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.

Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

“…Nitrosation of the cinnamic alcohol fragment in quinoline 87 followed by a four‐step functional group interconversion afforded hybrid 89 with satisfactory overall yield (Scheme ). Furoxan 89 displayed significant activity against the parasites P. falciparum , S. mansoni , and A. ceylanicum , which allows consideration of hybrid 89 as a drug candidate for the treatment of various parasitic diseases …”

“… Synthesis of furoxan‐based amodiaquine structural analogues . Reagents and conditions : a) NaNO 2 , AcOH, RT, 10 h, 57 %; b) TBSONHTs, DIAD, PPh 3 , THF, 55 °C, 72 h, 62 %; c) CsF, MeCN, RT, 30 min, 48 %; d) SOCl 2 , DMF, 0 °C, 10 min, 96 %; e) 4 m HCl, dioxane, MeOH, RT, 30 min, 98 %.…”

Heterocyclic N-Oxides - An Emerging Class of Therapeutic Agents

“…[152] The regioisomeric furoxan 174 was obtained by thermal isomerization of 173 in toluene. The peptidomimetic scaffolds 177 were assembled by initial conversion of the azide to amine function via the Staudinger reduction.…”

“…[151] It has been shown that the quinine core common to amodiaquine and chloroquine possess activity against other parasitic diseases, most notably schistosomiasis. Thus, Mott and coworkers [152] applied the concept of drug hybridization in the development of a new therapy by combining the beneficial features of furoxans (known NO donor) and that of the quinine core (Figure 42). …”

Synthesis, structural characterization and cytotoxic activity of heterocyclic compounds containing the furoxan ring

“…), [7][8][9] including the 1,2,5-oxadiazole 2-oxides (furoxans) which are capable of exogenous NO release at the presence of thiol cofactors. 10,11 Furoxans comprise a valuable class of five-membered heterocycles and can serve as a privileged motif in medicinal and pharmaceutical chemistry owing to their significant biological activities, for example neuroprotective and precognitive, 12 cytotoxic, 13,14 antihelmintic, 15 antibacterial 16 and fungicidal 17 , connected with the high capacity of furoxans to produce a large flux of NO. It was established that NO exerts a cytotoxic effect at high concentrations, while low levels of NO are potentially protective, particularly in the CNS.…”