Antileishmanial Activity of 5-Methyl-2,2′ : 5′,2″-terthiophene Isolated from Porophyllum ruderale is Related to Mitochondrial Dysfunction in Leishmania amazonensis

Abstract

Recently, our group isolated and reported the antiproliferative activity in promastigotes and axenic amastigote forms of Leishmania amazonensis treated with 5-methyl-2,2':5',2″-terthiophene (compound A) and 5'-methyl-[5-(4-acetoxy-1-butynyl)]-2,2'-bi-thiophene (compound B) isolated from the aerial parts of Porophyllum ruderale. Here, we demonstrated that both compounds exhibited activity against intracellular amastigotes showing IC50 values of 37 and 51 µg/mL for compounds A and B, respectively. Both compounds showed low levels of toxicity for human cells, even at the highest concentrations (hemolytic index < 10 % at 500 µg/mL). Promastigotes treated with compound A showed an alteration in the mitochondrial membrane when observed by flow cytometry through labeling with rhodamine 123 and this was confirmed by transmission electron microscopy. Alterations on morphology (rounded cells) were observed by scanning electron microscopy in parasites treated with the compounds. Further studies should be performed employing compounds A and B for the development of new drugs for chemotherapy of leishmaniasis.

Linalool, a Piper aduncum essential oil component, has selective activity against Trypanosoma cruzi trypomastigote forms at 4°C

“…Therefore, Pa EO may be acting on the parasite mitochondrion. Accordingly, it has been already shown that other natural products induce depolarisation of mitochondrial membrane in Trypanosomatids such as T. cru zi and Leishmania ( Inacio et al 2012 , Caleare et al 2013 , Ribeiro et al 2013 , Takahashi et al 2013 , Aliança et al 2014 , Corpas-López et al 2016 , Sülsen et al 2016 ).…”

Cell death and ultrastructural alterations in Leishmania amazonensis caused by new compound 4-Nitrobenzaldehyde thiosemicarbazone derived from S-limonene

“…Monzote et al (2014) [ 23 ] suggested that the antileishmania activity of the essential oil and major constituents (i.e., ascaridole, carvacol, and caryophllene oxide) of Chenopodium ambroisiodes against L. amazonensis promastigotes is correlated with mitochondrial dysfunction, reflected by ∆Ψm. Further studies by our group demonstrated ultrastructural mitochondrial alterations and ∆Ψm changes in parasites treated with thiophene derivatives isolated from the aerial parts of Porophyllum ruderale , a β-carbolinic compound ( N -butyl-1-[4-dimethylamino]phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide), and eupomatenoid-5, a neolignan isolated from the leaves of Piper regnellii [ 24 - 27 ]. Luque-Ortega et al (2010) [ 28 ] also showed that benzophenone-derived bisphosphonium salts present antileishmania activity against promastigotes of the Leishmania donovani causing a dramatically swollen mitochondrion in treated parasites, and a decrease of the electrochemical mitochondrial potential.…”

Asteraceae Plants as Sources of Compounds Against Leishmaniasis and Chagas Disease

“…The authors showed that although both compounds were not able to induce damage in the parasite membrane, the 5-methyl-2,2′:5′,2″-terthiophene provoked depolarization of mitochondrial membrane potential of L. amazonensis promastigotes. The ultrastructural analysis confirmed this effect since mitochondria swelling were observed for promastigote and amastigote forms treated with 5-methyl-2,2′:5′,2″-terthiophene (Takahashi et al, 2013).…”

“…In addition, Takahashi et al (2013) provided some insights into the action of these thiophene derivatives. The authors showed that although both compounds were not able to induce damage in the parasite membrane, the 5-methyl-2,2′:5′,2″-terthiophene provoked depolarization of mitochondrial membrane potential of L. amazonensis promastigotes.…”