Approachable Synthetic Methodologies for Second-Generation β-Lactamase Inhibitors: A Review

Abstract

Some antibiotics that are frequently employed are β-lactams. In light of the hydrolytic process of β-lactamase, found in Gram-negative bacteria, inhibitors of β-lactamase (BLIs) have been produced. Examples of first-generation β-lactamase inhibitors include sulbactam, clavulanic acid, and tazobactam. Many kinds of bacteria immune to inhibitors have appeared, and none cover all the β-lactamase classes. Various methods have been utilized to develop second-generation β-lactamase inhibitors possessing new structures and facilitate the formation of diazabicyclooctane (DBO), cyclic boronate, metallo-, and dual-nature β-lactamase inhibitors. This review describes numerous promising second-generation β-lactamase inhibitors, including vaborbactam, avibactam, and cyclic boronate serine-β-lactamase inhibitors. Furthermore, it covers developments and methods for synthesizing MβL (metallo-β-lactamase inhibitors), which are clinically effective, as well as the various dual-nature-based inhibitors of β-lactamases that have been developed. Several combinations are still only used in preclinical or clinical research, although only a few are currently used in clinics. This review comprises materials on the research progress of BLIs over the last five years. It highlights the ongoing need to produce new and unique BLIs to counter the appearance of multidrug-resistant bacteria. At present, second-generation BLIs represent an efficient and successful strategy.

Keywords: boronate; diazabicyclooctanes (DBOs); drug synthesis; metallo-β-lactamases; β-lactamase inhibitors.

Scheme 1

Synthesis of novel avibactam derivatives via sulfonyl amidine.

Scheme 2

Synthesis of new avibactam derivative with amidine.

Scheme 3

Synthesis of novel substituted amidine analogs.

Scheme 4

Synthesis of new imidate derivatives.

Scheme 5

Synthesis of amide derivatives.

Scheme 6

Synthesis of IID572 by photo-redox coupling.

Scheme 7

Synthesis of β-lactamase inhibitor IID572.

Scheme 8

Synthesis of 2-sulfinyl-diazabicyclooctane derivative.

Scheme 9

Synthesis of triazole-containing DBOs.

Scheme 10

Synthesis of VNRX-7145.

Scheme 11

Synthesis of novel transition-state analogs of boronic acid.

Scheme 12

Synthesis of triazolylmethaneboronate.

Scheme 13

Synthesis of 2-mercaptomethyl-thiazolidines (MMTZs).

Scheme 14

Synthesis of 2-substituted (S)-3-mercapto-2-methylpropanamido) acetic acid derivatives.

Scheme 15

Synthesis of N-aryl mercaptoacetamide derivative.

Scheme 16

Synthesis of new mercaptopropionamide derivatives.

Scheme 17

Synthesis of mercaptopropanamide-substituted aryl tetrazoles.

Scheme 18

Synthesis of amino carboxylic acid analog.

Scheme 19

Synthesis of 1,2,4-triazole-3-thione derivatives.

Scheme 20

Synthesis of 1,2,4-triazole-3-thione analogs.

Scheme 21

Synthesis of 4-amino-1,2,4-triazole-3-thione derivatives.

Scheme 22

Synthesis of 1,2,4-triazole-3-thione derivatives.

Scheme 23

Synthesis of 4-alkyl-1,2,4-triazole-3-thione derivatives.

Scheme 24

Synthesis of NH-1,2,3-triazole.

Scheme 25

Synthesis of aminoguanidine analog.

Scheme 26

Synthesis of thiol-based inhibitors by integrating catechol moieties.

Scheme 27

Synthesis of the thiols.

Scheme 28

Synthesis of cephalosporin–thiol conjugates.

Scheme 29

Synthesis of alkylthio-substituted thiols.

Scheme 30

Synthesis of indole carboxylate EBL-3183.

Scheme 31

Synthesis of aryl sulfonyl hydrazones that are conjugated.

Scheme 32

Synthesis of halogen-substituted triazolethioacetamides.

Scheme 33

Synthesis of H₂dedpa derivatives.

Scheme 34

Synthetic route of rhodanine derivatives and thioenolates.

Scheme 35

Synthesis of rhodanine-derived ene–rhodanine derivatives.

Scheme 36

Synthesis of isatin-β-thiosemicarbazone derivatives (IBTs).

Scheme 37

Synthesis of Zndm19.

Scheme 38

Synthesis of sulfa hydantoin derivatives.

Scheme 39

Synthesis of α-aminophosphonate derivatives.

Scheme 40

Synthesis of 8-thioquinoline conjugate derivatives.

Scheme 41

Synthesis of isosteres.

Scheme 42

Synthesis of a series of bioisosteres.

Scheme 43

Synthesis of 1,2-benzisothiazol-3(2H)-one derivative.

Scheme 44

Synthesis of N-sulfamoylpyrrole-2-carboxylates.

Scheme 45

Synthesis of 1H-imidazole-2-carboxylic acid.

Scheme 46

Synthesis of imidazole derivatives.

Scheme 47

Synthesis of BP1.

Scheme 48

Synthesis of 4-pyridine sulfonamide analogs.

Scheme 49

Synthesis of metal chelators.

Scheme 50

Synthesis of benzoxazole and benzimidazole–zinc chelator.

Scheme 51

Synthesis of prochelator PcephPT.

Scheme 52

Synthesis of zinc chelator tris-picolylamine (TPA).

Scheme 53

Synthesis of phosphonamidate monoesters.

Scheme 54

Synthesis of new thiazole thioacetamide derivatives.

Scheme 55

Synthesis of 4-amino-1,2,4-triazole-3-thione scaffold.

Scheme 56

Synthesis of C-2 substituted bicyclic boronates.

Scheme 57

Synthesis of taniborbactam (VNRX-5133).

Scheme 58

Synthesis of VNRX-5133.

Scheme 59

Synthesis of 3-aryl-substituted benzoxazole derivative.

Scheme 60

Synthesis of triarylated azetidinimines.

Scheme 61

Synthesis of QPX7728.

Scheme 62

Synthesis of QPX7728.

Figure 1

Structure–activity relationship (SAR) of different heterocyclic compounds.