Approval of avibactam
by the FDA has led to the recognition of
1,6-diazabicyclo[3.2.1]octane (DBO) derivatives as attractive compounds
for β-lactamase inhibition. We achieved a concise and collective
synthesis of 2-thio-substituted DBO derivatives. The synthesis involves
diastereoselective photo-induced Barton decarboxylative thiolation,
which can be applied to large-scale synthesis. The DBO analogues exhibited
strong inhibitory activities against serine β-lactamases and
acceptable solution stabilities for clinical development.
The
current worldwide emergence of carbapenem-resistant enterobacterales
(CREs) constitutes an important growing clinical and public health
threat. Acquired carbapenemases are the most important determinants
of resistance to carbapenems. In the development of the previously
reported tricyclic β-lactam skeleton which exhibits potent antibacterial
activities against several problematic β-lactamase-producing
CREs without a β-lactamase inhibitor, we found that these activities
were reduced against clinical isolates with resistance mechanisms
other than β-lactamase production. These mechanisms were the
reduction of outer membrane permeability with the production of β-lactamases
and the insertion of four amino acids into penicillin-binding protein
3. Here, we report the discovery of a potent compound that overcomes
these resistance mechanisms by the conversion of the alkoxyimino moiety
of the aminothiazole side chain in which a hydrophilic functional
group is introduced and the carboxylic acid of the alkoxyimino moiety
is converted to reduce the negative charge of the whole molecule from
2 to 1. This potent tricyclic β-lactam is a promising drug candidate
for infectious diseases caused by CREs due to its potent therapeutic
efficacy in the neutropenic mouse lung infection model and low frequency
of producing spontaneously resistant mutants.
Coadministration
of β-lactam and β-lactamase inhibitor
(BLI) is one of the well-established therapeutic measures for bacterial
infections caused by β-lactam-resistant Gram-negative bacteria,
whereas we have only two options for orally active BLI, clavulanic
acid and sulbactam. Furthermore, these BLIs are losing their clinical
usefulness because of the spread of new β-lactamases, including
extended-spectrum β-lactamases (ESBLs) belonging to class A
β-lactamases, class C and D β-lactamases, and carbapenemases,
which are hardly or not inhibited by these classical BLIs. From the
viewpoints of medical cost and burden of healthcare personnel, oral
therapy offers many advantages. In our search for novel diazabicyclooctane
(DBO) BLIs possessing a thio-functional group at the C2 position,
we discovered a 2-sulfinyl-DBO derivative (2), which
restores the antibacterial activities of an orally available third-generation
cephalosporin, ceftibuten (CTB), against various serine β-lactamase-producing
strains including carbapenem-resistant Enterobacteriaceae (CRE). It
can be orally absorbed via the ester prodrug modification and exhibits
in vivo efficacy in a combination with CTB.
By
the emergence and worldwide spread of multi-drug-resistant Gram-negative
bacteria, there have been growing demands for efficacious drugs to
cure these resistant infections. The key mechanism for resistance
to β-lactam antibiotics is the production of β-lactamases,
which hydrolyze and deactivate β-lactams. Diazabicyclooctane
(DBO) analogs play an important role as one of the new classes of
β-lactamase inhibitors (BLIs), and several compounds such as
avibactam (AVI) have been approved by the FDA, along with many derivatives
under clinical or preclinical development. Although these compounds
have a similar amide substituent at the C2 position, we have recently
reported the synthesis of novel DBO analogs which possess a thio functional
group. This structural modification enhances the ability to restore
the antimicrobial activities of cefixime (CMF) against pathogens producing
classes A, C, and D serine β-lactamases compared with AVI and
expands the structural tolerance at the six position. Furthermore,
some of these analogs showed intrinsic microbial activities based
on multipenicillin binding protein (PBP) inhibition. This is the unique
feature which has never been observed in DBOs. One of our DBOs had
a pharmacokinetic profile comparable to that of other DBOs. These
results indicate that the introduction of a thio functional group
into DBO is a novel and effective modification to discover a clinically
useful new BLI.
A series of 7-aminothiadiazolylcephalosporins having a 1-(substituted)-1H-imidazo [4,5-b]pyridinium group at the C-3' position of the cephem nucleus were synthesized and evaluated-yl]methyl-3-cephem-4-carboxylate sulfate (S-3578) showed extremely potent broad spectrum activity against both Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative bacteria including Pseudomonas aeruginosa, and good water solubility.
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