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) ethersubstituted 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 animalindependent because it becomes an active compound via a pHtriggered intramolecular cyclization−elimination reaction. As a proof-of-concept, the utility of this novel amino AOCOM ether prodrug approach was demonstrated on an antimalarial compound series representing a variety of antimalarial 4(1H)-quinolones, which entered and failed preclinical development over the last decade. With the amino AOCOM ether prodrug moiety, the 3-aryl-4(1H)-quinolone preclinical candidate was shown to provide single-dose cures in a rodent malaria model at an oral dose of 3 mg/kg, without the use of an advanced formulation technique.

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. The potential of these products in subsequent reactions was verified by the conversion to 3,4-dihydro-2H-1,3-thiazine-containing bisamides, β-lactams, and methoxy amides.

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.

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. In a hitherto unknown multicomponent reaction the α-sulfinyl imines react with an isocyanide under acidic conditions in an alcoholic solution to the respective α-alkoxy isothioureas in good yields. In addition to the investigations on this unexpected synthesis the regioselectivity of the acylation of the synthesized compounds is described. A rearrangement, which is accelerated by EDC and HOBt, between both possible regioisomers was found.

A new three‐step synthetic pathway to generate polycyclic annulated hydantoins via rarely investigated heterocyclic imines is described. This procedure includes a one‐pot reaction forming imines as precursor structures (e.g., Asinger reaction), followed by an Ugi reaction to build up a bisamide structure that allows a ring‐closing reaction to the targeted hydantoins via substitution. This pathway leads to a multiplicity of substances with a potential pharmacological activity.