1,2 African trypanosomiasis is one of the most neglected tropical diseases as shown by the lack of safe drugs to treat both (early and late) stages of the illness. These drugs, which have been used for decades, are subject to treatment failure (drug resistance) and have severe drawbacks such as unacceptable toxicity and parenteral administration. 3 Cationic drugs are an important class of trypanocides used for the treatment of human and veterinary trypanosomiasis (e.g., pentamidine, diminazene, homidium, and isomethamidium). 4,5 In previous studies we have shown that a new class of cationic compounds, mono-and bisphosphonium salt derivatives with a diphenyl scaffold, have submicromolar activities against T. brucei and Leishmania parasites. 6,7 These compounds display a good selectivity index relative to human cell lines, are not cross-resistant with existing trypanocides, and require only a short exposure time for trypanocidal activity. 6 Like other dicationic trypanocides, 8,9 the bisphosphonium salts are expected to accumulate in the mitochondria. Indeed, a mitochondrial target for these compounds was demonstrated in Leishmania. 7 Structure−activity relationship (SAR) studies revealed that bulky substituents on the phosphorus atoms are required to achieve submicromolar EC 50 values within this series. In the present work, we wanted to learn whether the nature of the cationic center was important for the observed trypanocidal activity of these hit compounds. Thus, new cationic analogues of the hits with a nitr...

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New Benzophenone-Derived Bisphosphonium Salts as Leishmanicidal Leads Targeting Mitochondria through Inhibition of Respiratory Complex II

Cited by 121 publications

References 50 publications

The 8-Aminoquinoline Analogue Sitamaquine Causes Oxidative Stress in Leishmania donovani Promastigotes by Targeting Succinate Dehydrogenase

The 8-Aminoquinoline Analogue Sitamaquine Causes Oxidative Stress in Leishmania donovani Promastigotes by Targeting Succinate Dehydrogenase

Enterocin AS-48 as Evidence for the Use of Bacteriocins as New Leishmanicidal Agents

SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts

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