Synthesis and Anti‐Mycobacterium tuberculosis Activity of Imidazo[2,1‐b][1,3]oxazine Derivatives against Multidrug‐Resistant Strains

Abstract

The emergence of multidrug‐resistant strains of M. tuberculosis has raised concerns due to the greater difficulties in patient treatment and higher mortality rates. Herein, we revisited the 2‐nitro‐6,7‐dihydro‐5H‐imidazo[2,1‐b][1,3]oxazine scaffold and identified potent new carbamate derivatives having MIC90 values of 0.18–1.63 μM against Mtb H37Rv. Compounds 47–49, 51–53, and 55 exhibited remarkable activity against a panel of clinical isolates, displaying MIC90 values below 0.5 μM. In Mtb‐infected macrophages, several compounds demonstrated a 1‐log greater reduction in mycobacterial burden than rifampicin and pretomanid. The compounds tested did not exhibit significant cytotoxicity against three cell lines or any toxicity to Galleria mellonella. Furthermore, the imidazo[2,1‐b][1,3]oxazine derivatives did not show substantial activity against other bacteria or fungi. Finally, molecular docking studies revealed that the new compounds could interact with the deazaflavin‐dependent nitroreductase (Ddn) in a similar manner to pretomanid. Collectively, our findings highlight the chemical universe of imidazo[2,1‐b][1,3]oxazines and their promising potential against MDR‐TB.

Advances in Diagnostics and Drug Discovery against Resistant and Latent Tuberculosis Infection

“…generation of a new second alternative group of molecules against MDR and XDR MTB, derivatives of Imidazo [2,1-b] [1,3]oxazine, an important pharmacophore group of pretomanid and delamanid (Figure 5). In general, these compounds did not present cytotoxicity and they added that the possible mechanism of action would be related to the interaction with the deazaflavin-dependent nitroreductase holoenzyme present in pretomanid with MIC values < 0.5 μM, which proves their potential against LTBI since they are capable of crossing macrophages and entering the bacterial membrane of dormant strains [130]. On the other hand, sulfonamide derivatives have also generated great importance against LTBI since their analogues have not shown cytotoxicity and various microbiological applications have been reported.…”

Short and Efficient Synthesis of the Antituberculosis Agent Pretomanid from (R)-Glycidol

“…Several synthetic pathways to pretomanid ( 1 ) have been investigated so far. ,− The first route was reported by Barry and Baker (Pathogenesis Corp.) in 1997 . Starting from the explosive 2,4-dinitroimidazole, pretomanid ( 1 ) was prepared in five steps and 17% overall yield.…”