Aqueous fate of furaltadone: Kinetics, high-resolution mass spectrometry - based elucidation and toxicity assessment of photoproducts.

Furaltadone (FTD) is an antibiotic belonging to the nitrofurans group. It has been broadly used in livestock and aquaculture for therapeutic purposes, as well as for stimulating promotion. Although the European Union has imposed restrictions on the use of FTD since 1995 due to concerns regarding its toxicity, in many cases FTD has been excessively and/or illegally applied in productive animals in developing countries, because of its high efficacy and low-cost. Unlike other nitrofuran compounds, the hydrolytic and photolytic behavior of FTD in natural aquatic systems has not been thoroughly investigated. To this end, hydrolysis in different pH values and photolysis in aquatic environment, including lake, river and sea water have been both examined. Hydrolysis was found to have an insignificant impact on degradation of FTD in the aquatic environment relevant pH values, whereas indirect photolysis proved to be the main route of its elimination. The identification of tentative photoproducts (PPs) was performed using ultra high performance liquid chromatography coupled to hybrid LTQ/Orbitrap high resolution mass spectrometry. A possible pathway for photolytic transformation of FTD was proposed. Additionally, in silico simulations were used to evaluate the toxicity such as the mutagenicity of FTD and PPs. Complementary to the low-cost and time-limited simulations, an in vitro method (Vibrio Fischeri bioluminescence) was also used to assess ecotoxicity.

A coordination driven 'heat-set' Zr-gel: efficient fluorophore probe for selective detection of Fe3+ and nitrofuran-based antibiotics and smart approach for UV protection.

Nature creates definite architecture with fluorescence capabilities and superior visual adaptation in many organisms, e.g., cephalopods, which differentiates them from their surroundings in the context of colour and texture that allows them to use this in defence, communication, and reproduction. Inspired by nature, we have designed a coordination polymer gel (CPG)-based luminescent soft material where the photophysical properties of the material can be tuned using a low molecular weight gelator (LMWG) with chromophoric functionalities. Herein, a water-stable coordination polymer gel-based luminescent sensor was created using zirconium oxychloride octahydrate as a metal source and H3TATAB (4,4',4''-((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tribenzoic acid) as a LMWG. The tripodal carboxylic acid gelator H3TATAB with a triazine backbone induces rigidity in the coordination polymer gel network structure along with the unique photoluminescent properties. The xerogel material can selectively detect Fe3+ and nitrofuran-based antibiotics (i.e., NFT) in aqueous medium through luminescent 'turn-off' phenomena. This material is a potent sensor because of the ultrafast detection of the targeted analytes (Fe3+ and NFT), with consistent efficacy in quenching activity up to five consecutive cycles. More interestingly, colorimetric, portable handy paper strip, thin film-based smart detection approaches (under an ultraviolet (UV) source) were introduced to make this material a viable sensor probe in real-time applications. In addition, we developed a facile method to synthesize CPG-polymer composite material that can be utilized as a transparent thin film to protect against UV radiation (200-360 nm), with approximately 99% absorption efficacy.

Repurposing of 5-nitrofuran-3,5-disubstituted isoxazoles: A thriving scaffold to antitrypanosomal agents.

Chagas disease (CD) is a neglected disease caused by the protozoan Trypanosoma cruzi. The two drugs used in the treatment schedules exhibit adverse effects and severe toxicity. Thus, searching for new antitrypanosomal agents is urgent to provide improved treatments to those affected by this disease. 5-Nitrofuran-isoxazole analogs were synthesized by cycloaddition reactions [3+2] between chloro-oximes and acetylenes in satisfactory yields. We analyzed the structure-activity relationship of the analogs based on Hammett's and Hansch's parameters. The 5-nitrofuran-isoxazole analogs exhibited relevant in vitro antitrypanosomal activity against the amastigote forms of T. cruzi. Analog 7s was the trending hit of the series, showing an IC50 value of 40 nM and a selectivity index of 132.50. A possible explanation for this result may be the presence of an electrophile near the isoxazole core. Moreover, the most active analogs proved to act as an in vitro substrate of type I nitroreductase rather than the cruzain, enzymes commonly investigated in molecular target studies of CD drug discovery. These findings suggest that 5-nitrofuran-isoxazole analogs are promising in the studies of agents for CD treatment.

Simultaneous determination of five metabolites of nitrofurans including the metabolite nifursol in shrimp and fish by UPLC- MS/MS: in-house method validation according to commission implementing regulation (EU) 2021/808.

For the simultaneous identification and quantification of five nitrofurans metabolites in farmed shrimp and fish, 3-amino-2-oxazolidinone (AOZ), 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ), 1-aminohydantoine (AHD), semicarbazide (SEM), and 3,5-dinitrosalicylic acid hydrazide (DNSH), an accurate, precise, and specific method was developed. The mixture of water and methanol (60/40; v/v) was found to be the final optimised solvent for injection. The analytical run duration was 7 min, and the mobile phase included 2 mM methanol and ammonium formate. The new reference point for action (RPA) of 0.50 µg kg-1 as per EC/1871/2019 was taken into consideration and evaluated for the performance characteristics as per the CIR (EC)/2021/808 criteria. Specificity, relative retention time (≤0.25%) relative ion ratio (≤40%), linearity (0.25 to 2.0 µg kg-1), trueness (between 82.8 and 118.1%), repeatability (RSDr ≤14%), within lab reproducibility (RSDwr ≤16.9%), CCα (0.32-0.36 µg kg-1), ruggedness and relative matrix effect (≤14.26%) achieved acceptable values.

Quantum Dot Nanobeads as Multicolor Labels for Simultaneous Multiplex Immunochromatographic Detection of Four Nitrofuran Metabolites in Aquatic Products.

A multicolor immunochromatographic assay platform based on quantum dot nanobeads (QBs) for the rapid and simultaneous detection of nitrofuran metabolites in different aquatic products is documented. These metabolites include 3-amino-2-oxazolidinone (AOZ), 1-aminohydantoin (AHD), semicarbazide (SEM), and 3-amino-5-morpholino-methyl-1,3-oxazolidinone (AMOZ). QBs with emission colors of red, yellow, green, and orange were employed and functionalized with the corresponding antibodies to each analyte to develop a multicolor channel. The visual detection limits (cutoff values) of our method for AOZ, AHD, SEM, and AMOZ reached up to 50 ng/mL, which were 2, 20, 20, and 20 times lower than those of traditional colloidal gold test strips, respectively. The test strip is capable of detection within 10 min in real samples while still achieving good stability and specificity. These results demonstrate that the developed multicolor immunochromatographic assay platform is a promising technique for multiplex, highly sensitive, and on-site detection of nitrofuran metabolites.

Furazolidone and Nitrofurazone Metabolic Studies in Crucian Carp by Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry.

In this work, the detection of the furazolidone (FZD) and nitrofurazone (NFZ) metabolites residuals in crucian carp are focused. Crucian carps of identical size were exposed to the mixed nitrofuran antibiotics under optimized bath conditions at a concentration of 50 mg/L, 26 ± 0.5°C for 24 h. Then, liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (LC-ESI-MSMS) was performed after the drug exposure experiments when the nitrofuran metabolites were enriched in organisms. During the period of 0-144 h, residue levels of the 3-amino-2-oxazolidinone (AOZ) gradually decreased with a prolonged sampling time. The changing trend in semicarbazide (SEM) with the sample collection duration is divided into two stages, and its concentration showed a trend of rising first and then falling. The metabolite concentration-time curve demonstrates that 24 h was used as a sampling time, and fish muscle was selected as tissue samples in the further quantitative study. A novel crucian carp-enrichment procedure coupled to LC-ESI-MSMS quantitative method was further explored based on much metabolite data. According to the exponential curve of the SEM-to-AOZ concentration ratio at a precisely designed FZD-to-NFZ mass ratio, the final FZD content of the veterinary NFZ antibiotics was 0.069 ± 0.005% (in terms of mass).

Design, synthesis and biological evaluation of nitrofuran-1,3,4-oxadiazole hybrids as new antitubercular agents.

Three series of novel nitrofuran-1,3,4-oxadiazole hybrids were designed and synthesized as new anti-TB agents. The structure activity relationship study indicated that the linkers and the substituents on the oxadiazole moiety greatly influence the activity, and the substituted benzenes are more favoured than the cycloalkyl or heterocyclic groups. Besides, the optimal compound in series 2 was active against both MTB H37Rv strain and MDR-MTB 16883 clinical isolate and also displayed low cytotoxicity, low inhibition of hERG and good oral PK, indicating its promising potential to be a lead for further structural modifications.

In Vitro and In Vivo Trypanocidal Efficacy of Synthesized Nitrofurantoin Analogs.

African trypanosomes cause diseases in humans and livestock. Human African trypanosomiasis is caused by Trypanosoma brucei rhodesiense and T. b. gambiense. Animal trypanosomoses have major effects on livestock production and the economy in developing countries, with disease management depending mainly on chemotherapy. Moreover, only few drugs are available and these have adverse effects on patients, are costly, show poor accessibility, and parasites develop drug resistance to them. Therefore, novel trypanocidal drugs are urgently needed. Here, the effects of synthesized nitrofurantoin analogs were evaluated against six species/strains of animal and human trypanosomes, and the treatment efficacy of the selected compounds was assessed in vivo. Analogs 11 and 12, containing 11- and 12-carbon aliphatic chains, respectively, showed the highest trypanocidal activity (IC50 < 0.34 µM) and the lowest cytotoxicity (IC50 > 246.02 µM) in vitro. Structure-activity relationship analysis suggested that the trypanocidal activity and cytotoxicity were related to the number of carbons in the aliphatic chain and electronegativity. In vivo experiments, involving oral treatment with nitrofurantoin, showed partial efficacy, whereas the selected analogs showed no treatment efficacy. These results indicate that nitrofurantoin analogs with high hydrophilicity are required for in vivo assessment to determine if they are promising leads for developing trypanocidal drugs.

Nifuroxazide mitigates cholestatic liver injury by synergistic inhibition of Il-6/Β-catenin signaling and enhancement of BSEP and MDRP2 expression.

Cholestasis is a complex hepatic disorder underlined with retention of the highly toxic bile components within the hepatocytes. Nifuroxazide (NIF); a nitrofuran derivative, is widely used drug for treatment of acute and chronic diarrhea. The current study was performed to investigate the curative effect of NIF (25 and 50 mg/kg) on lithocholic acid (LCA)-induced cholestasis and compare the observed impact to that of ursodeoxycholic acid (UDCA). Intriguingly, NIF significantly attenuated LCA-induced cholestatic injury. NIF successfully reversed cholestatic injury to a similar extent compared to the mainstay drug, UDCA. NIF administration remarkably attenuated liver/body index and restored liver functions. Moreover, it restored the disrupted balance in oxidative homeostasis. On the other hand, NIF induced a marked improvement in histopathological and immuno-histochemical analysis of liver specimens. Ultimately, NIF mitigated inflammatory response and proliferative ability of hepatocytes with significant reduction in hepatic expression of proliferatingcellnuclearantigen(PCNA), cluster of differentiation 68 (CD68), interlukin-6 (Il-6) and ß-catenin. Interestingly, NIF successfully increased bile transformation with increased the hepatic expression of bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MDRP2). Nevertheless, molecular docking of NIF with ß-catenin and BSEP showed a better alignment inside the pocket with strong interaction for both protein binding sites. In conclusion, NIF attenuated experimentally-induced cholestatic dysfunction with an underlined synergistic inhibition of Il-6/Β-catenin pathways and direct enhancement of bile acids transporters gene expression.

Evaluation of trypanocidal properties of ferrocenyl and cyrhetrenyl N-acylhydrazones with pendant 5-nitrofuryl group.

Four N-acylhydrazones of general formulae [R1-C(O)-NH-N=C(R2)(5-nitrofuryl)] with (R1 = ferrocenyl or cyrhetrenyl and R2 = H or Me) are synthesized and characterized in solution and in the solid-state. Comparative studies of their stability in solution under different experimental conditions and their electrochemical properties are reported. NMR studies reveal that the four compounds are stable in DMSO­d6 and complementary UV-Vis studies confirm that they also exhibit high stability in mixtures DMSO:H2O at 37 °C. Electrochemical studies show that the half-wave potential of the nitro group of the N-acylhydrazones is smaller than that of the standard drug nifurtimox and the reduction process follows a self-protonation mechanism. In vitro studies on the antiparasitic activities of the four complexes and the nifurtimox against Trypanosoma cruzi and Trypanosoma brucei reveal that: i) the N-acylhydrazones have a potent inhibitory growth activity against both parasites [EC50 in the low micromolar (in T. cruzi) or even in the nanomolar (in T. brucei) range] and ii) cyrhetrenyl derivatives are more effective than their ferrocenyl analogs. Parallel studies on the L6 rat skeletal myoblast cell line have also been conducted, and the selectivity indexes determined. Three of the four N-acylhydrazones showed higher selectivity towards T. brucei than the standard drug nifurtimox. Additional studies suggest that the organometallic compounds are bioactivated by type I nitroreductase enzymes.

Analogs of nitrofuran antibiotics are potent GroEL/ES inhibitor pro-drugs.

In two previous studies, we identified compound 1 as a moderate GroEL/ES inhibitor with weak to moderate antibacterial activity against Gram-positive and Gram-negative bacteria including Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, and SM101 Escherichia coli (which has a compromised lipopolysaccharide biosynthetic pathway making bacteria more permeable to drugs). Extending from those studies, we developed two series of analogs with key substructures resembling those of known antibacterials, nitroxoline (hydroxyquinoline moiety) and nifuroxazide/nitrofurantoin (bis-cyclic-N-acylhydrazone scaffolds). Through biochemical and cell-based assays, we identified potent GroEL/ES inhibitors that selectively blocked E. faecium, S. aureus, and E. coli proliferation with low cytotoxicity to human colon and intestine cells in vitro. Initially, only the hydroxyquinoline-bearing analogs were found to be potent inhibitors in our GroEL/ES-mediated substrate refolding assays; however, subsequent testing in the presence of an E. coli nitroreductase (NfsB) in situ indicated that metabolites of the nitrofuran-bearing analogs were potent GroEL/ES inhibitor pro-drugs. Consequently, this study has identified a new target of nitrofuran-containing drugs, and is the first reported instance of such a unique class of GroEL/ES chaperonin inhibitors. The intriguing results presented herein provide impetus for expanded studies to validate inhibitor mechanisms and optimize this antibacterial class using the respective GroEL/ES chaperonin systems and nitroreductases from E. coli and the ESKAPE bacteria.

Nitrofuran drugs beyond redox cycling: Evidence of Nitroreduction-independent cytotoxicity mechanism.

Nitrofurans (5-nitro-2-hydrazonylfuran as pharmacophore) are a group of widely used antimicrobial drugs but also associated to a variety of side effects. The molecular mechanisms that underlie the cytotoxic effects of nitrofuran drugs are not yet clearly understood. One-electron reduction of 5-nitro group by host enzymes and ROS production via redox cycling have been attributed as mechanisms of cell toxicity. However, the current evidence suggests that nitrofuran ROS generation by itself is uncapable to explain the whole toxic effects associated to nitrofuran consumption, proposing a nitro-reduction independent mechanism of toxicity. In the present work, a series of nitrated and non-nitrated derivatives of nitrofuran drugs were synthesized and evaluated in vitro for their cytotoxicity, ROS-producing capacity, effect on GSH-S-transferase and antibacterial activity. Our studies showed that in human cells non-nitrated derivatives were less toxic than parental drugs but, unexpectedly preserved the ability to generate intracellular ROS in similar amounts to nitrofurans despite not entering into a redox cycle mechanism. In addition, some non-nitrated derivatives although being uncapable to generate ROS exhibited the highest cell toxicity among all derivatives. Inhibition of cytosolic glutathione-S-transferase activity by some derivatives was also observed. Finally, only nitrofuran derivatives displayed antibacterial effect. Results suggest that the combined 2-hydrazonylfuran moiety, redox cycling of 5-nitrofuran, and inhibitory effects on antioxidant enzymes, would be finally responsible for the toxic effects of the studied nitrofurans on mammalian cells.

Efficient identification of novel anti-glioma lead compounds by machine learning models.

Glioblastoma multiforme (GBM) is the most devastating and widespread primary central nervous system tumor. Pharmacological treatment of this malignance is limited by the selective permeability of the blood-brain barrier (BBB) and relies on a single drug, temozolomide (TMZ), thus making the discovery of new compounds challenging and urgent. Therefore, aiming to discover new anti-glioma drugs, we developed robust machine learning models for predicting anti-glioma activity and BBB penetration ability of new compounds. Using these models, we prioritized 41 compounds from our in-house library of compounds, for further in vitro testing against three glioma cell lines and astrocytes. Subsequently, the most potent and selective compounds were resynthesized and tested in vivo using an orthotopic glioma model. This approach revealed two lead candidates, 4m and 4n, which efficiently decreased malignant glioma development in mice, probably by inhibiting thioredoxin reductase activity, as shown by our enzymological assays. Moreover, these two compounds did not promote body weight reduction, death of animals, or altered hematological and toxicological markers, making then good candidates for lead optimization as anti-glioma drug candidates.

Broad spectrum detection of veterinary drugs with a highly stable metal-organic framework.

The broad spectrum detection of veterinary drugs is very important for rapid and large-scale safe screen of animal-derived foods. Metal-organic frameworks (MOFs), as a kind of emerged functional porous materials are quite promising in the chemical sensing and molecular detection. In this work, we report the high-performance broad spectrum detection of 15 commonly-used veterinary drugs through the fluorescence quenching in a newly-designed chemically stable Al-based MOF, Al3(µ3-O)(OH)(H2O)2(PPTTA)3/2 (BUT-22). To the best of our knowledge, this is the first systematic investigation for the application of MOFs in the detection/sensing of veterinary drugs through fluorescence quenching method. The quenching efficiencies of the tested veterinary drugs on BUT-22 are all beyond 82%, and the limits of detection (LOD) are low at parts per billion (ppb) levels. Interestingly, BUT-22 also enables the selective detection of nicarbazin (NIC) through the clearly-observed red shift of its maximum fluorescence emission wavelength. Moreover, the fluorescence quenching mechanism was explored with the help of theoretical calculations. Our work indicates that MOFs are favorable materials for the detection of veterinary drugs, being potentially useful in monitoring drug residues of animal-derived foods.

Design, synthesis, antileishmanial, and antifungal biological evaluation of novel 3,5-disubstituted isoxazole compounds based on 5-nitrofuran scaffolds.

Nineteen 3,5-disubstituted-isoxazole analogs were synthesized based on nitrofuran scaffolds, by a [3 + 2] cycloaddition reaction between terminal acetylenes and 5-nitrofuran chloro-oxime. The compounds were obtained in moderate to very good yields (45-91%). The antileishmanial activity was assayed against the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. Alkylchlorinated compounds 14p-r were active on both the promastigote and amastigote forms, with emphasis on compound 14p, which showed strong activity against the amastigote form (IC50 = 0.6 µM and selectivity index [SI] = 5.2). In the alkyl series, compound 14o stands out with an IC50 = 8.5 µM and SI = 8.0 on the amastigote form. In the aromatic series, the most active compounds were those containing electron-donor groups, such as trimethoxy isoxazole 14g (IC50 = 1.2 µM and SI = 20.2); compound 14h, with IC50 = 7.0 µM and SI = 6.1; and compound 14j containing the 4-SCH3 group, with IC50 = 5.7 µM and SI = 10.2. In addition, the antifungal activity of 19 nitrofuran isoxazoles was evaluated against five strains of Candida (C. albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata). Eleven isoxazole derivatives were active against C. parapsilosis, and compound 14o was found to be the most active (minimal inhibitory concentration [MIC] = 3.4 µM) for this strain. Compound 14p was active against all the strains tested, with an MIC = 17.5 µM for C. glabrata, lower than that of the fluconazole used as the reference drug.

Toward a repositioning of the antibacterial drug nifuroxazide for cancer treatment.

Nifuroxazide (NFX) is a broad-spectrum antibacterial drug that has been used for the treatment of infectious diarrhoea since 1966. In 2008, the discovery of potent inhibition of the transcription factor signal transducer and activator of transcription STAT3 by NFX prompted studies as a potential anticancer agent. Subsequently, it was shown that NFX induces cancer cell apoptosis and inhibits tumour growth. Recently, NFX was identified as a potent inhibitor of aldehyde dehydrogenase ALDH1 that selectively kills ALDHhigh cancer-initiating cells. These two landmark discoveries - STAT3 and ALDH1 inhibition - strongly support the potential repositioning of NFX as a targeted anticancer agent. The related antiparasitic drug nifurtimox is undergoing clinical development for the treatment of paediatric tumours. The anticancer potential of NFX is highlighted here.

Current development of 5-nitrofuran-2-yl derivatives as antitubercular agents.

Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB) and still remains one of the foremost fatal infectious diseases, infecting nearly a third of the worldwide population. The emergencies of multidrug-resistant and extensively drug-resistant tuberculosis (MDR and XDR-TB) prompt the efforts to deliver potent and novel anti-TB drugs. Research aimed at the development of new anti-TB drugs based on nitrofuran scaffold led to the identification of several candidates that were effective against actively growing as well as latent mycobacteria with unique modes of action. This review focuses on the recent advances in nitrofurans that could provide intriguing potential leads in the area of anti-TB drug discovery.

Pro-Nifuroxazide Self-Assembly Leads to Triggerable Nanomedicine for Anti-cancer Therapy.

Transcription factor STAT3 has been shown to regulate genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of great biological significance. However, many small-molecule agents with potential effects through STAT3 modulation in cancer therapy lack aqueous solubility and high off-target toxicity, hence impeding efficient bioavailability and activity. This work, for the first time, reports a prodrug-based strategy for selective and safer delivery of STAT3 inhibitors designed toward metastatic and drug-resistant breast cancer. We have synthesized a novel lipase-labile SN-2 phospholipid prodrug from a clinically investigated STAT3 inhibitor, nifuroxazide (Pro-nifuroxazide), which can be regioselectively cleaved by the membrane-abundant enzymes in cancer cells. Pro-nifuroxazide self-assembled to sub 20 nm nanoparticles (NPs), and the cytotoxic ability was screened in ER(+)-MCF-7 and ER(-)-MD-MB231 cells at 48-72 h using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide proliferation assay. Results indicated that Pro-nifuroxazide NPs are multifold more effective toward inhibiting cancer cells in a time-dependent manner compared to parent nifuroxazide. A remarkable improvement in the local concentration of drugs to as high as ∼240 fold when assembled into NPs is presumably the reason for this functional improvement. We also introduced molecular dynamics simulations to generate Pro-nifuroxazide nano-assembly, as a model assembly from triggerable anti-cancer drugs, to provide molecular insights correlating physicochemical and anti-cancer properties. In silico properties of Pro-nifuroxazide including size, chemistry of NPs and membrane interactions with individual molecules could be validated by in vitro functional activities in cells of breast cancer origin. The in vivo anti-cancer efficiencies of Pro-nifuroxazide NPs in nude mice xenografts with MCF-7 revealed remarkable growth inhibition of as high as 400%. Histopathological analysis corroborated these findings to show significantly high nuclear fragmentation and retracted cytoplasm. Immunostaining on tumor section demonstrated a significantly lower level of pSTAT-3 by Pro-nifuroxazide NP treatment, establishing the inhibition of STAT-3 phosphorylation. Our strategy for the first time proposes a translatable prodrug agent self-assembled into NPs and demonstrates remarkable enhancement in IC50, induced apoptosis, and reduced cancer cell population through STAT-3 inhibition via reduced phosphorylation.

Double prodrugs of a fosmidomycin surrogate as antimalarial and antitubercular agents.

A series of eleven double prodrug derivatives of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. A pivaloyloxymethyl (POM) phosphonate prodrug modification was combined with various prodrug derivatisations of the hydroxamate moiety. The majority of compounds showed activity comparable with or inferior to fosmidomycin against P. falciparum. N-benzyl substituted carbamate prodrug 6f was the most active antimalarial analog with an IC50 value of 0.64 µM. Contrary to fosmidomycin and parent POM-prodrug 5, 2-nitrofuran and 2-nitrothiophene prodrugs 6i and 6j displayed promising antitubercular activities.

Attachment of a 5-nitrofuroyl moiety to spirocyclic piperidines produces non-toxic nitrofurans that are efficacious in vitro against multidrug-resistant Mycobacterium tuberculosis.

A selectively antimycobacterial compound belonging to the nitrofuran class of antimicrobials has been developed via conjugation of the nitrofuran moiety to a series of spirocyclic piperidines through an amide linkage. It proved to have comparable activity against drug-sensitive (H37Rv) strain as well as multidrug-resistant, patient-derived strains of Mycobacterium tuberculosis. The compound is druglike, showed no appreciable cytotoxicity toward human retinal pigment epithelial cell line ARPE-19 in concentrations up to 100 µM and displayed low toxicity when evaluated in mice.