Diamine and aminoalcohol derivatives active against Trypanosoma brucei

Olmo, Esther del; Diaz-Gonzalez, Rosario; Escarcena, Ricardo; Carvalho, Luís M.; Bustos, Luis A.; Navarro, Miguel; Feliciano, Arturo San

doi:10.1016/j.bmcl.2011.10.108

Cited by 9 publications

(12 citation statements)

References 14 publications

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“…In this regard, the previously proposed role of ␤-amino alkanols as pseudoanalogs for sphingosine is appealing (16). The presence of vesicles inside the flagellar pocket of Leishmania treated with compound 9 resembles the pattern observed for parasites defective in key enzymes of sphingolipid metabolism (50,51).…”

Section: Discussionmentioning

confidence: 83%

“…Despite their potential antiprotozoal application, knowledge of their mechanisms of action on these organisms is limited and dispersed. Hypotheses based on their structural homology with other metabolites, e.g., interference of alkyl-substituted amino alkanols on sphingolipid metabolism, have been advanced (16). Clearly, a deeper insight into the targets of ␤-amino alkanols might boost the further chemotherapeutic development of these compounds.…”

Section: Discussionmentioning

confidence: 99%

“…This can be caused by interference in membrane traffic and mechanistically is intermediate between the two polarized patterns of compounds 5 and 8. Interestingly, other ␤-amino alkanols induced in T. b. brucei the phenotype known as "big eye" with the formation of a huge vacuole inside the parasite, which is associated to interference in endocytosis and hence in membrane traffic (16).…”

Section: Discussionmentioning

confidence: 99%

“…It fulfills the Lipinski rule of five (55) for considering a compound as a putative hit: clogP of 3.9 (Ͻ5), MW of 229.4 (Ͻ500), 2 (Ͻ10) hydrogen bond acceptors, 2 (Ͻ5) hydrogen bond donors, and the conditions used by the Drugs for Neglected Diseases Initiative (DNDi) (EC 50 of Ͻ1 M, SI of Ͼ10) (16). Other theoretical, structure-derived parameters for skin absorption and toxicity (see the supplemental material) are encouraging enough to proceed with animal studies where the real potential of these compounds and their possible synergisms with immune mechanisms of the host might be revealed.…”

Section: Discussionmentioning

confidence: 99%

“…Proof of concept for their use as leishmanicidal agents has been also reported (13)(14)(15). Nevertheless, aside from mitochondrial swelling and alterations in endocytic traffic, observed in African trypanosomes treated with some substituted ␤-amino alkanols (16), their mechanisms of action on trypanosomatids remain mostly unknown.…”

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confidence: 99%

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Mechanisms of Action of Substituted β-Amino Alkanols on Leishmania donovani

Abengózar

Bustos

García-Hernández

et al. 2015

Antimicrob Agents Chemother

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Leishmaniasis is the protozoan disease second in importance for human health, superseded only by malaria; however, the options for chemotherapeutic treatment are increasingly limited due to drug resistance and toxicity. Under this perspective, a quest for new chemical compounds is urgently needed. An N-substituted 2-aminoalkan-1-ol scaffold has been shown to be a versatile scaffold for antiparasitic activity. Knowledge about its mechanism of action is still rather limited. In this work, we endeavored to define the leishmanicidal profile of such ␤-amino alkanol derivatives using a set of 15 N-mono-and disubstituted surrogates, tested on Leishmania donovani promastigotes and intracellular amastigotes. The best compound (compound 5), 2-ethylaminododecan-1-ol, had a 50% effective concentration (EC 50 ) of 0.3 M and a selectivity index of 72 for infected THP-1 cells and was selected for further elucidation of its leishmanicidal mechanism. It induced fast depletion of intracellular ATP content in promastigotes in the absence of vital dye intracellular entry, ruling out plasma membrane permeabilization as its origin. Confocal and transmission electron microscopy analyses showed that compound 5 induced severe mitochondrial swelling and vesiculation. Polarographic analysis using an oxygen electrode demonstrated that complex II of the respiratory chain (succinate reductase) was strongly inhibited by compound 5, identifying this complex as one of the primary targets. Furthermore, for other ␤-amino alkanols whose structures differed subtly from that of compound 5, plasma membrane permeabilization or interference with membrane traffic was also observed. In all, N-substituted ␤-amino alkanols were shown as appealing leishmanicidal candidates deserving further exploration.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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