Identification and Profiling of Hydantoins—A Novel Class of Potent Antimycobacterial DprE1 Inhibitors

Abstract

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

Unexpected Coelenterazine Degradation Products of Beroe abyssicola Photoprotein Photoinactivation

“…Because there were no known synthetic methods for hydantoin-substituted enamides, we developed a new strategy based on oxime acylation (Scheme ). The readily available 5-arylidene-substituted hydantoin 1′ and p -methoxy derivative of 2-bromoacetophenone 2′ were used in a substitution reaction to obtain an intermediate ketone 3′ , which was subsequently converted to the corresponding oxime 4′ . The compound 4′ was then used in Fe-catalyzed acylation to obtain enamide 5′ ( Z / E = 61/39).…”

Consensus Pharmacophore identification for antimycobacterial DprE1 inhibitory activity of substituted hydantoins.

“…The various steps involved are (1) ChemSketch 12 freeware was used to draw ninety-five structures, (2) Structure optimization of all the structures using MMFF94 force field existing in TINKER, (3) In the next step, Open3dAlign software was executed to align all the optimized structures, (4) Consensus pharmacophore modeling was completed using LIQUID plugin (installed on PyMOl 2.2) using the default settings [4][5][6].…”

“…It is a vector borne neglected disease and recent reports suggest the emergence of resistance against existing drugs. The emergence of resistance is cause of high concern; therefore, developing novel therapeutics is an urgent need to eliminate this lethal disease [1][2][3]. Unfortunately, developing a new drug is a lengthy and expensive exercise; therefore, alternative methods like Computer Aided Drug Designing (CADD) must be used to derive a new therapeutic agent.…”

“…Consensus pharmacophore modeling is extensively utilized as it is fast, easy and identifies the common pharmacophoric scaffolds associated with the anticipated activity [4][5][6]. Recently, Rogacki et al [3] identified hydantoin derivatives as potent anti-TB compounds. The tested hydantoin derivatives have high degree of variation in anti-TB profile because of wide difference in substituents.…”

Ruthenium(II)-Catalyzed Regioselective [3 + 2] Spiroannulation of 2H-Imidazoles with 2-Alkynoates

“…Spirocyclic skeletons are important synthetic targets due to their diversified biological activities and have been used as core components of various functional materials and ligands . With the rapid development of C–H bond functionalization, transition-metal-catalyzed annulation reactions have proven to be a powerful tool for obtaining various challenging but synthetically valuable spirocyclic molecules .…”