Hydroxamic acids are outstanding zinc chelating groups that can be used to design potent and selective metalloenzyme inhibitors in various therapeutic areas. Some hydroxamic acids display a high plasma clearance resulting in poor in vivo activity, though they may be very potent compounds in vitro. We designed a 57-member library of hydroxamic acids to explore the structure-plasma stability relationships in these series and to identify which enzyme(s) and which pharmacophores are critical for plasma stability. Arylesterases and carboxylesterases were identified as the main metabolic enzymes for hydroxamic acids. Finally, we suggest structural features to be introduced or removed to improve stability. This work thus provides the first medicinal chemistry toolbox (experimental procedures and structural guidance) to assess and control the plasma stability of hydroxamic acids and realize their full potential as in vivo pharmacological probes and therapeutic agents. This study is particularly relevant to preclinical development as it allows obtaining compounds equally stable in human and rodent models.

Herein is reported a safe and economical multigram synthesis of 6-fluoromenadione, an intermediate in the synthesis of novel antiparasitic agents. The keys to this 6-steps sequence process involves the condensation of the readily available starting 4'-fluoropropiophenone and glyoxylic acid, a bromination-elimination sequence from the 7-fluoro-3-methyltetral-1-one allowing the aromatization of the naphthol intermediate, which is then oxidized into the corresponding 6-fluoromenadione. The multigram process has been demonstrated from 25 g starting material scale with an improved overall yield of 50%, and then applied to five other 7-substituted-3-methyltetralones and their corresponding 6substituted-menadiones.

A second generation route to protected modified dinucleotides encompassing a difluorophosphinothioyl unit in replacement of the phosphoryl diester is described. It relies on (i) the preparation of 6’‐iodonucleosides, (ii) their coupling with a furanosyl 3’‐difluoromethyl H‐phosphinothioate, and (iii) the introduction of the second nucleobase. Thus, a short and high yielding preparation of 6’‐iodonucleosides from commercially available materials is reported, and their coupling reaction with a furanosyl 3’‐difluoromethyl H‐phosphinothioate satisfactorily delivered the desired protected bisfuranosyl derivatives featuring both a difluorophosphinothioyl unit and a nucleobase unambiguously installed on the anomeric position of the bottom furanose. Introduction of the second nucleobase generated the desired heterodinucleotides in low yields. Careful analysis of the materials indicates that the classical Vorbrüggen conditions may induce the trans‐N‐glycosylation process to take place, resulting in the competitive replacement of a nucleobase with another one, thereby generating mixtures of homo‐ and heterodinucleotides.