Novel Gallate Triphenylphosphonium Derivatives with Potent Antichagasic Activity

Abstract

Chagas disease is one of the most neglected tropical diseases in the world, affecting nearly 15 million people, primarily in Latin America. Only two drugs are used for the treatment of this disease, nifurtimox and benznidazole. These drugs have limited efficacy and frequently induce adverse effects, limiting their usefulness. Consequently, new drugs must be found. In this study, we demonstrated the in vitro trypanocidal effects of a series of four gallic acid derivatives characterized by a gallate group linked to a triphenylphosphonium (TPP+) moiety (a delocalized cation) via a hydrocarbon chain of 8, 10, 11, or 12 atoms (TPP+-C8, TPP+-C10, TPP+-C11, and TPP+-C12, respectively). We analyzed parasite viability in isolated parasites (by MTT reduction and flow cytometry) and infected mammalian cells using T. cruzi Y strain trypomastigotes. Among the four derivatives, TPP+-C10 and TPP+-C12 were the most potent in both models, with EC50 values (in isolated parasites) of 1.0 ± 0.6 and 1.0 ± 0.7 μM, respectively, and were significantly more potent than nifurtimox (EC50 = 4.1 ± 0.6 μM). At 1 μM, TPP+-C10 and TPP+-C12 induced markers of cell death, such as phosphatidylserine exposure and propidium iodide permeabilization. In addition, at 1 μM, TPP+-C10 and TPP+-C12 significantly decreased the number of intracellular amastigotes (TPP+-C10: 24.3%, TPP+-C12: 19.0% of control measurements, as measured by DAPI staining) and the parasite’s DNA load (C10: 10%, C12: 13% of control measurements, as measured by qPCR). Based on the previous mode of action described for these compounds in cancer cells, we explored their mitochondrial effects in isolated trypomastigotes. TPP+-C10 and TPP+-C12 were the most potent compounds, significantly altering mitochondrial membrane potential at 1 μM (measured by JC-1 fluorescence) and inducing mitochondrial transition pore opening at 5 μM. Taken together, these results indicate that the TPP+-C10 and TPP+-C12 derivatives of gallic acid are promising trypanocidal agents with mitochondrial activity.

Conjugates of 2,4-Dihydroxybenzoate and Salicylhydroxamate and Lipocations Display Potent Antiparasite Effects by Efficiently Targeting the Trypanosoma brucei and Trypanosoma congolense Mitochondrion

“…22 The triphenylphosphonium (TPP) cation is one of the most successful LC for mitochondria targeting, [23][24][25] and the use of the "TPP strategy" to deliver trypanocidal drugs to the mitochondrion of trypanosomes has recently been demonstrated. 7, Lipophilic cations can cross lipid bilayers by noncarrier mediated transport and accumulate specifically into mitochondria driven by the plasma and mitochondrial transmembrane potentials. [27][28][29][30] The strong accumulation of dications by the charged mitochondria allows the targeting of its various essential functions with relatively low extracellular drug concentrations.…”

“…4 Hence, this essential organelle represents a good chemotherapeutic target for the development of trypanocidal drugs. [5][6][7] Among the many validated mitochondrial targets of T. brucei (e.g. kDNA and topoisomerases, tRNA import, fatty acid biosynthesis), 8 the mitochondrial respiration of the parasite is a particularly attractive target.…”

Mitochondria targeting nano agents in cancer therapeutics

“…The most prominent example is triphenylphosphonium (TPP) cation, a positively charged phosphorus atom surrounded by three hydrophobic phenyl groups that impart an extended hydrophobic surface (14). The TPP moiety has been employed as a probe to explore the mitochondrial membrane potential for over 40 years and consequently its behaviour and interaction with mitochondria are well defined (11).…”

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

“…Other boronic acids, such as NO-03 and NO-13,a lso exhibited good effects, albeit with less potency than NO-12,a nd NO-13 presented better performance than NO-03.T hese resultsi ndicateb oronic acids as effective platformsu pon which new molecules with improved actions against T. cruzi can be designed.A lso, it seems that the mechanism of action is more favored with para-substituted boronic acids with ester-substituted vinyl nitriles. The EC 50 value measured for NO-12 (0.795 mm)i sm ore than 10 times superior to the EC 50 value described for benznidazole [43] and more than four times superior to the EC 50 value of nifurtimox; [44] both drugs are used in the current therapy of Chagas disease. Boronic acid NO-12 exhibitedl ower potency than bortezomib [45] and DDD85646, both strong proteasome inhibitors with trypanocidal activity against T. brucei.…”