Effective anti-leishmanial activity of minimalist squaramide-based compounds

Abstract

In order to evaluate the in vitro leishmanicidal activity of N,N'-Squaramides derivatives, compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites, against Leishmania infantum, Leishmania braziliensis and Leishmania donovani a series of 18compounds was prepared and assayed on extracellular and intracellular parasite forms. Infectivity and cytotoxicity tests were performed on J774.2 macrophage cells using meglumine antimoniate (Glucantime) as the reference drug. Changes in metabolite excretion by H-NMR and the ultrastructural alterations occurring in the parasites treated using transmission electron microscopy (TEM), was analyzed. Compounds 1, 7, 11, 14 and 17 were the more active and less toxic. Infection rates showed that the order of effectiveness was 17> 11 > 14 > 7 for both L. infantum and L. braziliensis and in the same way, the compound 1 for L. donovani. All these compounds have altered the typical structure of the promastigotes, glycosomes and mitochondria. These severe modifications by the compounds are the ultimate reasons for the alterations observed in the excretion products. The Squaramide 17 (3-(butylamino)-4-((3-(dimetilamino)propyl)(methyl)amino)cyclobut-3-en-1,2-dione) was clearly the most efficient of all compounds. The data appear to confirm that the severe modifications generated in organelles such as glycosomes or mitochondria by the compounds are the ultimate reasons for the alterations observed in the excretion products of all species. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-leishmanial agent.

Bisperoxovandium (pyridin‐2‐squaramide) targets both PTEN and ERK1/2 to confer neuroprotection

“…Squaramide is a functional group existing in many bioactive compounds. Some squaramide‐based compounds have anti‐leishmanial activity (Marin et al, ). Both in vitro and in vivo studies have confirmed that N,N′‐squaramides are effective against Chagas disease (Olmo et al, ).…”

Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors

“…Squaramide can be considered as a motif of interest enabling formation of H-bonds bioisosteric to functionalities like carboxylic and amino acids, urea, guanidine, cyanoguanidine, and different phosphate groups [30]. More recently, mono- and bis-squaramide-based derivatives were investigated as treatment for insect-transmitted parasite diseases such as leishmaniasis [31], malaria [32], and Chagas disease [33].…”

<p>The neuroprotective effect of bisperoxovandium (pyridin-2-squaramide) in intracerebral hemorrhage</p>

“…Bisperoxovandium (pyridine-2-carboxyl)[bpV(pic)], a commercially available PTEN inhibitor, confers a protective effect in brain injury and cognitive deficits of isoflurane exposures 14,15. Squaramide is a functional group existing in many bioactive compounds that have various biological activities 16–19. Because of its functional activity, stability, low cost of starting materials, and straightforward synthesis, squaramide is an appropriate molecule for the development of affordable agents.…”