Dronedarone, an Amiodarone Analog with Improved Anti-Leishmania mexicana Efficacy

Abstract

g Dronedarone and amiodarone are cationic lipophilic benzofurans used to treat cardiac arrhythmias. They also have activity against the parasitic protozoan Trypanosoma cruzi, the causative agent of Chagas' disease. They function by disrupting intracellular Ca 2؉ homeostasis of the parasite and by inhibiting membrane sterol (ergosterol) biosynthesis. Amiodarone also has activity against Leishmania mexicana, suggesting that dronedarone might likewise be active against this organism. This might be of therapeutic interest, since dronedarone is thought to have fewer side effects in humans than does amiodarone. We show here that dronedarone effectively inhibits the growth of L. mexicana promastigotes in culture and, more importantly, has excellent activity against amastigotes inside infected macrophages (the clinically relevant form) without affecting the host cell, with the 50% inhibitory concentrations against amastigotes being 3 orders of magnitude lower than those obtained previously with T. cruzi amastigotes (0.65 nM versus 0.75 M). As with amiodarone, dronedarone affects intracellular Ca 2؉ homeostasis in the parasite, inducing an elevation of intracellular Ca 2؉ levels. This is achieved by rapidly collapsing the mitochondrial membrane potential and inducing an alkalinization of acidocalcisomes at a rate that is faster than that observed with amiodarone. We also show that dronedarone inhibits parasite oxidosqualene cyclase, a key enzyme in ergosterol biosynthesis known to be vital for survival. Overall, our results suggest the possibility of repurposing dronedarone as a treatment for cutaneous, and perhaps other, leishmaniases.

Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109

“…3B). These results are similar to the effects of dronedarone on L. mexicana (5). Likewise, we find that SQ109 causes a release of Ca 2ϩ from internal Ca 2ϩ (Ca 2ϩ i ) stored in organelles ( Fig.…”

“…Similar results were obtained with amiodarone and dronedarone in T. cruzi and L. mexicana (1)(2)(3)(4)(5). Here, as shown in Fig.…”

“…In previous work (1)(2)(3)(4)(5), we discovered that the antiarrhythmia drugs amiodarone (Fig. 1, compound 1) and dronedarone ( Fig.…”

Antiinfectives targeting enzymes and the proton motive force

“…SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent than was SQ109 (2) against M. tuberculosis H37Rv [0.063 vs. 0.25 μg/mL minimal inhibitory concentration (MIC)], and that at least one protonatable nitrogen in the linker was essential for activity. The latter observation suggested to us that SQ109 (2) and ethanolamine (3) might have activity as uncouplers, collapsing the proton motive force (PMF; ΔP) used to drive ATP synthesis, because we had observed similar uncoupling effects for lipophilic bases, US Food and Drug Administration (FDA)-approved drugs, in trypanosomatid parasites (14,15). The PMF is given by Mitchell (16,17): ΔP = Δψ − ZΔpH, where Δψ is the electrical or membrane potential component of ΔP, ΔpH is the transmembrane pH gradient, and Z is 2.303RT/F where R is the gas constant, T is temperature (in kelvins), and F is the Faraday constant.…”

“…There has also been very recent interest in the development of DNP analogs such as DNP methyl ether (37), for treating diabetes, and of controlledrelease DNP formulations (38) as mild hepatic mitochondrial uncouplers for treating hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes. Niclosamide (12) and tizoxanide (14) are both FDA-approved, and closantel (15) is an anthelmintic uncoupler in veterinary use, and all could provide leads for new and improved inhibitors that target other pathogens. There has also been considerable renewed interest (39) in the use of pyrazinoic acid (16), which functions, at least in part, as a protonophore uncoupler, for treating TB (39,40), stimulating our interest in discovering new TB drug leads with uncoupler activity.…”