α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as bacterial PBP inhibitors : synthesis and biochemical assessment

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