The
clinical effectiveness of carbapenem antibiotics such as meropenem
is becoming increasingly compromised by the spread of both metallo-β-lactamase
(MBL) and serine-β-lactamase (SBL) enzymes on mobile genetic
elements, stimulating research to find new β-lactamase inhibitors
to be used in conjunction with carbapenems and other β-lactam
antibiotics. Herein, we describe our initial exploration of a novel
chemical series of metallo-β-lactamase inhibitors, from concept
to efficacy, in a survival model using an advanced tool compound (ANT431)
in conjunction with meropenem.
The clinical effectiveness of the
important β-lactam class of antibiotics is under threat by the
emergence of resistance, mostly due to the production of acquired
serine- (SBL) and metallo-β-lactamase (MBL) enzymes. To address
this resistance issue, multiple β-lactam/β-lactamase inhibitor
combinations have been successfully introduced into the clinic over
the past several decades. However, all of those combinations contain
SBL inhibitors and, as yet, there are no MBL inhibitors in clinical
use. Consequently, there exists an unaddressed yet growing healthcare
problem due to the rise in recent years of highly resistant strains
which produce New Delhi metallo (NDM)-type metallo-carbapenemases.
Previously, we reported the characterization of an advanced MBL inhibitor
lead compound, ANT431. Herein, we discuss the completion of a lead
optimization campaign culminating in the discovery of the preclinical
candidate ANT2681, a potent NDM inhibitor with strong potential for
clinical development.
Benzotriazoles are a highly important class of compounds with
broad-ranging applications in such diverse areas as medicinal chemistry, as
auxiliaries in organic synthesis, in metallurgical applications, in aircraft
deicing and brake fluids, and as antifog agents in photography. Although there
are numerous approaches to N-substituted benzotriazoles, the essentially one
general method to N-unsubstituted benzotriazoles is via diazotization of
o-phenylenediamines, which can be limited by the
availability of suitable precursors. Other methods to N-unsubstitued
benzotriazoles are quite specialized. Although reduction of
1-hydroxy-1H-benzotriazoles is known the reactions are not
particularly convenient or broadly applicable. This presents a limitation for
easy access to and availability of diverse benzotriazoles. Herein, we
demonstrate a new, broadly applicable method to diverse
1H-benzotriazoles via a mild diboron-reagent mediated
deoxygenation of 1-hydroxy-1H-benzotriazoles. We have also
evaluated sequential deoxygenation and Pd-mediated C–C and C–N
bond formation as a one-pot process for further diversification of the
benzotriazole moiety. However, results indicated that purification of the
deoxygenation product prior to the Pd-mediated reaction is critical to the
success of such reactions. The overall chemistry allows for facile access to a
variety of new benzotriazoles. Along with the several examples presented, a
discussion of the advantages of the approaches is described, as also a possible
mechanism for the deoxygenation process.
Convenient syntheses of 2-chloro- and 2-tosyloxy-2'-deoxyinosine as their tert-butyldimethylsilyl ethers are described. Both compounds can be synthesized via a common route and rely on commercially available 2'-deoxyguanosine. The present method leading to the chloro nucleoside is operationally simpler compared to previously reported glycosylation techniques where isomeric products were obtained. Both electrophilic nucleosides can be used for the preparation of N-substituted 2'-deoxyguanosine analogues via displacement of the leaving groups, and a comparison of their reactivities shows the chloro analogue to be superior. Interestingly, a Pd catalyst-mediated, two-step, one-pot conversion of an allyl-protected chloro nucleoside intermediate to the final modified 2'-deoxyguanosine derivatives is also feasible. On the basis of these observations, initial assessments of Pd-catalyzed aryl amination as well as a C-C cross-coupling have also been performed with the chloro and tosyloxy nucleoside substrates. Results indicate a potentially high synthetic utility of 2-chloro-2'-deoxyinosine and in many instances this derivative can supplant the bromo and fluoro analogues that are more cumbersome to prepare or are not readily available.
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