Synthesis of Long‐Chain β‐Lactones and Their Antibacterial Activities against Pathogenic Mycobacteria

Abstract

In the quest for new antibacterial agents, a series of novel long‐ and medium‐chain mono‐ and disubstituted β‐lactones was developed. Their activity against three pathogenic mycobacteria—M. abscessus, M. marinum, and M. tuberculosis—was assessed by the resazurin microtiter assay (REMA). Among the 16 β‐lactones synthesized, only 3‐hexadecyloxetan‐2‐one (VM005) exhibited promising activity against M. abscessus, whereas most of the β‐lactones showed interesting activities against M. marinum, similar to that of the classical antibiotic, isoniazid. Regarding M. tuberculosis, six compounds were found to be active against this mycobacterium, with β‐lactone VM008 [trans‐(Z)‐3‐(hexadec‐7‐en‐1‐yl)‐4‐propyloxetan‐2‐one] being the best growth inhibitor. The promising antibacterial activities of the best compounds in this series suggest that these molecules may serve as leads for the development of much more efficient antimycobacterial agents.

Lipolytic enzymes inhibitors: A new way for antibacterial drugs discovery

“…Functioning as a versatile (Ser/Cys)-hydrolase inhibitor, Orlistat was indeed found to inhibit enzymes belonging to the Cutinase-like family proteins, including the essential M. tb phospholipase/thioesterase Cut6 (Rv3802c) [24][25][26]; enzymes belonging to the hormonesensitive lipase (HSL) family member proteins (i.e., Lip-HSL) [27,28]; as well as the mycolyltransferase Antigen 85C [29,30]. When tested as a possible anti-mycobacterial agent, Orlistat impaired M. tb growth with a minimum inhibitory concentration (MIC) of around 15-30 µM [26,28,31,32], and displayed a strong synergistic effect with vancomycin resulting in a MIC drop of around 16-fold [31]. Lipids analysis confirmed that Orlistat destabilized the outer membrane of the cell envelope by reducing the amount of phthiocerol dimycocerosate (PDIM) content in the mycobacterial cell wall, therefore facilitating the action of vancomycin [31].…”

“…Various structural modifications based on the Orlistat pharmacophore have been further investigated in order to improve the specificity and antibacterial potency of the new synthesized analogs (Scheme 1) [26,32,34]. Of interest, compound Cpd-12, bearing an L-thiazolidyl ester side chain, and analogs Cpd-17 to Cpd-20 bearing L-and D-prolyl ester side chains displayed a 10-fold lower MIC against M. tb growth and also improved inhibitory concentrations, i.e., IC50 values of 0.2-0.8 µM toward Cut6, compared with Orlistat (IC50 = 3.8 µM) [26].…”

Pipeline of anti‐Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities

“…Orlistat, an FDA‐approved antiobesity drug, has modest activity toward both smooth and rough variants of M. abscessus CIP 104536 (44.4 and 57.0 μg/ml, respectively) 151 . However, the design of orlistat‐related compounds did not lead to any improvements in antimycobacterial activity.…”

Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species

“… THL is more stable than Lipstatin and is commercially available as Orlistat, an approved antiobesity drug . The strained four-membered ring of β-lactone class has displayed a promising inhibition activity against various serine/cysteine hydrolases . THL has been shown to inhibit the activity of Ag85C, which affects bacterial growth, viability, and pathogenesis. , THL inhibits both dormant and active forms of M. tuberculosis . − Covalent inhibition of Ag85C results from a nucleophilic attack on the carbonyl carbon of the β-lactone ring of THL via serine 124 (Ser 124 ), leading to an acyl–enzyme-type inhibitor–enzyme complex (Figure ).…”

“…Chemical proteomics is rapidly evolving area of chemical biology that uses a small molecular probe to understand protein activity in complex proteomes. To facilitate studies on the selectivity of our newly synthesized compounds, we also sought to develop routes to new chemical probes since THL has also found use as a scaffold to probe for α/β hydrolase activity. − We note that long-chain β-lactones that lack the peptidyl side chain of THL are known to have antimycobacterial activity . Therefore, we synthesized THL probe 2 by adding an alkyne handle in place of the peptidyl arm (Figure ).…”