Diversity-Oriented Synthesis Yields a Novel Lead for the Treatment of Malaria

Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of Plasmodium falciparum asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure–activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound 27 has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238.Chemistry and Chemical Biolog

Re-reading Yoder in Order to Conscientiously Engage Technology through the Practices of the Church

This dissertation builds on the work of one of the most prominent Mennonite theologians of the twentieth century, John Howard Yoder (1927-1997), in order to argue that the practices of the church make it possible for Christians to conscientiously engage technology. It lays the groundwork for this argument by first demonstrating the theological significance of technology, and then demonstrating the relevance of Yoder\u27s thought for this topic. Technological artifacts, systems, and ways of thinking merit theological consideration because they are not morally neutral—particular technologies do not simply meet human needs and desires, but come to shape our needs and desires, and thus our vision of what is good. Yoder\u27s thought is helpful because, far from reflecting a sectarian preoccupation with ethics, it pushes the church toward deeper theological engagement with social issues. In addition, Yoder\u27s discussion of the biblical concept of principalities and powers is especially relevant for grappling with technology. Picking up on Yoder\u27s preference for particularity, the rest of this dissertation is structured around a study of three examples of technology: the automobile, genetically modified food, and the Internet. This study demonstrates that the conscientious engagement of technology happens when the church, as the body of Christ, resists the seduction of the power of particular technologies by re-describing them within the narrative of God\u27s salvation of the world. More specifically, the church is able to testify to the reality that Christ has defeated and disarmed the powers, including the power of technology. This testimony is most clearly evident in the practices of the church, practices that make visible the distinctive marks of the church—viewed in the light of these marks, technological ideals are put in their proper place and are no longer granted the status of moral imperatives. What Yoder failed to appreciate was the extent to which these practices not only bear witness to the marks of the church, but contribute to the formation of these marks. Furthermore, there are a whole host of tactics related to our everyday encounters with particular technologies that can also contribute to this crucial work of moral formation

Diversity-Oriented Synthesis Yields a Novel Lead for the Treatment of Malaria

Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of <i>Plasmodium falciparum</i> asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure–activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound <b>27</b> has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

Antimalarial drugs have thus far been chiefly derived from two sources—natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets