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A series of 21 new 7′H-spiro[azetidine-3,5′-furo [3,4-d]pyrimidine]s substituted at the pyrimidine ring second position were synthesized. The compounds showed high antibacterial in vitro activity against M. tuberculosis. Two compounds had lower minimum inhibitory concentrations against Mtb (H37Rv strain) compared with isoniazid. The novel spirocyclic scaffold shows excellent properties for anti-tuberculosis drug development.

Deubiquitylases (DUBs) are key regulators of the ubiquitin system which cleave ubiquitin moieties from proteins and polyubiquitin chains. Several DUBs have been implicated in various diseases and are attractive drug targets. We have developed a sensitive and fast assay to quantify in vitro DUB enzyme activity using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Unlike other current assays, this method uses unmodified substrates, such as diubiquitin topoisomers. By analysing 42 human DUBs against all diubiquitin topoisomers we provide an extensive characterization of DUB activity and specificity. Our results confirm the high specificity of many members of the OTU and JAB/MPN/Mov34 metalloenzyme DUB families and highlight that all USPs tested display low linkage selectivity. We also demonstrate that this assay can be deployed to assess the potency and specificity of DUB inhibitors by profiling 11 compounds against a panel of 32 DUBs. Deubiquitylases (DUBs) remove ubiquitin chains from proteins. Here the authors develop a mass spectrometry-based DUB activity screen using unmodified diubiquitin isomers to characterize substrate specificity for 42 human DUBs, and assess the potency and selectivity of 11 DUB inhibitors.

Regorafenib, a multi-kinase inhibitor, has limited efficacy in hepatocellular carcinoma (HCC) due to dose-dependent toxicity. The present study explored whether low-dose Regorafenib combined with Nifuroxazide exerts enhanced anti-tumor effects in HCC models. In vitro experiments with HepG2 cells showed the combination inhibited cell viability, proliferation and migration, induced apoptosis and reduced expression of key proteins, including phosphorylated signal transducer and activator of transcription 3 (STAT3). In vivo, H22 tumor-bearing mice treated with the combination exhibited suppressed tumor growth without systemic toxicity, along with changes in apoptotic proteins, enhanced tumor-infiltrating immune cells and improved systemic immune responses. These findings indicated that the combination exerts enhanced suppression of HCC by inhibiting STAT3 and remodeling anti-tumor immunity, providing preclinical evidence for a safe and effective strategy.

The use of the concept of privileged structures significantly accelerates the search for new leads and their optimization. 6-(methylsulfonyl)-8-(4-methyl-4H-1,2,4-triazol-3-yl)-2-(5-nitro-2-furoyl)-2,6-diazaspiro[3.4]octane 1 has been identified as a lead, with MICs of 0.0124–0.0441 μg/mL against MTb multiresistant strains. Several series of structural analogues have been synthesized, including variations in the periphery and simplifications of their scaffolds. All synthesized compounds were tested against the MTb H37Rv strain and ESKAPE panel of pathogens using serial broth dilutions. However, an attempt to optimize structure of 1 did not lead to the development of more active compounds which can work against MTb, but to substances with high activity against S. aureus. Induced-fit docking and MM-GBSA calculations determined a change in the likely biotarget from deazaflavin-dependent nitroreductase to azoreductases. The privileged nature of the scaffold was demonstrated by the detection of a different type of activity.

A series of 13 new 3-substituted 5-(5-nitro-2-furyl)-1,2,4-oxadiazoles was synthesized from different aminonitriles. All compounds were screened in the disc diffusion test at a 100 μg/mL concentration to determine the bacterial growth inhibition zone presence and diameter, and then the minimum inhibitory concentrations (MICs) were determined for the most active compounds by serial dilution. The compounds showed antibacterial activity against ESKAPE bacteria, predominantly suppressing the growth of 5 species out of the panel. Some compounds had similar or lower MICs against ESKAPE pathogens compared to ciprofloxacin, nitrofurantoin, and furazidin. In particular, 3-azetidin-3-yl-5-(5-nitro-2-furyl)-1,2,4-oxadiazole (2h) inhibited S. aureus at a concentration lower than all comparators. Compound 2e (5-(5-nitro-2-furyl)-3-[4-(pyrrolidin-3-yloxy)phenyl]-1,2,4-oxadiazole) was active against Gram-positive ESKAPE pathogens as well as M. tuberculosis. Differences in the molecular periphery led to high selectivity for the compounds. The induced-fit docking (IFD) modeling technique was applied to in silico research. Molecular docking results indicated the targeting of compounds against various nitrofuran-associated biological targets.

The reductively activated nitroaromatic class of antimicrobials, which include nitroimidazole and the more metabolically labile nitrofuran antitubercular agents, have demonstrated some potential for development as therapeutics against dormant TB bacilli. In previous studies, the pharmacokinetic properties of nitrofuranyl isoxazolines were improved by incorporation of the outer ring elements of the antitubercular nitroimidazole OPC-67683. This successfully increased stability of the resulting pentacyclic nitrofuran lead compound Lee1106 (referred to herein as 9a). In the current study, we report the synthesis and antimicrobial properties of 9a and panel of 9a analogs, which were developed to increase oral bioavailability. These hybrid nitrofurans remained potent inhibitors of Mycobacterium tuberculosis with favorable selectivity indices (>150) and a narrow spectrum of activity. In vivo, the pentacyclic nitrofuran compounds showed long half-lives and high volumes of distribution. Based on pharmacokinetic testing and lack of toxicity in vivo, 9a remained the series lead. 9a exerted a lengthy post antibiotic effect and was highly active against nonreplicating M. tuberculosis grown under hypoxia. 9a showed a low potential for cross resistance to current antitubercular agents, and a mechanism of activation distinct from pre-clinical tuberculosis candidates PA-824 and OPC-67683. Together these studies show that 9a is a nanomolar inhibitor of actively growing as well as nonreplicating M. tuberculosis.

Nifuroxazide (NFX), an antibacterial agent, also exhibits notable antitumor effects by inhibiting STAT3 signaling, which is often aberrantly activated and linked to chemoresistance in tumors such as hepatocellular carcinoma (HCC). Combining NFX with chemotherapy may enhance therapeutic efficacy, but its poor solubility limits oral bioavailability. To address this, we developed a biomimetic delivery system by loading NFX into murine macrophage-like RAW264.7 cells (Mφ-NFX). This strategy aims to improve drug delivery, enhance antitumor effects, with the potential to circumvent or overcome drug resistance. We evaluated the efficacy of Mφ-NFX alone and in combination with Oxaliplatin in vitro and in preclinical HCC models. Macrophages effectively carried and delivered NFX to tumor cells and tissues without significant toxicity to the carriers. Additionally, NFX promoted macrophage polarization toward the M1 phenotype within the tumor microenvironment. Mφ-NFX significantly inhibited tumor growth and increased the M1/M2 macrophage ratio. Co-treatment with Mφ-NFX and Oxaliplatin demonstrated enhanced tumor suppression and modulation of the tumor microenvironment. Mechanistically, NFX and Oxaliplatin acted synergistically via inhibition of the AKT/β-catenin pathway. In conclusion, this macrophage-based NFX delivery platform offers improved antitumor activity and sensitization to chemotherapy, presenting a promising strategy for HCC treatment. Graphical abstract

Chikungunya virus (CHIKV) is a reemerging arbovirus causing disease on a global scale, and the potential for its epidemics remains high. CHIKV has caused millions of cases and heavy economic burdens around the world, while there are no available approved antiviral therapies to date. In this study, nifuroxazide, an FDA-approved antibiotic for acute diarrhea or colitis, was found to significantly inhibit a variety of arboviruses, although its antiviral activity varied among different target cell types. Nifuroxazide exhibited relatively high inhibitory efficiency in yellow fever virus (YFV) infection of the hepatoma cell line Huh7, tick-borne encephalitis virus (TBEV) and west nile virus (WNV) infection of the vascular endothelial cell line HUVEC, and CHIKV infection of both Huh7 cells and HUVECs, while it barely affected the viral invasion of neurons. Further systematic studies on the action stage of nifuroxazide showed that nifuroxazide mainly inhibited in the viral replication stage. In vivo, nifuroxazide significantly reduced the viral load in muscles and protected mice from CHIKV-induced footpad swelling, an inflammation injury within the arthrosis of infected mice. These results suggest that nifuroxazide has a potential clinical application as an antiviral drug, such as in the treatment of CHIKV infection.

A small set of twelve compounds of a nitrofuran carboxamide chemotype was elaborated from a readily available 2,6-diazaspiro[3.4]octane building block, exploring diverse variants of the molecular periphery, including various azole substituents. The in vitro inhibitory activities of the synthesized compounds were assessed against Mycobacterium tuberculosis H37Rv. As a result, a remarkably potent antitubercular lead displaying a minimal inhibitory concentration of 0.016 μg/mL was identified.

Nitrofurans belong to the class of drugs typically used as antibiotics or antimicrobials. The defining structural component is a furan ring with a nitro group attached. In the present investigation, electron attachment to 2-nitrofuran (C4H3NO3), which is considered as a potential radiosensitizer candidate for application in radiotherapy, has been studied in a crossed electron–molecular beams experiment. The present results indicate that low-energy electrons with kinetic energies of about 0–12 eV effectively decompose the molecule. In total, twelve fragment anions were detected within the detection limit of the apparatus, as well as the parent anion of 2-nitrofuran. One major resonance region of ≈0–5 eV is observed in which the most abundant anions NO2−, C4H3O−, and C4H3NO3− are detected. The experimental results are supported by ab initio calculations of electronic states in the resulting anion, thermochemical thresholds, connectivity between electronic states of the anion, and reactivity analysis in the hot ground state.