Amino acids as selective acylating agents: regioselective N1-acylation of imidazolidin-4-one derivatives of the antimalarial drug primaquine

Abstract

a b s t r a c tThe acylation of bioactive primaquine-based imidazolidin-4-ones was studied using N a -Boc-protected glycine as acylating agent. Two synthesis routes, eight different coupling methods and seven distinct solvents were compared. Mild carbodiimide-based couplings on high dielectric constant solvents such as DMF or MeCN increased acylation yields, whereas alcohols inhibited carbodiimide-mediated acylations to take place. Achievement of the synthetic goals was limited by the size of the imidazolidin-4-one ring substituents R 1 , R 2 and R 3 , but resort to MW-assisted synthesis allowed overcoming such obstacle, though with very modest reaction yields. All reactions involving a Boc-protected amino acid were regioselective, independent of reaction conditions employed. In contrast, regioselective acetylation of the imidazolidin-4-ones could only be achieved by resort to very mild coupling procedures.

Imidazoquines as Antimalarial and Antipneumocystis Agents

“…Briefly, once prepared as previously described,29 imidazolidin-4-one precursors 4 were coupled to N α -Boc-protected amino acids (BocAAOH) by means of a carbodiimide (diisopropylcarbodiimide, DIC) as condensation agent, in the presence of 1-hydroxybenzotriazole (HOBt) as auxiliary nucleophile. Boc was then removed from the condensation product by acidolysis with trifluoroacetic acid (TFA), yielding the target compounds 5 in good yields and with correct spectroscopic data.…”

“…Nonetheless, our previous work has shown that R 1 substituents on imidazolidin-4-ones 4 (i) should be small (H, Me) for higher transmission blocking activities,2 and (ii) do not have a marked influence on compounds activity against both blood-stage P. falciparum or P. carinii 28. Bulky substituents on the imidazolidin-4-one’s C-2 carbon are also detrimental towards N -acylation, so only propanone-derived imidazolidin-4-ones are efficiently N -acylated 29. Nevertheless, insertion of larger substituents on the imidazolidin-4-one’s C-2, as those previously reported by us,26,28 would probably lead to a decreased water-solubility of final compounds 5 .…”

“…NaHCO 3 and the organic layer dried over anhydrous MgSO 4 and evaporated to dryness. The residue was submitted to column chromatography on silica using DCM/acetone, to give the Boc-protected imidazoquines, Boc-5 , as yellow-orange oils presenting correct spectral data 26,29. Each compound Boc-5 was then dissolved in TFA at 30% in DCM and the reaction allowed proceeding for 2 h at room temperature.…”

“…In view of initial promising results, we undertook the N 1 -acylation of imidazolidin-4-ones 4 with amino acids, i.e., the preparation of structures 5 (Scheme 1),29 aimed at (i) fully suppressing hydrolysis of the imidazolidin-4-one ring through acylation of its N-1 nitrogen, (ii) increasing the compounds’ aqueous solubility by insertion of a basic amino group, and (iii) potentially increasing the compounds’ antimalarial activity, given the relevant role usually attributed to the basic amino group of PQ 18. A set of different structures 5 , where the amino acids’ side chains (R 1 and R 2 ) were varied, was prepared in order to check for the influence of these substituents on compound properties.…”

PRIMACENES: novel non-cytotoxic primaquine-ferrocene conjugates with anti-Pneumocystis carinii activity

“…The relevance of such a group has been proposed earlier 33 and confirmed by our previous studies with PQ peptide and peptidomimetic (imidazoquine) derivatives. [23][24][25][26][27][28][29][30][31] To check this hypothesis, we are now working on the synthesis and in vitro evaluation of second-generation primacenes bearing basic amino groups.…”