Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Abstract

Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.

Cascade strategy for triggered radical release by magnetic nanoparticles grafted with thermosensitive alkoxyamine

“…The alkoxyamine derivative carrying the coordinative phosphonic acid function on one hand and the nitroxyl moiety with thermosensitive C-ON bond on the other hand have been chosen here as a pool of radicals because: (i) the thermal lability of the C-ON bond of some alkoxyamines is well documented, [34][35][36][37] (ii) they can be covalently anchored to the IONP surface through the coordination of the phosphonate functionality, (iii) when attached to the magnetic nanoparticles surface, we expect that they will be activated under an ac field at lower reaction temperature since magnetic nanoparticles are able to create hot spots in their local environment, (iv) they may be used as radical source for biomedical applications since their high potential in the fight against tumors, parasites or bacteria through radicals release triggered by chemical, enzymatic, and physical (light excitation) events [38][39][40][41][42][43] has recently been demonstrated, [44][45][46] and the toxicity of non-activated alkoxyamines is low, (v) alkoxyamine may also be used as radical initiators for triggered and controlled polymerization in the systems where the simple heating is not possible. Note that to the best of our knowledge, the combination of thermosensitive alkoxyamines with magnetic nanoparticles activated by a magnetic field has never been reported up to date.…”

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

“…The different compounds were evaluated in vitro for their antiplasmodial activity against the P. falciparum resistant strain F32-ART, selected after 144 intermittent and increasing doses of artemisinin, according to our published procedures. , Briefly, the antimalarial effect was first determined by Sybr Green at two doses (1 and 10 μM), in triplicate, and on two independent experiments. For compounds inducing around or more than 50% parasite growth inhibition at 10 μM, a new chemosensitivity assay using four doses, each one tested in triplicate, was then performed to determine their exact IC 50 values.…”

Smart Alkoxyamines: A New Tool for Smart Applications

“…The possibility to trigger C–ON homolysis by coordination with a metal cation has been discussed and tentatively applied with 21 as a drug against malaria and bilharzia …”

“…The possibility to trigger C−ON homolysis by coordination with a metal cation has been discussed and tentatively applied with 21 as a drug against malaria and bilharzia. 63 For the concept described in Figure 21 to be effective, three criteria must be met: (1) The prodrug must be very stable so that it is not toxic before activation. (2) The activation step must be rapid and efficient in order to generate enough activated drug in situ.…”