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This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure−activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.

Crystallization in the microdomains of crystalline−amorphous diblock copolymers may induce domain coalescence when the crystallization temperature lies above the Tg of the amorphous matrix. In this study, the perturbation of microdomain structure driven by isothermal crystallization and postannealing in a poly(ethylene oxide)-block-poly(1,4-butadiene) (PEO-b-PB) and PEO-b-PB/PB homopolymer (h-PB) blends consisting of spherical PEO domains in the melt state is systematically investigated to reveal whether the presence of homopolymer in the amorphous matrix would hinder or facilitate the microdomain coalescence driven by the crystallization. Three samples with nearly the same volume fraction and length of PEO block are adopted for the study; the first is an asymmetric PEO-b-PB that contains no h-PB, the second is a blend containing 12 wt % of h-PB, and the third is a blend consisting of 63 wt % of h-PB. Characterization of the domain structure after isothermal crystallization and postannealing treatment by SAXS and TEM indicates that the blend containing the higher h-PB content exhibits the stronger resistance against microdomain coalescence. The resistance is proposed to stem from the diffusion barrier associated with the rejection of a portion of h-PB originally dissolved in the coronal regions of the micelles during the coalescence process.

We studied the crystallization behavior in a diblock copolymer/homopolymer blend system exhibiting “dry-brush” phase behavior in the melt. A nearly symmetric poly(ethylene oxide)-block-polybutadiene (PEO-b-PB) was blended with a PB homopolymer (h-PB) having approximately the same molecular weight as that of the PB block, thereby yielding the dry-brush blends wherein h-PB was localized in the PB microdomain, causing expansion of PB domain thickness without introducing transformation in microdomain morphology. Even though the lamellar identity of PEO domain retained throughout the blend composition, the lamellar units became increasingly isolated as characterized by the formations of cylindrical and spherical vesicles at high h-PB compositions. Over the major composition range (wh-PB ≤ 0.7), crystallization of PEO blocks in the vesicle wall was able to take place at the undercooling comparable to that of PEO homopolymer, implying that the crystallization mechanism was analogous to the homopolymer crystallization initiated predominantly through heterogeneous nucleation followed by long-range crystal growth. At the compositions (wh-PB ≥ 0.8) where most PEO lamellae formed shells of spherical vesicles in the melt, the crystallization was effectively confined within the individual vesicle, and it only occurred at very deep undercooling (ΔT > 70 K). The corresponding isothermal crystallization followed the first-order kinetics prescribed by a nucleation-controlled crystallization wherein the crystallization started from homogeneous nuclei followed by essentially instantaneous crystal growth to fill the vesicle wall. In general, the confinement effect exerted by dry-brush blending was far less effective than the corresponding wet-brush blending.