A furoxan-amodiaquine hybrid as a potential therapeutic for three parasitic diseases()

Abstract

Parasitic diseases continue to have a devastating impact on human populations worldwide. Lack of effective treatments, the high cost of existing ones, and frequent emergence of resistance to these agents provide a strong argument for the development of novel therapies. Here we report the results of a hybrid approach designed to obtain a dual acting molecule that would demonstrate activity against a variety of parasitic targets. The antimalarial drug amodiaquine has been covalently joined with a nitric oxide-releasing furoxan to achieve multiple mechanisms of action. Using in vitro and ex vivo assays, the hybrid molecule shows activity against three parasites - Plasmodium falciparum, Schistosoma mansoni, and Ancylostoma ceylanicum.

Fig. 1

Small molecule anti-parasitic therapies.

Fig. 2

Proposed structure of a furoxan–amodiaquine hybrid.

Fig. 3

TGR activity inhibition for furoxan 6 and hybrid 15.

Fig. 4

Ex vivo S. mansoni parasite killing assay.

Fig. 5

Ex vivo hookworm parasite killing assay of ABZ 2 at 100 μM and hybrid 15 at 100 μM.

Scheme 1

Reagents and conditions: (a) HCl, MeOH, 89% (b) conc. HCl, reflux in sealed tube, 6 h, 77% (c) tBuNH₂, py, DMF, 80 °C, 80% (d) ethyl acrylate, K₂CO₃, Pd(OAc)₂, dppp, DMF, MW, 130 °C, 7 h, 81% (e) DIBALH, CH₂Cl₂, −78 °C, 74% (f) NaNO₂, AcOH, 57% (crude) (g) TBSONHTs, DEAD, PPh₃, THF, 62% (h) CsF, MeCN, 48% (i) SOCl₂, 0 °C, DMF, 99% and (j) 4.0 M HCl in dioxane, 99%.