Synthesis of the 1,5-Benzothiazepane Scaffold - Established Methods and New Developments.

The 1,5-benzothiazepane structure is an important heterocyclic moiety present in a variety of commercial drugs and pharmaceuticals. This privileged scaffold exhibits a diversity of biological activities, including antimicrobial, antibacterial, anti-epileptic, anti-HIV, antidepressant, antithrombotic and anticancer properties. Its important pharmacological potential renders research into the development of new and efficient synthetic methods of high relevance. In the first part of this review, an overview of different synthetic approaches toward 1,5-benzothiazepane and its derivatives is provided, ranging from established protocols to recent (enantioselective) methods that promote sustainability. In the second part, several structural characteristics influencing biological activity are briefly explored, providing a few insights into the structure-activity relationships of these compounds.

α-Unsaturated 3-Amino-1-carboxymethyl-ß-lactams as Bacterial PBP Inhibitors: Synthesis and Biochemical Assessment.

Innovative monocyclic ß-lactam entities create opportunities in the battle against resistant bacteria because of their PBP acylation potential, intrinsically high ß-lactamase stability and compact scaffold. α-Benzylidene-substituted 3-amino-1-carboxymethyl-ß-lactams were recently shown to be potent PBP inhibitors and constitute eligible anchor points for synthetic elaboration of the chemical space around the central ß-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 ß-lactam electrophilicity and extended electron flow after enzymatic attack. Additionally, increased ß-lactamase stability and intermolecular target interaction were envisioned by tackling both the substitution pattern of the aromatic ring and the ß-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 ß-lactamases was ruled out, providing new insights in the SAR landscape of monocyclic ß-lactams as eligible PBP or ß-lactamase inhibitors.