Tuberculosis is the leading cause of death worldwide from infectious diseases. With the development of drug-resistant strains of Mycobacterium tuberculosis, there is an acute need for new medicines with novel modes of action. Herein we are reporting the discovery and profiling of a novel hydantoin-based family of antimycobacterial inhibitors of the decaprenylphospho-beta-Dribofuranose 2-oxidase (DprE1). In this study we have prepared a library of more than a 100 compounds and evaluated them for their biological and physicochemical properties. The series is characterized by high enzymatic and whole-cell activity, low cytotoxicity and a good overall physicochemical profile. Additionally we show that the series acts via reversible inhibition of the DprE1 enzyme. Overall, the novel compound family forms an attractive base for progression to further stages of optimization and may provide a promising drug candidate in the future.in-situ deprotection gave the acid 19, which was reduced to the alcohol 20 with borane-THF complex. 18 One-pot mono-tosylation, ether formation 19 and subsequent second tosylation of the alcohol gave the oxetane 21, which was used to alkylate the hydantoin 5 and provide the final product 42. Scheme 3. Preparation of analogues 43a-b and 44 a a Reagents and conditions: (a) HONH2HCl, MW, 100°C, 30min; (b) Red-Al, toluene, 120°C, 1h.Alternatively, the ketone of the parent compounds 1 and 24 could be modified as shown on Scheme 3. Thus, microwave irradiation of a solution of 1 and hydroxylamine led to formation of two isomeric oximes 20 (43a and b). Lastly, Red-Al mediated reduction 21 of 24 provided alcohol 44 as a diastereoisomeric mixture. 42F CN <4.0

As a follow up to the antimycobacterial screening exercise and the release of GSK´s first Tres Cantos Antimycobacterial Set (TCAMS-TB), this paper presents the results of a second antitubercular screening effort of two hundred and fifty thousand compounds recently added to the GSK collection. The compounds were further prioritized based on not only antitubercular potency but also on physicochemical characteristics. The 50 most attractive compounds were then progressed for evaluation in three different predictive computational biology algorithms based on structural similarity or GSK historical biological assay data in order to determine their possible mechanisms of action. This effort has resulted in the identification of novel compounds and their hypothesized targets that will hopefully fuel future TB drug discovery and target validation programs alike.

In this study, a new series of more than 60 quinoline derivatives has been synthesized and evaluated against Mycobacterium tuberculosis (H37Rv). Apart from the SAR exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity, and metabolic stability of the series. The best compounds obtained exhibited MIC values in the low micromolar range, excellent intracellular antimycobacterial activity, and an improved physicochemical profile without cytotoxic effects. Further investigation revealed that the amide bond was the source for the poor blood stability observed, while some of the compounds exhibited hERG affinity. Compound 83 which contains a benzoxazole ring instead of the amide group was found to be a good alternative, with good blood stability and no hERG affinity, providing new opportunities for the series. Overall, the obtained results suggest that further optimization of solubility and microsomal stability of the series could provide a strong lead for a new anti-TB drug development program.

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.

e Worldwide, the Mycobacterium bovis BCG vaccine is one of the most widely used vaccines. However, it appears to be ineffective in preventing pulmonary tuberculosis. Here, we show that pulmonary BCG vaccination of mice with a broad dose range provides superior protection against Mycobacterium tuberculosis challenge compared to that of subcutaneous vaccination.