Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

Abstract

The increasing emergence of bacteria producing β-lactamases enzymes (BLEs), able to inactivate the available β-lactam antibiotics (BLAs), causing the hydrolytic opening of their β-lactam ring, is one of the global major warnings. According to Ambler classification, BLEs are grouped in serine-BLEs (SBLEs) of class A, C, and D, and metal-BLEs (MBLEs) of class B. A current strategy to restore no longer functioning BLAs consists of associating them to β-lactamase enzymes inhibitors (BLEsIs), which, interacting with BLEs, prevent them hydrolyzing to the associated antibiotic. Worryingly, the inhibitors that are clinically approved are very few and inhibit only most of class A and C SBLEs, leaving several class D and all MBLEs of class B untouched. Numerous non-clinically approved new molecules are in development, which have shown broad and ultra-broad spectrum of action, some of them also being active on the New Delhi metal-β-lactamase-1 (NDM-1), which can hydrolyze all available BLAs except for aztreonam. To not duplicate the existing review concerning this topic, we have herein examined BLEsIs by a chemistry approach. To this end, we have reviewed both the long-established synthesis adopted to prepare the old BLEsIs, those proposed to achieve the BLEsIs that are newly approved, and those recently reported to prepare the most relevant molecules yet in development, which have shown high potency, providing for each synthesis the related reaction scheme.

Keywords: metal-β-lactamases; multi-drug resistant (MDR) bacteria; optimized synthetic procedures; serine β-lactamases; β-lactam antibiotics; β-lactamase enzymes; β-lactamase enzymes inhibitors.

Figure 1

The β-lactam core structures. Penams (1), carbapenams (2), oxapenams (3) (a); penems (4), carbapenems (5), oxapenems (6) (b); cephems (7), carbacephems (8), oxacephem (9) (c); cepham (10), carbacepham (11), oxacephem (12) (d); monobactam (13) (e).

Figure 2

Chemical structure of carbapenems.

Scheme 1

Inactivation of BLAs through the hydrolytic action of SBLEs.

Scheme 2

Biosynthesis of CA (C₈H₉NO₅, MW: 199.16), IUPAC name: (2R,3Z,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo [3.2.0] heptane-2-carboxylic acid.

Scheme 3

Synthesis of sulbactam from 6-APA (C₈H₁₁NO₅S, MW = 233.2), IUPAC name: (2S,5R)-3,3-dimethyl-4,4,7-trioxo-4lambda6-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid.

Scheme 4

Synthesis of tazobactam from 6-APA (C₁₀H₁₂N₄O₅S, MW = 300.3), IUPAC name: 3S-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo [3.2.0] heptan-2S-carboxylic acid 4,4-dioxide.

Scheme 5

Synthesis of tazobactam according to the method proposed by Shuhao et al.

Scheme 6

Synthesis of tebipenem pivoxil (C₂₂H₃₁N₃O₆S₂, MW: 497.6), IUPAC name: 2,2-dimethylpropanoyloxymethyl (4R,5S,6S)-3-[1-(4,5-dihydro-1,3-thiazol-2-yl) azetidin-3-yl] sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate.

Scheme 7

Synthesis of enmetazobactam, formerly AAI101 (C₁₁H₁₄N₄O₅S, MW = 314.3), IUPAC name: (2S,3S,5R)-3-methyl-3-[(3-methyltriazol-3-ium-1-yl)-methyl]-4,4,7-trioxo-4λ6-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate.

Scheme 8

Synthetic route to prepare 6-methylidene-penem carboxylic acid sodium salts starting from 6-APA.

Scheme 9

Synthetic route to prepare LN-1-255 from 6-APA (C₂₂H₁₉N₂NaO₉S, MW = 510.4), IUPAC name: (2S,3R,5R,6Z)-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, 3-[[[(3,4-dihydroxyphenyl) acetyl] oxy] methyl]-3-methyl-7-oxo-6-(2-pyridinylmethylene)-4,4-dioxide, monosodium salt.

Scheme 10

Synthesis of avibactam (MF: C₇H₁₁N₃O₆S, MW = 265.25), IUPAC name: [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo [3.2.1] octan-6-yl] hydrogen sulphate.

Scheme 11

Synthesis of relebactam (C₁₂H₂₀N₄O₆S, MW = 348.4, IUPAC name: [(2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo [3.2.1] octan-6-yl] hydrogen sulphate.

Scheme 12

Synthesis of zidebactam (C₁₃H₂₁N₅O₇S, MW = 391.4), IUPAC name: [(2S,5R)-7-oxo-2-[[[(3R)-piperidine-3-carbonyl] amino] carbamoyl]-1,6-diazabicyclo [3.2.1] octan-6-yl] hydrogen sulphate.

Scheme 13

Synthesis of WCK-4234 (C₇H₈N₃NaO₅S, MW = 269.3), IUPAC name: sodium (2S,5R)-2-cyano-7-oxo-1,6-diazabicyclo [3.2.1] octan-6-yl sulfate.

Scheme 14

Part A: Synthesis of the ethyl bromo-fluoroacetates I and II used to prepare compounds 10 and ETX-0282 of Part B. Part B: Synthesis of ETX-1317 and of its orally administrable prodrug ETX-0282. ETX-1317 (C₁₀H₁₂FN₃O₅, MW = 295.2), IUPAC name: (2R)-2-(((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl)-oxy)-2-fluoroacetic acid. ETX-0282 (C₁₃H₁₈FN₃O₅, MW = 315.3), IUPAC name: isopropyl (R)-2-(((1R,2R,5R)-2-carbamoyl-4-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl)-oxy)-2-fluoroacetate.

Scheme 15

Synthesis of durlobactam (C₈H₁₁N₃O₆S, MW = 277.36, IUPAC name, [(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] hydrogen sulphate.

Scheme 16

Synthesis of ANT-3310 (C₆H₉ FN₂O₅S, MW = 240.2), IUPAC name, (2R,5R)-2-fluoro-7-oxo-1,6-diazabicyclo [3.2.1] octan-6-yl hydrogen sulphate.

Scheme 17

Synthesis of nacubactam (C₈H₁₆N₄O₇S, MW = 324.3), IUPAC name, [(2S,5R)-2-(2-aminoethoxycarbamoyl)-7-oxo-1,6-diazabicyclo [3.2.1] octan-6-yl] hydrogen sulphate.

Scheme 18

Synthesis of vaborbactam (formerly RPX-7009) (C₁₂H₁₆BNO₅S, MW = 297), IUPAC name, 2-[(3R,6S)-2-hydroxy-3-[(2-thiophen-2-ylacetyl)-amino]-oxaborinan-6-yl]-acetic acid.

Scheme 19

Synthesis of taniborbactam (formerly VNRX-5133), (C₁₉H₂₈BN₃O₅, MW = 389.3), IUPAC name: (3R)-3-[[2-[4-(2-aminoethylamino)-cyclohexyl]-acetyl]-amino]-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid.

Scheme 20

Synthesis of ({4-[tert-Butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)-amino]-cyclohexyl}-acetic acid (I).

Scheme 21

Synthesis of VNRX-7145, also known as ledaborbactam etzadroxil, which is the orally bioavailable prodrug of ledarbobactam (VNRX-5236). VNRX-7145 (C₁₉ H₂₆ B N O₇, MW 391.2), IUPAC name: 2-hydroxy-3-propionylamino-3,4-dihydro-2H-1-oxa-2-bora-naphthalene-8-carboxylic acid 2-ethyl-butyryloxymethyl ester. VNRX-5236 (C₁₂ H₁₄ B N O₅, MW 263.1), IUPAC name: 2-hydroxy-3-propionylamino-3,4-dihydro-2H-1-oxa-2-bora-naphthalene-8-carboxylic acid.

Scheme 22

Synthesis of xeruborbactam (formerly QPX7728), (C₁₀H₈BFO₄, MW = 221.98), IUPAC name: 5-fluoro-2-hydroxy-1,1a,2,7b-tetrahydro-3-oxa-2-bora-cyclopropa[a]naphthalene-4-carboxylic acid.

Scheme 23

Synthesis of ANT-2681 ANT-2681 (C₁₂H₁₂F₂N₈O₄S₂, MW = 434.4), IUPAC name: 5-((4-(2-Carbamimidoylhydrazine-1-carboxamido)-3,5-difluorophenyl) sulphonamide) thiazole-4-carboxamide.