α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as Bacterial PBP Inhibitors: Synthesis and Biochemical Assessment

Abstract

Innovative monocyclic β‐lactam entities create opportunities in the battle against resistant bacteria because of their PBP acylation potential, intrinsically high β‐lactamase stability and compact scaffold. α‐Benzylidene‐substituted 3‐amino‐1‐carboxymethyl‐β‐lactams were recently shown to be potent PBP inhibitors and constitute eligible anchor points for synthetic elaboration of the chemical space around the central β‐lactam ring. The present study discloses a 12‐step synthesis of ten α‐arylmethylidenecarboxylates using a microwave‐assisted Wittig olefination as the crucial reaction step. The library was designed aiming at enhanced β‐lactam electrophilicity and extended electron flow after enzymatic attack. Additionally, increased β‐lactamase stability and intermolecular target interaction were envisioned by tackling both the substitution pattern of the aromatic ring and the β‐lactam C4‐position. The significance of α‐unsaturation was validated and the R39/PBP3 inhibitory potency shown to be augmented the most through decoration of the aromatic ring with electron‐withdrawing groups. Furthermore, ring cleavage by representative β‐lactamases was ruled out, providing new insights in the SAR landscape of monocyclic β‐lactams as eligible PBP or β‐lactamase inhibitors.

Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams—Important Structural Motifs in Medicinal Chemistry

“…2-(1,3-Dioxoisoindolin-2-yl)acetyl chloride ( 18 ), quantitative yield, yellow amorphous solid. 1 H NMR (400 MHz, CDCl 3 ) 7.95–7.89 (m, 1H), 7.82–7.76 (m, 1H), 4.83 (s, 1H); as reported [ 51 ].…”

Synthesis of 4‐imidoyl‐, 4‐oxiranyl‐ and 4‐propargyloxyphenyl‐substituted β‐lactam building blocks

“…The first envisioned building blocks concerned imine‐based β‐lactam substrates because of our in‐house experience with similar systems [2]. In contrast to their celebrated oxygen counterparts (i.e., 4‐formyl‐β‐lactams) [3], 4‐imidoyl‐β‐lactams have received considerably less attention in the literature.…”

Synthesis and Evaluation of Novel Iminosugars Prepared from Natural Amino Acids

“…The synthesis of the novel iminosugars started from l -serine or l -alanine as the chiral pool. Both amino acids were protected using di- tert -butyl dicarbonate (Boc 2 O) [ 26 ]. Without further purification, these latter intermediates were submitted to coupling with N , O -dimethylhydroxylamine and, for the l -serine derivative, protection with tert -butyldimethylsilyl of the hydroxy group.…”