Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice

Abstract

Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from self-healing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drug-resistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (ΔΨm) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches.

Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities

“…The first one could be related with the inhibition of the enzymatic systems of the protozoan by blocking the utilization of iron by the parasite, a mode of action which was observed for the African species [46]. The second one could be related with the loss of mitochondrial transmembrane potential [47].…”

Cinnamic Acid Conjugates in the Rescuing and Repurposing of Classical Antimalarial Drugs

“…Therefore, this work conveyed the disclosure of CAD as inhibitors of the new permeability pathways (NPP) induced by Plasmodium in erythrocytes to enable the translocation of carbohydrates and amino acids [46][47][48][49]. Following this pioneering discovery, other authors have proposed different CA-inspired compounds as potential therapeutic agents against malaria [26,28,29], as well as other parasitic diseases [50][51][52]. In view of this, reports have emerged over the past decade where conjugation to CA was proposed as a useful strategy for the rescuing of known antimalarials [53][54][55].…”

m‐Nitrocinnamic Acid Containing Lipophilic Peptide Exhibits Selective Growth Inhibition Activity against Leishmania major

“…Recently, Schurigt et al. reported that cinnamic acid bornyl ester from Valeriana wallichi exhibits in vivo antileishmanial activity . Inspired by these reports, here we have synthesized a series of nitro compounds containing m ‐nitrocinnamic acid, α‐aminoisobutyric acid (Aib) and L‐leucine.…”