Effect of 1, 2, 3-triazole salts, non-classical bioisosteres of miltefosine, on Leishmania amazonensis. Issue 12 (15th June 2017)

• Record Type: Journal Article
• Authors: Stroppa, Pedro H.F.; Antinarelli, Luciana M.R.; Carmo, Arturene M.L.; Gameiro, Jacy; Coimbra, Elaine S.; da Silva, Adilson D.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 12(2017)
• Page Start: 3034
• Page End: 3045
• Publication Date: 2017-06-15
• Subjects: 1/2/3-Triazoles -- Leishmania -- Miltefosine -- Antileishmanial activity -- Apoptosis -- Necrosis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.03.051
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Some new non-classical bioisosteres of miltefosine were synthesized and assayed against Leishmania amazonensis . DhmtAc, with an acetate anion and a side chain of 10 carbon atoms, showed selective biological activity. DhmtAc was more effective than the miltefosine prototype. The anti-leishmanial activity is mediated via apoptosis and necrosis. Abstract: Here, we report the effect of new non-classical bioisosteres of miltefosine on Leishmania amazonensis . Fifteen compounds were synthesized and the compounddhmtAc, containing an acetate anion, a side chain of 10 carbon atoms linked to N-1 and a methyl group linked to N-3, showed high and selective biological activity against L. amazonensis . On the intracellular amastigotes, stages of the parasite related to human disease, the IC50 values were near or similar to the 1.0 μM (0.9, 0.8 and 1.0 μM on L. amazonensis- WT, and two transgenic L. amazonensis expressing GFP and RFP, respectively), being more active than miltefosine. Furthermore, dhmtAc did not show toxic effects on human erythrocytes and macrophages (CC50 = 115.9 μM) being more destructive to the intracellular parasites (selectivity index > 115). Promastigotes and intramacrophage amastigotes treated withdhmtAc showed low capacity for reversion of the effect of the compound. A study of the mechanism of action of this compound showed some features of metazoan apoptosis, including cell volume decreases, loss of mitochondrial membrane potential, ROS production, an increase in the intracellular lipid bodies, in situ labeling of DNA fragments by TUNEL labeling and phosphatidylserine exposure to the outerleaflet of the plasma membrane. In addition, the plasma membrane disruption, revealed by PI labeling, suggests cell death by necrosis. No increase in autophagic vacuoles formation in treated promastigotes was observed. Taken together, the data indicate that the bioisostere of miltefosine, dhmtAc, has promising antileishmanial activity that is mediated via apoptosis and necrosis.