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

Abstract

Electrospray ionization-ion trap mass spectrometry (ESI-MS) of imidazolidin-4-one peptidemimetic derivatives of the antimalarial drug primaquine (PQ) is reported. These compounds contain the imidazolidin-4-one moiety either at the N-or the C-terminal of a dipeptide backbone, thus respectively mimicking PQ-Amino Acid-Proline (PQAAPro) and PQProAA derivatives of PQ. Both the peptidomimetics and precursors previously developed by us are promising drug candidates, as they were found to be active against rodent Plasmodium berghei malaria and Pneumocystis carinii pneumonia. Collision-induced dissociation (GD) and tandemmass spectra (MS) of the title compounds, and fragmentation pathways thereof, led to the following findings: (1) CID patterns present some parallelism with the reactivity towards hydrolysis previously found for the same or related compounds; (2) a positional shift of the imidazolidin-d-one ring is reflected on both degree and pathways of fragmentation, which makes tandem-MS a key tool for differentiation of imidazolidin-i-one isomers; (3) the major MS/MS fragmentation of PQProAA mimetics involves release of a neutral diketopiperazine (DKP), in parallel to the "diketopiperazine pathway" described in tandem-MS studies of oligopeptides; (4) the relative abundance of a major fragment in tandem-MS spectra is inversely correlated with the size of the N-terminal AA in PQProAA mimetics. Overall, this work embodies an original and valuable contribution towards a deeper insight into the molecular properties of novel antimalarials, which can be viewed as representative of both the 8-aminoquinoline and, especially, the imidazolidin-4-one structural classes. aAm Soc Mass Spectrom 2008, 19, 1476-1490 ) © 2008 American Society for Mass SpectrometryO ver the past decade, electrospray ionization mass spectrometry (ESI-MS) has been used for the most diverse analytical purposes. This technique has provided deeper insight into the structural properties and stability of numerous compounds, from natural products [1-3] to synthetic drugs [4-8], peptides [9-23], and heterocycles [24][25][26][27][28], among many others. Notwithstanding, little has been done on the application of this technique to the study of relevant antimalarials such as primaquine (PQ, 1) or related structures. Analytical methods focused on PQ or its analogues have been so far applied to pharmacokinetics studies and metabolite scrutiny [29][30][31][32][33][34][35][36][37] or isomer characterization [38,39]. Examples of mass spectrometry techniques employed to the study/analysis of PQ and related compounds include fast atom bombardment mass spectral (FAB-MS) analysis of PQ oxidation products [32] and supercritical fluid chromatography-mass Address reprint requests to Dr. P.

Imidazoquines as Antimalarial and Antipneumocystis Agents

“…Importantly, stability was not affected by the substitution pattern at the terminal amino acid or the imidazolidin-4-one moiety. Such stability had already been reported on previous studies involving some of these imidazoquines and their precursors 4 25–27,47,48. Overall, these results suggest that the oral availability of compounds 5 is unlikely to be limited by compound stability.…”

Helical peptides from VEGF and Vammin hotspots for modulating the VEGF–VEGFR interaction

“…The expected peptides 9-12 were not isolated as such, but as sulphones, compounds 15-18 (Scheme 1) due to overoxidation of the Met side-chain. 54 NMR and mass spectra data of the isolated compounds agreed with the sulphone structure (ESI †). 55 …”

Peptidomimetic and Organometallic Derivatives of Primaquine Active against Leishmania infantum

“…Synthetic procedures and structural data have been reported elsewhere for compounds 3a to e (40) and 4b (38). Other compounds of the PQ-Pro-Xaa series, i.e., 4a and c to i, were synthesized as previously described for compound 4b (38), and spectroscopic data as well as high-pressure liquid chromatography (HPLC) traces are available upon request.…”

“…Synthetic procedures and structural data have been reported elsewhere for compounds 3a to e (40) and 4b (38). Other compounds of the PQ-Pro-Xaa series, i.e., 4a and c to i, were synthesized as previously described for compound 4b (38), and spectroscopic data as well as high-pressure liquid chromatography (HPLC) traces are available upon request. Synthetic procedures and chromatographic/spectroscopic data were reported elsewhere for compounds 5 to 10 (19,20), except for compound 7h, for which relevant procedures and data are available upon request.…”

“…Cyt pound 4 ( Fig. 1) (2,26,38,40). Compounds 3 and 5 to 10 have previously revealed remarkable activity against PQ-sensitive pathogens, namely, Plasmodium (malaria) and Pneumocystis (pneumocystic pneumonia), in some cases with better performances than that of PQ at the activity and/or toxicity level (19,20,36,40).…”