Neglected tropical diseases such as Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis have a significant global health impact in predominantly developing countries, although these diseases are spreading due to increased international travel and population migration. Drug repurposing with a focus on increasing antiparasitic potency and drug-like properties is a cost-effective and efficient route to the development of new therapies. Here we identify compounds that have potent activity against Trypanosoma cruzi and Leishmania donovani, and the latter were progressed into the murine model of infection. Despite the potent in vitro activity, there was no effect on parasitemia, necessitating further work to improve the pharmacokinetic properties of this series. Nonetheless, valuable insights have been obtained into the structure-activity and structure-property relationships of this compound series.

Human African trypanosomiasis (HAT) is one of 20 neglected tropical diseases as designated by the World Health Organization. It is largely found in remote areas of sub-Saharan Africa, where disease treatment and monitoring is limited. Recent efforts to eradicate HAT have seen the number of infected people worldwide reduced, and in 2016 only 2184 new cases were reported. Despite this, HAT continues to be a risk for a severe epidemic, and resurgence has historically been observed even from such low case numbers. Therefore, efforts to find new treatments for HAT are ongoing. Herein, we discuss the disease progression, the current treatments for HAT and their associated shortcomings, and some of the approaches being employed to identify new treatments. We also look at some of the tools that are used to diagnose and stage the progression of HAT.

Previously we reported the results from an effort to improve Gram-negative antibacterial activity in the oxazolidinone class of antibiotics via a systematic medicinal chemistry campaign focused entirely on C-ring modifications. In that series we set about testing if the efflux and permeation barriers intrinsic to the outer membrane of Escherichia coli could be rationally overcome by designing analogs to reside in specific property limits associated with Gram-negative activity: i) low MW (<400), ii) high polarity (clogD7.4 <1), and iii) zwitterionic character at pH 7.4. Indeed, we observed that only analogs residing within these limits were able to overcome these barriers. Herein we report the results from a parallel effort where we explored structural changes throughout all three rings in the scaffold for the same purpose. Compounds were tested against a diagnostic MIC panel of Escherichia coli and Staphylococcus aureus strains to determine the impact of combining structural modifications in overcoming the OM barriers and in bridging the potency gap between the species. The results demonstrated that distributing the charge-carrying moieties across two rings was also beneficial for avoidance of the outer membrane barriers. Importantly, analysis of the structure-permeation relationship (SPR) obtained from this and the prior study indicated that in addition to MW, polarity, and zwitterionic character, having ≤4 rotatable bonds is also associated with evasion of the OM barriers. These combined results provide the medicinal chemist with a framework and strategy for overcoming the OM barriers in GNB in antibacterial drug discovery efforts.

Multidrug antibiotic resistance poses an increasingly urgent threat to global health and the world economies. Among antibiotic resistant species, gram negative bacteria present the utmost urgency as they have become resistant to nearly all available treatment options. Combating antibacterial resistance should include continuous introduction of new antibiotic classes; however over the last 40 years there has been a void in antibiotic drug discovery. Extending the spectrum of activities of current classes of antibiotics is another approach. The oxazolidinones are a class of antibiotics that work by interfering with protein translation and are mainly active against gram‐positive bacteria. Linezolid, marketed under the trade name Zyvox®, was the first FDA‐approved oxazolidinone for the treatment of pathogenic gram‐positive bacteria. One focus of this work is to optimize the properties of oxazolidinones in order to penetrate the lipopolysaccharide layer of gram‐negative bacteria while maintaining their target potency. The rational lead optimization campaign based on the linezolid scaffold involves keeping a low molecular weight (MW <400 Da), and high polarity (clog D <1) to allow passage through the porins and to be able to escape the bacterial efflux pumps. A focused library of oxazolidinone analogs was synthesized and evaluated for activity in a panel of wild‐type and outer membrane‐ and or efflux pump‐compromised Escherichia coli and Staphylococcus aureus . Several C‐ring modification analogs offered moderate activity against gram negative bacteria and seem to improve membrane permeability and evasion of the efflux pumps. A subset of these compounds was tested in the context of an in vitro transcription and translation assay and most were found to be comparable to linezolid in terms of efficacy.

Novel antibacterials with activity against the Gram-negative bacteria associated with nosocomial infections, including Escherichia coli and other Enterobacteriaceae, are urgently needed due to the increasing prevalence of multidrug-resistant strains. A major obstacle that has stalled progress on nearly all small-molecule classes with potential for activity against these species has been achieving sufficient whole-cell activity, a difficult challenge due to the formidable outer membrane and efflux barriers intrinsic to these species. Using a set of compound design principles derived from available information relating physicochemical properties to Gram-negative entry or activity, we synthesized and evaluated a focused library of oxazolidinone analogues, a currently narrow spectrum class of antibacterials active only against Gram-positive bacteria. In this series, we have explored the effectiveness for improving Gram-negative activity by identifying and combining beneficial structural modifications in the C-ring region. We have found polar and/or charge-carrying modifications that, when combined in hybrid C-ring analogues, appear to largely overcome the efflux and/or permeability barriers, resulting in improved Gram-negative activity. In particular, those analogues least effected by efflux and the permeation barrier had significant zwitterionic character.