Characterization of primaquine imidazolidin-4-ones with antimalarial activity by electrospray ionization-ion trap mass spectrometry

Abstract

The extensive characterization by electrospray ionization-ion trap mass spectrometry (ESI-MS n ) of 20 imidazolidin-4-ones derived from the antimalarial primaquine was well obtained. These compounds are being under investigation as potential antimalarials, as they have been previously found to be active against rodent P. berghei malaria and to be highly stable under physiological conditions. Experiments by collision-induced dissociation (CID) in the nozzle-skimmer region or by tandem-MS have shown the title compounds to be remarkably stable. Mechanisms are proposed to explain the major fragmentations observed in ESI-MS n experiments. Overall, this work represents an unprecedented contribution to a deeper insight into imidazolidin-4-one antimalarials based on a classic 8-aminoquinolinic scaffold. Data herein reported and discussed may be an useful guide for future studies on therapeutically relevant molecules possessing either the 8-aminoquinoline or the imidazolidin-4-one motifs.

Schistosoma haematobium: Identification of new estrogenic molecules with estradiol antagonistic activity and ability to inactivate estrogen receptor in mammalian cells

“…Such reactions might have occurred directly via Michael addition or indirectly through generation of reactive oxygen species (ROS) and led to structures (Scheme 1) compatible with the m/z values observed (Table 1). To confirm this hypothesis, and given our previous experience in tandem-MS studies to establish fragmentation mechanisms involving compounds relevant in other parasitic diseases (Vale et al, 2008a(Vale et al, ,b, 2009, we decided to further analyse the serum from a schistosoma-infected individual by LC-MS/MS. Species detected after MS 2 fragmentation of components 1-4, as illustrated in Fig.…”

Electrospray ionization-ion trap mass spectrometry study of PQAAPro and PQProAA mimetic derivatives of the antimalarial primaquine

“…Methanolic solutions of the compounds containing 0.1% acetic acid were infused into the ESI probe at a rate of 3 L/min. All other details of the experimental setup in the MS studies were as recently described [45], with the exception that the Vs CID parameter varied between 10 and 100 V in fragmentation studies on the NSR. The relevance of the experimental procedures adopted in our MS studies have been recently explained in our previous work concerning compounds derived from 3 [45].…”

“…Our research group has been working on the development of PQ derivatives with antimalarial activity and increased oral bioavailability, obtained by N-acylation of the parent drug with amino acids and further modification of the N-acyl derivatives (2) by insertion of an imidazolidin-4-one moiety (3) [40][41][42][43][44][45], which is commonly employed in the design of protease-resistant peptidomimetics [46][47][48][49][50][51][52].…”

“…This bioactivity pattern reflects the therapeutic profile of PQ itself, but hydrolysis studies have shown imidazolidin-4-ones 3 to be astonishingly stable, thus being active per se [40 -42]. To get a better understanding of structural properties of compounds derived from 3, we have recently engaged in an ESI-MS study of a family of 20 such compounds [45]. Experiments by CID in the nozzleskimmer region (NSR) and by tandem-MS have shown imidazolidin-4-ones 3 to be remarkably stable, reflecting our observations in aqueous media despite the distinct degradation pathways [45].…”

“…To get a better understanding of structural properties of compounds derived from 3, we have recently engaged in an ESI-MS study of a family of 20 such compounds [45]. Experiments by CID in the nozzleskimmer region (NSR) and by tandem-MS have shown imidazolidin-4-ones 3 to be remarkably stable, reflecting our observations in aqueous media despite the distinct degradation pathways [45]. We have now stepped forward to the synthesis and study of two new families of PQ imidazolidin-4-ones, 5 and 6, obtained from PQ.…”