New phenalenone analogues with improved activity against Leishmania species

• Published in: Biomedicine & pharmacotherapy 2020-12, Vol.132, p.110814-110814, Article 110814
• Main Authors: López-Arencibia, Atteneri, Bethencourt-Estrella, Carlos J., Freijo, Mónica B., Reyes-Batlle, María, Sifaoui, Ines, Nicolás-Hernández, Desirée San, McNaughton-Smith, Grant, Lorenzo-Morales, Jacob, Abad-Grillo, Teresa, Piñero, José E.
• Format: Article
• Language: English
• Subjects: Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Apoptosis - drug effects; apoptosis-like; chemotherapy; Leishmania - drug effects; Leishmania amazonensis; Membrane Potential, Mitochondrial - drug effects; Phenalenes - chemistry; Phenalenes - pharmacology; Phenalenones; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - pharmacology
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110814

[Display omitted] •The five phenalenone derivatives are potential anti-leishmanial agents.•Phenalenone 8 is 9-times more selective than the reference drug miltefosine.•Derivatives decrease mitochondrial potential and increase phosphatidylserine exposure.•The five phenalenones induce apoptosis-like in Leishmania amazonensis. The in vitro activity against Leishmania spp. of five novel designed compounds, phenalenone derivatives, is described in this study. Previous works have shown that some phenalenones present leishmanicidal activity, some of which could induce programmed cell death events in L. amazonensis parasites. In this research, we focused on the determination of the programmed cell death evidence by detecting the characteristic features of the apoptosis-like process, such as phosphatidylserine exposure and mitochondrial membrane potential, among others. The results showed that the new derivatives have comparable or better activity and selectivity than the commonly prescribed anti-leishmanial drug. This result was obtained by inducing stronger mitochondrial depolarization or more intense phosphatidylserine exposure than miltefosine, highlighting compound 8 with moreover 9-times better selectivity index. In addition, the new five molecules activated the apoptosis-like process in the parasite. All the signals observed were indicative of the death process that the parasites were undergoing.