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We identified an amino-benzothiazole scaffold from a whole cell screen against recombinantMycobacterium tuberculosisunder expressing the essential signal peptidase LepB. The seed molecule had two-fold higher activity against the LepB hypomorph. Through a combination of purchase and chemical synthesis we explored the structure activity relationship for this series; 34 analogs were tested for anti-tubercular activity and for cytotoxicity against eukaryotic cells. We identified molecules with improved potency and reduced cytotoxicity. However, molecules did not appear to target LepB directly and did not inhibit protein secretion. Key compounds showed good permeability, low protein binding, and lack of CYP inhibition, but metabolic stability was poor with short half-lives. The seed molecule showed good bactericidal activity against both replicating and non-replicating bacteria, as well as potency against intracellularM. tuberculosisin murine macrophages. Overall, the microbiological properties of the series are attractive if metabolic stability can be improved, and identification of the target could assist in development of this series.

Precision medicine is an emerging field in healthcare that seeks to tailor preventive and therapeutic strategies to the unique physiology, biochemistry, lifestyles, and genetics of individual patients. There are several technologies that are key to the successful delivery of precision medicine including pharmacogenomics, pharmacometabolomics, improved point-of-care testing, and therapeutically-tailored medications. The inclusion of additive manufacturing (AM) technology, more commonly known as 3D printing, in the manufacture of oral dosage forms such as tablets, provides an avenue for the implementation of precision medicine in current healthcare practice via the prescription of specific dosage forms and drug combinations tailored to individual needs. Widespread commercialization of AM of pharmaceuticals has the potential to disrupt the supply chain used by the healthcare industry worldwide with the cost-saving potential of minimizing waste related to unused, expired medications. Despite the potential of this technology, many clinical and regulatory challenges will need to be addressed prior to large-scale implementation of AM fabricated therapeutics for precision medicine applications. This review investigates both the potential and the challenges of delivering AM fabricated medications for therapeutic use in precision medicine applications.

Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available materials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one‐step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.

Attaching dendritically branched side chains to each repeat unit of a linear polymer produces molecular building blocks of nanometer-sized dimensions called dendronized polymers. The structure of these complex molecular architectures is highly tunable and, therefore, of interest for a wide range of potential applications. The first examples of dendronized polymers prepared by living ring-opening metathesis polymerization of oxanorbornenedicarboximide macromonomers with poly(alkyl ether) dendrons are reported. Small-angle X-ray scattering experiments on bulk samples confirm that the diameter of the individual cylindrical polymers can be tailored by the choice of dendron generation or the length of the hydrocarbon peripheral group. Analysis of the SAXS data based on a core-shell model indicates that although the diameter of the cylinder increases with generation, the size of the core does not change; this suggests that these dendrons only loosely encapsulate the polymer backbone. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 3221–3239

The general secretion (Sec) pathway is a conserved essential pathway in bacteria and is the primary route of protein export across the cytoplasmic membrane. During protein export, the signal peptidase LepB catalyzes the cleavage of the signal peptide and subsequent release of mature proteins into the extracellular space. We developed a target-based whole cell assay to screen for potential inhibitors of LepB, the sole signal peptidase in Mycobacterium tuberculosis, using a strain engineered to underexpress LepB (LepB-UE). We screened 72,000 compounds against both the Lep-UE and wild-type (wt) strains. We identified the phenylhydrazone (PHY) series as having higher activity against the LepB-UE strain. We conducted a limited structure–activity relationship determination around a representative PHY compound with differential activity (MICs of 3.0 μM against the LepB-UE strain and 18 μM against the wt); several analogues were less potent against the LepB overexpressing strain. A number of chemical modifications around the hydrazone moiety resulted in improved potency. Inhibition of LepB activity was observed for a number of compounds in a biochemical assay using cell membrane fraction derived from M. tuberculosis. Compounds did not increase cell permeability, dissipate membrane potential, or inhibit an unrelated mycobacterial enzyme, suggesting a specific mode of action related to the LepB secretory mechanism.

Tuning properties by programming the surface functional group composition of surface-block dendrimers has been limited to dendrimers with only two types of surface functionality (i.e., surface-diblock dendrimers). The Passerini reaction provides dendrimer products from precursor dendrons in reasonable yields. This proof-of-principle experiment opens the door to making surface-triblock dendrimers.

Polymer chemistry has embraced multicomponent reactions for synthesizing multifunctional materials, including structurally perfect multimodal dendrimers. An unexpected substituent effect dramatically shortens the time required for the convergent synthesis of dendrimers via the Passerini three-component reaction.