Artermisinin and its derivatives are now the mainstays of antimalarial treatment; however, their mechanism of action is only poorly understood. We report on the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are disubstituted with alkyl or benzyl side chains show efficient inhibition of the growth of both chloroquine-sensitive and -resistant strains of Plasmodium falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to that of its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides cause the early accumulation of endocytic vesicles, while artemisinin causes the disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures, while the novel endoperoxides cause myelin body formation as well as the accumulation of endocytic vesicles. An early event following endoperoxide treatment is the redistribution of the pH-sensitive probe LysoSensor Blue from the digestive vacuole to punctate structures. By contrast, neither artemisinin nor the novel endoperoxides caused alterations in the morphology of the endoplasmic reticulum nor showed antagonistic antimalarial activity when they were used with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of the mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggest that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.Artemisinin is a sesquiterpene lactone antimalarial with a 1,2,4-trioxane heterocyclic core that incorporates a peroxide linkage that is essential for its activity (44). Artemisinin is of major importance as a frontline treatment for malaria, particularly as it is active against chloroquine (CQ)-resistant strains of Plasmodium falciparum (20,23,24,45,66,74). Several groups have reported on pathways for the synthesis of artemisinin, but all require numerous steps and have low yields (5, 35). As a result, artemisinin-based antimalarials are produced semisynthetically from extracts of Artemisia annua. A period of over 1 year is needed for the horticultural, harvesting, extraction, and manufacturing processes (34,41,45), which limits the ease of scale-up of production and makes artemisinin derivatives much more expensive than traditional antimalarials, such as CQ and sulfadoxine-pyrimethamine. Indeed, artemisinin combinations are too costly for many patients, and the supply of counterfeit or inferior drugs is a major problem (4, 45, 71). Another issue is the fact that artemisinin and its derivatives are not suitable for prophylaxis or for use as a monotherapy due to their very short half-lives in vivo. T...

Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, M. tuberculosis. Here, we report a binder of MtDTBS, cyclopentylacetic acid 2 (K D = 3.4 ± 0.4 mM), identified via in silico screening. X-ray crystallography showed that 2 binds in the 7,8-diaminopelargonic acid (DAPA) pocket of MtDTBS. Appending an acidic group to the para-position of the aromatic ring of the scaffold revealed compounds 4c and 4d as more potent binders, with K D = 19 ± 5 and 17 ± 1 μM, respectively. Further optimization identified tetrazole 7a as a particularly potent binder (K D = 57 ± 5 nM) and inhibitor (K i = 5 ± 1 μM) of MtDTBS. Our findings highlight the first reported inhibitors of MtDTBS and serve as a platform for the further development of potent inhibitors and novel therapeutics for the treatment of tuberculosis.

A new chemical transformation for the construction of diversely functionalized cyclopropanes utilizing 1,2-dioxines and stabilized phosphorus ylides as the key precursors is presented. Through a series of mechanistic studies we have elucidated a clear understanding of the hitherto unknown complex relationship between 1, 2-dioxines 1a-e, and their isomeric cis/trans gamma-hydroxy enones (23 and 21a-e), cis/trans hemiacetals 24a-e, and beta-ketoepoxides (e.g., 26), and how these precursors can be utilized to construct diversely functionalized cyclopropanes. Furthermore, several new synthetically useful routes to these structural isomers are presented. Key features of the cyclopropanation include the ylide acting as a mild base inducing the ring opening of the 1,2-dioxines to their isomeric cis gamma-hydroxy enones 23a-e, followed by Michael addition of the ylide to the cis gamma-hydroxy enones 23a-e and attachment of the electrophilic phosphorus pole of the ylide to the hydroxyl moiety, affording the intermediate 1-2lambda(5)-oxaphospholanes 4 and setting up the observed cis stereochemistry between H1 and H3. Cyclization of the resultant enolate (30a or 30b), expulsion of triphenylphosphine oxide, and proton transfer from the reaction manifold affords the observed cyclopropanes in excellent diastereomeric excess. The utilization of Co(SALEN)(2) in a catalytic manner also allows for a dramatic acceleration of reaction rates when entering the reaction manifold from the 1,2-dioxines. While cyclopropanation is favored by the use of ester-stabilized ylides, the use of keto- or aldo-stabilized ylides results in a preference for 1,4-dicarbonyl formation through a competing Kornblum-De La Mare rearrangement of the intermediate hemiacetals. This finding can be attributed to subtle differences in ylide basicity/nucleophilicity. In addition, the use of doubly substituted ester ylides allows for the incorporation of another stereogenic center within the side chain. Finally, our studies have revealed that the isomeric trans gamma-hydroxy enones and the beta-keto epoxides are not involved in the cyclopropanation process; however, they do represent an alternative entry point into this reaction manifold.

The combination of chiral cobalt beta-ketoiminato or cobalt salen complexes and meso 1,2-dioxines leads to catalytic asymmetric ring-opening affording enantio-enriched cis gamma-hydroxy enones; subsequent capture by an ylide affords enantio-enriched cyclopropanes.

A concise, high yielding route to the naturally occurring enantiomer of grenadamide utilizing a 3,6-disubstituted 1,2-dioxine starting material is presented. The route allows for ease in synthesizing grenadamide derivatives varying at cyclopropyl carbons 2 and 3, with access to both enantiomers. Evidence for phosphorus-assisted deprotonation of 1,2-dioxines is also discussed.