Design and Synthesis of Pyrrolidine-5,5-trans-lactams (5-Oxo-hexahydro-pyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 1. The α-Methyl-trans-lactam Template

Abstract

Mechanism-based inhibitors of human cytomegalovirus (HCMV) protease have been designed based on the pyrrolidine-5,5-trans-lactam ring system. New routes to the beta-methyl-, desmethyl-, and alpha-methyl-pyrrolidine-5,5-trans-lactam templates have been developed from 2,4-diaminobutyric acid. ESI/MS studies have shown that these inhibitors can bind covalently and reversibly to the viral enzyme in a time-dependent manner by a mechanism which is consistent with acylation of HCMV deltaAla protease at the active site nucleophile Ser 132. SAR in this series of pyrrolidine-5, 5-trans-lactams has defined the relative stereochemisty of the methyl substituent adjacent to the lactam carbonyl, the functionality on the lactam nitrogen, and the mechanism of action of this novel series of serine protease inhibitors against the HCMV deltaAla protease. Activity decreases on moving from the alpha-methyl to the desmethyl to the beta-methyl series. This selectivity is the opposite of that observed for these templates against the elastase and thrombin enzymes. The activity against HCMV deltaAla protease is the greatest with inhibitors based on the Cbz-protected alpha-methyl-5,5-trans-lactam template which have low micromolar activity against the viral enzyme.

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

“…In related work, bicyclic lactam derived 'trans-lactam' inhibitors, ultimately derived from more complex natural products, were developed as potent inhibitors of nucleophilic serine proteases [101][102][103][104] (though these have not been d eveloped as PBP/serine β-lactamase inhibitors).…”

“…(B) Examples of 'new' β-lactam scaffolds also show promise, but they have not been commercially developed (AM-112 (10.9) [154] and LK-157 (10.10) [155]). (C) Examples of natural product derived non-β-lactam type scaffolds which are inhibitors of nucleophilic serine enzymes (trans-lactams (10.11) [101] and a related natural product from Lantana camara (10.11) [156], and the strigolactones (10.13) [157]); derivatives of these could be pursued as penicillin-binding protein/β-lactamase inhibitors. The road to avibactam -the first clinically useful non-β-lactam working somewhat like a β-lactam Review structural water are close to the ester link with the nucleophilic serine (Ser-70); the complex is apparently stabilized by interactions with the Lys-73:Ser-130 and Glu-166:Asn-170 'dyads' which are important in catalysis.…”

“…For example, oxapenems [154,179,180], such as AM-112, are potent β-lactamase inhibitors, though their synthesis is also challenging. Further, there is clearly scope for the development of new types of antibacterial-forming acyl-enzyme type complexes, perhaps based on natural products/inhibitors of nucleophilic serine (or nucleophilic cysteine) enzymes, such as lactivicins [111], trans-lactams [101] or compounds operating via an analogous mechanism of action, but which have been developed in other fields, for example, agrochemistry such as strigolactones [157] ( Figure 10). Other types of covalent inhibitors also future science group Review Wang, Abboud, Markoulides, Brem & Schofield show promise including transition state analogues such as boronates and phosphonates, which have the potential to target β-lactamases and PBPs [115,[118][119][120][121][122][123].…”

Macrocyclic Aminopyrimidines as Multitarget CDK and VEGF‐R Inhibitors with Potent Antiproliferative Activities

“…In the synthesis of hydroxy analogue 40 the published procedure by Borthwick et al was used to get hold of the orthogonally protected building block 37. [20] In this procedure, the amino acid moiety of 36 was temporarily protected via formation of a copper complex, the benzyloxycarbonyl (Z) group was introduced, and the copper complex was destroyed afterward with EDTA. Finally, the tert-butoxycar- bonyl (Boc) group was introduced, and the desired material was isolated in 72 % overall yield.…”

Synthesis and anti-HCMV activity of 1-acyl-β-lactams and 1-acylazetidines derived from phenylalanine

“…Most of these inhibitors contain classical serine protease inhibitor motifs based on an activated carbonyl group such as peptidyl ketoamides, 8;9 as well as mechanism-based inhibitors such as oxazazinones 10;11 and pyrrolidine-5,5-trans-lactams. [12][13][14] Among these latter inhibitors, a series of monocyclic b-lactams 1 (compound 1a being the prototype) has resulted in highly potent derivatives in the isolated enzyme assay, but their efficacy in cell culture was quite limited, as for all described inhibitors of this enzyme. 15 This paper deals with the synthesis and evaluation of a series of new azetidinones 2, derived from phenylalanine, which were designed on the basis of the structure of the reported b-lactam inhibitors 16 and of the residues implicated in the active site of the HCMV protease.…”