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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 (

Human African trypanosomiasis is a neglected tropical disease (NTD) that is fatal if left untreated. Although approximately 13 million people live in moderate- to high-risk areas for infection, current treatments are plagued by problems with safety, efficacy, and emerging resistance. In an effort to fill the drug development pipeline for HAT, we have expanded previous work exploring the chemotype represented by the compound NEU-1090, with a particular focus on improvement of absorption, distribution, metabolism and elimination (ADME) properties. These efforts resulted in several compounds with substantially improved aqueous solubility, although these modifications typically resulted in a loss of trypanosomal activity. We herein report the results of our investigation into the antiparasitic activity, toxicity, and ADME properties of this class of compounds in the interest of informing the NTD drug discovery community and avoiding duplication of effort.

From a high-throughput screen of 42 444 knownhuman kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold wasidentified to begin optimization for the treatment of human Africantrypanosomiasis. Previously reported data for analogous com-pounds against human kinases GSK-3β, CDK-2, and CDK-4 wereleveraged to try to improve the selectivity of the series, resulting in23awhich showed selectivity forT. b. bruceiover these threehuman enzymes. In parallel, properties known to influence theabsorption, distribution, metabolism, and excretion (ADME)profile of the series were optimized resulting in20gbeingprogressed into an efficacy study in mice. Though20gshowedtoxicity in mice, it also demonstrated CNS penetration in a PKstudy and significant reduction of parasitemia in four out of the sixmice., This work was supported by National Institutes of HealthGrants (R01AI114685 (M.P.P. and M.N.), R01AI082577(M.P.P.), R56AI099476 (M.P.P.), R01AI124046 (M.P.P.),R21AI127594 (M.P.P.), the Spanish Ministerio de Economía,Industria y Competitividad (M.N., Grant SAF2015-71444-P;D.G.P., Grant SAF2016-79957-R., and Subdirección Generalde Redes y Centros de Investigación Cooperativa (RICET)(M.N., Grant RD16/0027/0019; D.G.P., Grant RD16/0027/0014), Grant RTI2018-097210-B-100 (MINCIU-FEDER) toF.G. C.R.C. acknowledges grant support from the NIH-NIAID(Grant R21AI126296) and the Bill and Melinda GatesFoundation (Grant OPP1171488), as well as the technicalassistance of Brian M. Suzuki for screening adultS. mansoni.We are grateful to AstraZeneca for performing thein vitroADME experiments presented throughout and to CharlesRiver Labs for thein vitroADME data presented inTables S3−S5 in the Supporting Information. We thank GSK Tres Cantosopen lab foundation for running the PK studies discussed inthis publication. An academic license for ChemAxon (https://www.chemaxon.com) is gratefully acknowledged. We thankDr. Melissa Buskes for help in the preparation of thismanuscrip

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.

Human African trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2-(2-(((3-((1H-Benzo[d]imidazol-2-yl)amino)propyl)amino)methyl)-4,6-dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high-throughput screen of >42,000 compounds as a highly potent and fast-acting trypanocidal agent capable of curing a bloodstream infection of Trypanosoma brucei in mice. We have designed a library of analogues to probe the structure–activity relationship and improve the predicted central nervous system (CNS) exposure of NEU-1053. We report the activity of these inhibitors of T. brucei, the efficacy of NEU-1053 in a murine CNS model of infection, and identification of the target of NEU-1053 via X-ray crystallography.