Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1)-Quinolones with Single Dose Cures.

Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction.

Progress in the Optimization of 4(1)-Quinolone Derivatives as Antimalarials Targeting the Erythrocytic, the Exoerythrocytic and the Transmitting Stages of the Malaria Parasite.

Malaria is one of the leading infectious diseases occurring mainly in tropical and subtropical areas. Although available antimalarial tools have reduced the number of fatalities, there is still an urgent need for the development of new and more efficacious treatments to cure and eradicate malaria especially due to emerging resistance to all antimalarial drugs. Research was initiated to revisit antimalarial compounds which were deemed unsuitable as a result of poor understanding of physicochemical properties and the optimization thereof.

A three-component reaction for rapid access to underexplored 1,3-thiazine-2-thiones.

Driven by the shortage of known effective possibilities for the synthesis of 4-hydroxy-3,4-dihydro-2H-1,3-thiazine-2-thiones on the one hand and the promising potential of these structures as novel drug candidates on the other hand, synthetic access to 4-hydroxy-3,4-dihydro-2H-1,3-thiazine-2-thiones was developed. The desired products could be synthesized effectively and facilely starting from β-chlorovinyl aldehydes with the aid of a new MCR (multicomponent reaction). Furthermore, the 4-hydroxy-3,4-dihydro-2H-1,3-thiazine-2-thiones are shown to be appropriate substrates in the preparation of diverse annulated polycyclic systems.

A new multicomponent reaction: unexpected formation of derivatizable cyclic α-alkoxy isothioureas.

An unexpected formation of cyclic α-alkoxy isothioureas has been achieved. As is known, the heterocyclic imines 2,5-dihydro-1,3-thiazoles are convertible to bisamides with the aid of a carboxylic acid and an isocyanide (Ugi reaction). Herein, it is shown that 2,5-dihydro-1,3-thiazole S-monoxides-the respective α-sulfinyl imines-are characterized by an altered reaction behavior.

Regioselective air oxidation of sulfides to O,S-acetals in a bubble column.

In this paper the use of a bubble column for a metal-free, selective oxidation of α-alkylthio-imines to O,S-acetals is presented. During the synthesis, which is straightforward to perform, the sulfides are oxidized to α-alkoxy- or, respectively, α-hydroxysulfide by adding activated carbon in the presence of atmospheric oxygen only. We show that the use of the bubble column, which is unusual on laboratory scale, improves the efficiency of the reaction in comparison to common laboratory techniques.

Multicomponent reaction for the first synthesis of 2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6-diaryl-2H-1,3-thiazines as scaffolds for various 3,4-dihydro-2H-1,3-thiazine derivatives.

A two-step sequence for the synthesis of various 3,4-dihydro-2H-1,3-thiazines is presented. In the first step, 2H-1,3-thiazines were prepared by a new multicomponent reaction (MCR). Starting from β-chlorovinyl aldehydes, this MCR offers an efficient and facile access to 2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6-diaryl-2H-1,3-thiazines.