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

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.

In search of novel drugs against tuberculosis, we previously discovered and profiled a novel hydantoin-based family that demonstrated highly promising in vitro potency against Mycobacterium. tuberculosis. The compounds were found to be noncovalent inhibitors of DprE1, a subunit of decaprenylphosphoryl-β-D-ribose-2′-epimerase. This protein, localized in the periplasmic space of the mycobacterial cell wall, was shown to be an essential and vulnerable antimycobacterial drug target. Here, we report the further SAR exploration of this chemical family through more than 80 new analogues. Among these, the most active representatives combined submicromolar cellular potency and nanomolar target affinity with balanced physicochemical properties and low human cytotoxicity. Moreover, we demonstrate in vivo activity in an acute Mtb infection model and provide further proof of DprE1 being the target of the hydantoins. Overall, the hydantoin family of DprE1 inhibitors represents a promising noncovalent lead series for the discovery of novel antituberculosis agents.