A facile and efficient oxidative CÀH acylation of N-substituted pyrazolones using a-oxocarboxylic acids as an acyl group source was developed. A combination of Cu(OAc) 2 and K 2 S 2 O 8 enables the reaction to proceed smoothly under air and provides a wide array of 4-acylpyrazolone products in moderate to excellent yields. The mechanism of this transformation is believed to proceed via a copper-induced decarboxylation to form the acyl-copper species. This method provides a convenient and useful route for a direct installation of an acyl moiety into bioactive pyrazolone derivatives, which can be further utilized in many applications.
Metal‐free approach for direct C–H thiolation and thiocyanation of N‐substituted pyrazolones with disulfides and thiocyanate salts, respectively, are developed. These reactions allow the C–S bond coupling to proceed effectively under mild conditions, providing useful and convenient methods for preparation of a series of 4‐thio‐substituted pyrazolone analogues, which have potential applications in organic, medicinal and material chemistry. Preliminary mechanistic investigation suggested that radical processes are likely to involve in these transformations.
Pantothenamides are potent growth inhibitors of the malaria parasite Plasmodium falciparum. Their clinical use is, however, hindered due to the ubiquitous presence of pantetheinases in human serum, which rapidly degrade pantothenamides into pantothenate and the corresponding amine. We previously reported that replacement of the labile amide bond with a triazole ring not only imparts stability toward pantetheinases, but also improves activity against P. falciparum. A small library of new triazole derivatives was synthesized, and their use in establishing structure–activity relationships relevant to antiplasmodial activity of this family of compounds is discussed herein. Overall it was observed that 1,4‐substitution on the triazole ring and use of an unbranched, one‐carbon linker between the pantoyl group and the triazole are optimal for inhibition of intraerythrocytic P. falciparum growth. Our results imply that the triazole ring may mimic the amide bond with an orientation different from what was previously suggested for this amide bioisostere.
The Plasmodium parasites that cause malaria are adept at developing resistance to antimalarial drugs, necessitating the search for new antiplasmodials. Although several amide analogs of pantothenate (pantothenamides) show potent antiplasmodial activity, hydrolysis by pantetheinases (or vanins) present in blood rapidly inactivates them. We report herein the facile synthesis and biological activity of a small library of pantothenamide analogs in which the labile amide group is replaced with a variety of heteroaromatic rings. Several of the new analogs display antiplasmodial activity in the nanomolar range against P. falciparum and/or P. knowlesi in the presence of pantetheinase. A previously reported triazole and an isoxazole derivative presented here were further characterized and found to possess high selectivity indices, medium or high Caco-2 permeability, and medium or low microsomal clearance in vitro. Although we show here that the two compounds fail to suppress proliferation of P. berghei in vivo, pharmacokinetic and contact time data presented provide a benchmark for the compound profile required to achieve antiplasmodial activity in mice and should facilitate lead optimization.
A highly efficient iodine-catalyzed oxidative cross-dehydrogenative coupling reaction of quinoxalinones and indoles has been developed. Without the requirement of peroxide and acid, this reaction utilizes a catalytic amount of molecular iodine to facilitate the C–C bond formation under ambient air. This simple and easy-to-handle protocol represents an interesting synthetic alternative with a good scope and functional group compatibility.
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