Influence de l’opérateur biélectronique sur les transitions 2p → 3d dans l’oxyde de nickel (II)

Les structures observées dans les bandes d’absorptions LIII et LII de l’oxyde de nickel (II) sont comparées à ce que laisse attendre la théorie pour la configuration excitée 2p53d9 en symétrie approximativement sphérique. Il semble possible d’attribuer ces structures à un effet de répulsion interélectronique entre trous 2p et 3d. Celui-ci a pour effet de démultiplier les niveaux LIII et LII en une série de niveaux d’énergie, distribuée sur environ 5 eV

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (^)-primaquine with Na-protected amino acids, (ii) removal of the Naprotecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1- a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t1/2 5–30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging

H-1 and C-13 Nmr-Studies of Aminoglycoside Antibiotics

H-1 NMR spectroscopy was used to determine the conformations of the aminoglycoside antibiotic N-demethylclindamycin and two of its cyclic derivatives. The conformational features of these systems were determined by consideration of vicinal coupling constants and, in some cases, nuclear Overhauser enhancement (NOE) effects. H-1 and C-13 chemical shifts are reported and compared with previous results for the related antibiotic lincomycin. The stability of the two cyclized derivatives in aqueous solution was examined. Both cyclizations involved formation of a 4-imidazolidinone ring. It was found that the ring system based on cyclization with formaldehyde was stable in aqueous solution, whereas that based on benzaldehyde was not

Reactivity of imidazolidin-4-one derivatives of primaquine: implications for prodrug design

In contrast to peptide-based imidazolidin-4-ones, those synthesized from N-(alpha-aminoacyl) derivatives of the antimalarial drug, primaquine and ketones are unexpectedly stable in pH 7.4 at 37 C. The kinetics of hydrolysis of primaquine-based imidazolidin-4-ones were investigated in the pH range 0.3–13.5 at 60 C. The hydrolysis to the parent alpha-aminoacylprimaquine is characterized by sigmoidal shaped pH–rate profiles, reflecting the spontaneous decomposition of both unionized and protonated (at N-1) forms of the imidazolidin-4-one. The kinetically determined pKa values are ca. 3.6–4.0, i.e. 4 pKa units lower than those of amino acid amides, thus implying that hydrolysis of imidazolidin-4-ones at pH 7.4 involves the unionized form. Reactivity of this form decreases with the steric crowding of the amino acid alpha-substituent. In contrast, the rate constant for the spontaneous decomposition of the unionized form increases sharply for imidazolidin-4-ones derived from cyclic ketones, an observation that can be explained by the I-strain (internal strain) effect. These results are consistent with a mechanism of hydrolysis involving an SN1-type unimolecular cleavage of the imidazolidin-4-one C2–N3 bond with departure of an amide-leaving group. The mechanism for the decomposition of the protonated imidazolidin-4-one is likely to involve an amide-carbonyl oxygen protonated species, followed by the C2–N3 bond scission, as supported by computational studies. The results herein presented suggest that imidazolidin-4-ones derived from simple N-alkyl alpha-aminoamides are too stable and therefore may be useful as slow drug release prodrugs

Imidazolidin-4-one derivatives of primaquine as novel transmission-blocking antimalarials

Imidazolidin-4-one derivatives of primaquine were synthesized as potential double prodrugs of the parent drug. The title compounds inhibit the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The imidazolidin-4-ones are very stable, both in human plasma and in pH 7.4 buffer, indicating that they are active per se. Thus, imidazolidin-4-ones derived from 8-aminoquinolines represent a new entry in antimalarial structure-activity relationships