Azetidines kill Mycobacterium tuberculosis without detectable resistance by blocking mycolate assembly

Abstract

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10 million new cases and 1.5 million deaths in 2019. This global emergency is exacerbated by the emergence of multi-drug-resistant MDR-TB and extensively-drug-resistant XDR-TB, therefore new drugs and new drug targets are urgently required. From a whole-cell phenotypic screen a series of azetidines derivatives termed BGAz, that elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB were identified. These compounds demonstrate no detectable drug resistance. Mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from existing mycobacterial cell-wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as anti-tubercular chemotherapies.

Ring-Expansion Reactions of Epoxy Amides and Enamides: Functionalized Azetidines, Dihydrofurans, Diazocanes, or Dioxa-3-azabicyclonon-4-enes?

“…During the formation of the functionalized azetidines 3 , stereochemistry around the double bond in ( Z )-β-chloro-cinnamaldehydes is changed exclusively to E in the final product. The substituent at the para-position of Ar of the N -oxiranylmethyl benzenesulfonamide with electron-donating groups (R = H, Me, OMe) as well as electron-withdrawing groups (R = NO 2 , CF 3 ) led to products 3aa–ca and 3ga , and 3la in good to excellent yields. Halogen-substituted N -oxiranylmethyl benzenesulfonamide (R = Br, Cl) also afforded products 3da and 3eb in good yields.…”

“…We then examined the scope of the present reaction with other substrates. The reaction proceeded well with various substituents on Ar of N -oxiranylmethyl benzenesulfonamides as well as Ar group of β-chloro-cinnamaldehyde and afforded products 4aa–4ac , 4ba–4bd , 4ca–4cc , and 4da–4db in moderate to good yields (Scheme ). The reaction also proceeded well with N -oxiranylmethyl naphthyl-sulfonamide 1m and gave products 4ma–md in good yields.…”

“…Figure ). , Azabicycles are also found in various natural alkaloids. The azabicyclo[4.2.1]­non-4-ene is a sophisticated homolog of tropane alkaloids such as cocaine and atropine; it is also an analogue of morphino-mimeticisopavines .…”

Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials

“…Recently, azetidines endowed with bactericidal activity against Mycobacterium tuberculosis were also synthesized; mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. In addition, these compounds did not give rise to emerging specific resistance in mycobacterial model organisms; the inability to generate resistant mutants against the most active compounds suggests that this series of compounds may elicit pleiotropic activity or have non-specific modes of action, or have non-protein target(s) [ 19 ].…”