Diastereoselective synthesis of trifluoromethylated 1,3-dioxanes by intramolecular oxa-Michael reaction.

A highly diastereoselective synthesis of trifluoromethylated 1,3-dioxanes is described. The reaction proceeds by an addition/oxa-Michael sequence and works efficiently under mild reaction conditions, with a good substrate scope and acceptable to good yields.

Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target.

With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.

Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth.

With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-à-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound 3 was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles (1-2) are described, which were identified following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis. The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead 29, with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to 29, and under replicating conditions, 29 demonstrated bactericidal activity against M. tuberculosis. Unfortunately, compound 29 had no efficacy in an acute model of TB infection; this was most likely due to the in vivo exposure remaining above the minimal inhibitory concentration for only a limited time.

And the beak shall inherit - evolution in response to invasion.

The increased demographic performance of biological invaders may often depend on their escape from specifically adapted enemies. Here we report that native taxa in colonized regions may swiftly evolve to exploit such emancipated exotic species because of selection caused by invaders. A native Australian true bug has expanded it host range to include a vine imported from tropical America that has become a serious environmental weed. Based on field comparisons and historical museum specimens, we show that over the past 30-40 years, seed feeding soapberry bugs have evolved 5-10% longer mouthparts, better suited to attack the forest-invading balloon vines, which have large fruits. Laboratory experiments show that these differences are genetically based, and result in a near-doubling of the rate at which seeds are attacked. Thus a native biota that initially permits invasion may rapidly respond in ways that ultimately facilitate control.

Active learning with support vector machines in the drug discovery process.

We investigate the following data mining problem from computer-aided drug design: From a large collection of compounds, find those that bind to a target molecule in as few iterations of biochemical testing as possible. In each iteration a comparatively small batch of compounds is screened for binding activity toward this target. We employed the so-called "active learning paradigm" from Machine Learning for selecting the successive batches. Our main selection strategy is based on the maximum margin hyperplane-generated by "Support Vector Machines". This hyperplane separates the current set of active from the inactive compounds and has the largest possible distance from any labeled compound. We perform a thorough comparative study of various other selection strategies on data sets provided by DuPont Pharmaceuticals and show that the strategies based on the maximum margin hyperplane clearly outperform the simpler ones.