Good to excellent reactivity and regiocontrol have been achieved in the Cu(I)-catalyzed borylation of dialkyl internal alkynes with bis(pinacolato)diboron. The presence of a propargylic polar group (OH, OR, SAr, SO(2)Ar, or NHTs), in combination with PCy(3) as ligand, allowed maximizing the reactivity and site-selectivity (β to the propargylic function). DFT calculations suggest a subtle orbitalic influence from the propargylic group, matched with ligand and substrate size effects, as key factors involved in the high β-selectivity. The vinylboronates allowed the stereoselective synthesis of trisubstituted olefins, while allylic substitution of the SO(2)Py group without affecting the boronate group provided access to formal hydroboration products of unbiased dialkylalkynes.
With
the emergence of multidrug-resistant strains of Mycobacterium
tuberculosis there is a pressing need for new oral drugs
with novel mechanisms of action. Herein, we describe the identification
of a novel morpholino–thiophenes (MOT) series following phenotypic
screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure–activity
relationships of a range of analogues around the confirmed actives
are described. Optimized leads with potent whole cell activity against
H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine
model of infection are described. Mode-of-action studies suggest that
the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome c oxidoreductase, part of the bc1-aa3-type cytochrome c oxidase complex that is responsible for driving oxygen-dependent
respiration.
In accessing trisubstituted vinyl boronates from terminal alkynes, a propargyl directing (2-pyridyl)sulfonyl group allows terminal alkynes to undergo Cu-catalyzed B2(pin)2-borylation and subsequent Cu-catalyzed allylic alkylation with Grignard reagents without affecting the pinacolboronate moiety, thereby formally enabling a highly stereo- and regiocontrolled access to hydroboration products of unbiased dialkyl internal alkynes.
The α,β-unsaturated sulfones are suitable activated olefins in catalytic asymmetric conjugate β-boration. These substrates undergo smooth conjugate addition of bis(pinacolato)diboron [B(2)(pin)(2)] catalyzed by nonracemic Cu(I)-diphosphine complexes to provide, upon subsequent oxidation, β-hydroxy sulfones in good yields and high enantiocontrol.
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-a-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.
Screening of a GSK-proprietary library against intracellular Mycobacterium tuberculosis identified 1, a thioalkylbenzoxazole hit. Biological profiling and mutant analysis revealed that this compound is a prodrug that is bioactivated by the mycobacterial enzyme MymA. A hit-expansion program including design, synthesis, and profiling of a defined set of analogues with optimized drug-like properties led to the identification of an emerging lead compound, displaying potency against intracellular bacteria in the low micromolar range, high in vitro solubility and permeability, and excellent microsomal stability.
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