Quinoline-based antimalarial hybrid compounds.

Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the Plasmodium parasite against these drugs and the lack of licensed malaria vaccines have forced chemists to develop synthetic strategies toward novel biologically active molecules. A strategy that has attracted considerable attention in current medicinal chemistry is based on the conjugation of two biologically active molecules into one hybrid compound. Since quinolines are considered to be privileged antimalarial building blocks, the synthesis of quinoline-containing antimalarial hybrids has been elaborated extensively in recent years. This review provides a literature overview of antimalarial hybrid molecules containing a quinoline core, covering publications between 2009 and 2014.

Synthesis of halogenated 4-quinolones and evaluation of their antiplasmodial activity.

Treatment of 4-hydroxyquinolines with (2-methyl)allyl bromide in the presence of K2CO3 resulted in the formation of novel N-[(2-methyl)allyl]-4-quinolones through selective N-alkylation. Further reaction of N-(2-methylallyl)-4-quinolones with bromine or N-bromosuccinimide yielded the corresponding 3-bromo-1-(2,3-dibromo-2-methylpropyl)-4-quinolones and 3-bromo-1-(2-methylallyl)-4-quinolones, respectively. Furthermore, a copper-catalyzed C-N coupling of the latter 3-bromo-4-quinolones with (5-chloro)indole afforded novel 3-[(5-chloro)indol-1-yl]-4-quinolone hybrids. Antifungal and antiplasmodial assays of all new 4-quinolones were performed and revealed no antifungal properties but moderate antiplasmodial activities. All 15 compounds displayed micromolar activities against a chloroquine-sensitive strain of Plasmodium falciparum, and the five most potent compounds also showed micromolar activities against a chloroquine-resistant strain of P. falciparum with IC50-values ranging between 4 and 70 µM.

Evaluation of (4-aminobutyloxy)quinolines as a novel class of antifungal agents.

Antifungal assessment of eighteen 5-, 6- and 8-(4-aminobutyloxy)quinolines revealed a significant susceptibility of the tested fungi and yeast strains (Candida albicans, Rhodotorula bogoriensis, Aspergillus flavus and Fusarium solani) toward different halo-substituted 8-(4-aminobutyloxy)quinolines. The six most potent compounds displayed antifungal activities similar to those of established antifungal agents such as Amphotericin B, Fluconazole and Itraconazole, and one representative also showed a promising broad-spectrum antifungal profile. The introduction of an aminoalkoxy side chain at the 8-position of a halo-substituted quinoline core might thus provide a new class of lead structures in the search for novel antifungal agents.

Synthesis and antiplasmodial evaluation of novel (4-aminobutyloxy)quinolines.

A variety of 5-, 6- and 8-(4-aminobutyloxy)quinolines as novel oxygen analogues of known 4- and 8-(4-aminobutylamino)quinoline antimalarial drugs was generated from hydroxyquinolines through a three-step approach with a rhodium-catalyzed hydroformylation as the key step. Antiplasmodial assays of these new quinolines revealed micromolar potency for all representatives against a chloroquine-sensitive strain of Plasmodium falciparum, and three compounds showed submicromolar activity against a chloroquine-resistant strain of P. falciparum with IC(50)-values ranging between 150 and 680 nM.

Exploration of aziridine- and ß-lactam-based hybrids as both bioactive substances and synthetic intermediates in medicinal chemistry.

The concept of pharmacophore hybridization is attracting an increasing interest from medicinal chemists. Whereas the main motivation for the application of this methodology relates to the pharmacological advantages associated with hybrid molecules, molecular hybridization can also deliver a synthetic advantage through selective chemical modification of the more reactive entity within hybrid systems. Moreover, if both features are combined, new hybrid structures result displaying both a biological and a synthetic benefit, and elaboration of this methodology might culminate in structural diversity and chemical novelty. In this perspective, a new approach based on hybrid structures combining a biologically interesting yet rather chemically reactive nucleus with a privileged heterocyclic scaffold is discussed by means of ß-lactam-purine chimeras useful in antiviral research and aziridine-(iso)quinoline hybrids for antimalarial purposes.

Synthesis of 2-amino-3-arylpropan-1-ols and 1-(2,3-diaminopropyl)-1,2,3-triazoles and evaluation of their antimalarial activity.

A variety of 2-amino-3-arylpropan-1-ols, anti-2-amino-3-aryl-3-methoxypropan-1-ols and anti-2-amino-1-arylpropan-1,3-diols were prepared selectively through elaboration of trans-4-aryl-3-chloro-ß-lactams. In addition, a number of 2-(azidomethyl)aziridines was converted into novel 2-[(1,2,3-triazol-1-yl)methyl]aziridines by Cu(I)-catalyzed azide-alkyne cycloaddition, followed by microwave-assisted, regioselective ring opening by dialkylamine towards 1-(2,3-diaminopropyl)-1,2,3-triazoles. Although most of these compounds exhibited weak antiplasmodial activity, six representatives showed moderate antiplasmodial activity against both a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum with IC(50)-values of ≤25 µM.

Synthesis of functionalized 3-, 5-, 6- and 8-aminoquinolines via intermediate (3-pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines and evaluation of their antiplasmodial and antifungal activity.

(3-Pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines were prepared via cyclization of diallylaminoquinolines and 4-chloro-N-quinolinylbutanamides, respectively, as novel synthetic intermediates en route to N-functionalized 3-, 5-, 6- and 8-aminoquinolines with potential biological activity. (3-Pyrrolin-1-yl)quinolines were subjected to bromination reactions, and the reactivity of (2-oxopyrrolidin-1-yl)quinolines toward lithium aluminum hydride and methyllithium was assessed, providing an entry into a broad range of novel functionalized (pyrrolidin-1-yl)- and (hydroxyalkylamino)quinolines. Antiplasmodial evaluation of these novel quinolines and their functionalized derivatives revealed moderate micromolar potency against a chloroquine-sensitive strain of the malaria parasite Plasmodium falciparum, and the two most potent compounds also showed micromolar activity against a chloroquine-resistant strain of P. falciparum. Antifungal assessment of (hydroxyalkylamino)quinolines revealed three compounds with promising MIC values against Rhodotorula bogoriensis and one compound with potent activity against Aspergillus flavus.

Biocatalytic production of novel glycolipids with cellodextrin phosphorylase.

Glycolipids have gained increasing attention as natural surfactants with a beneficial environmental profile. They are typically produced by fermentation, which only gives access to a limited number of structures. Here we describe the biocatalytic production of novel glycolipids with the cellodextrin phosphorylase from Clostridium stercorarium. This enzyme was found to display a broad donor and acceptor specificity, allowing the synthesis of five different products. Indeed, using either α-glucose 1-phosphate or α-galactose 1-phosphate as glycosyl donor, sophorolipid as well as glucolipid could be efficiently glycosylated. The transfer of a glucosyl moiety afforded a mixture of products that precipitated from the solution, resulting in near quantitative yields. The transfer of a galactosyl moiety, in contrast, generated a single product that remained in solution at thermodynamic equilibrium. These glycolipids not only serve as a new class of biosurfactants, but could also have applications in the pharmaceutical and nanomaterials industries.