Search Results (26)

The increasing number of antibiotic-resistant pathogens forces us to accelerate the search for new antimicrobial agents. Based on this, we chose to synthesize a library of 1-(2-hydroxy-5-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives and evaluate their antibacterial activity against various pathogens. A series of (2-hydroxy-5-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid and its hydrazide derivatives were prepared and identified by the methods of IR, ¹H, and ¹³C NMR spectroscopy and a microanalysis technique. The resulting compounds were evaluated in vitro for their efficacy against the Gram-positive Staphylococcus aureus (ATCC 9144), Listeria monocytogenes (ATCC 7644), and Bacillus cereus (ATCC 11778) bacterial strains as well as the Gram-negative Escherichia coli (ATCC 8739) bacteria. Oxacillin, ampicillin, and cefuroxime were used as control antibiotics. Among the obtained compounds, hydrazone with a 5-nitrothien-2-yl fragment surpassed the control cefuroxime (7.8 μg/mL) against almost all strains tested. Hydrazone with a 5-nitrofuran-2-yl moiety showed a slightly lower but also potent effect on all bacterial strains. Moreover, hydrazone with a benzylidene moiety demonstrated very strong inhibition of S. aureus (3.9 μg/mL) in comparison with the antibacterial drug cefuroxime (7.8 μg/mL). In addition, some of these compounds exhibited remarkable bactericidal properties. In a complete biofilm disruption study, 5-nitrothienylhydrazone showed excellent results in disrupting S. aureus and E. coli biofilms. The test results show the potential of the newly obtained derivatives as a source of antibacterial agents. Therefore, further studies on the molecular optimization of these compounds are necessary for the development of new antibacterial drugs. Full article

The man-made load on the environment and the decrease in biodiversity cause a direct negative environmental impact on the existence of honey bees and beekeeping products. The priority directions of the food industry are the use of high-quality environmentally friendly raw materials and the prevention of the ingress and formation of harmful substances in food products, including honey. This implies the need to develop methods for assessing the environmental safety of the studied raw materials and products. The purpose of this study was to implement a mathematical modeling method for studying the environmental safety of honey. Five types of honey were studied: Robinia, rapeseed, linden, buckwheat, and sunflower. Mathematical models were built according to the following parameters: total activity of β-emitting radionuclides; residues of levomycetin (chloramphenicol), nitrofuran (according to AOZ and AMOZ), metronidazole, and pesticides (according to hexachloran); and the content of water-insoluble substances (mechanical impurities) and heavy metals. On the basis of the obtained data and established quality criteria, calculation graphic models were built. Using algebraic methods, they derived new formulas for calculating quality coefficients. Multivariate analysis and programming methods were used to evaluate honey using mathematical modeling. The most and least ecologically dangerous contaminants and their share of influence for different types of honey were determined based on the complex of research on negative factors. The proposed mathematical models can be implemented for practical use in specialized laboratories as a tool for determining the environmental safety of honey of various botanical origins. Full article

Antimetabolite antitumor drugs interfere with nucleic acid and DNA synthesis, causing cancer cell death. However, they also affect rapidly dividing normal cells and cause serious side effects. Doxifluridine (5′-deoxy-5-fluorouridine [5′-DFUR]), a 5-fluorouracil (5-FU) prodrug converted to 5-FU by thymidine phosphorylase (TP), exerts antitumor effects. Since TP is distributed in tumor and normal tissues, 5′-DFUR features side effects. Here we designed a series of novel 5′-DFUR derivatives based on high nitroreductase (NTR) levels in the hypoxic microenvironment of tumor tissues by introducing nitro-containing moieties into the 5′-DFUR structure. These derivatives exert their antitumor effects by producing 5-FU under the dual action of TP and NTR in the tumor microenvironment. The derivatives were synthesized and their stability, release, and cytotoxicity evaluated in vitro and antitumor activity evaluated in vivo. Compound 2c, featuring nitrofuran fragments, was stable in phosphate-buffered saline and plasma at different pH values and reduced rapidly in the presence of NTR. The in vitro cytotoxicity evaluation indicated that compound 2c showed excellent selectivity in the MCF-7 and HT29 cell lines. Moreover, it exhibited antitumor effects comparable to those of 5′-DFUR in vivo without significant toxic side effects. These results suggest that compound 2c is a promising antitumor prodrug. Full article

(1) Background: Nifuratel (NF113), derived from nitrofuran, has a specific anti-tumor effect. However, the potential mechanisms of NF113 in triple-negative breast cancer remain unknown. (2) Methods: In the study, CCK8 assay and colony formation assays were used to evaluate the inhibition effect of NF113 on cell proliferation. Apoptosis and cell cycle distribution were tested by flow cytometry. The mechanism of NF113’s anti-tumor effect was predicted by transcriptome sequencing and verified by using PCR and Western blot experiments. Breast cancer organoids constructed from the patient-derived tumor xenograft model and the MDA-MB-468 xenograft mouse model were established to evaluate the effect of NF113. (3) Results: Our study showed that NF113 had an anti-tumor effect on triple-negative breast cancer both in vitro and in vivo. NF113 also induced apoptosis and G2/M phase arrest in triple-negative breast cancer cells. Our experimental data further verified that NF113 reduced GADD5A mRNA and protein expression, which were significantly upregulated in breast cancer, with downstream CDC25C and AKT phosphorylation changes. (4) Conclusions: Our data provided compelling evidence that NF113 inhibited breast cancer growth via upregulating GADD45A. Conclusion: NF113 was able to exert inhibitory effects on the proliferation of triple-negative breast cancer in vivo and in vitro, which may induce G2/M phase arrest via the GADD45A/CyclinB/CDK1 pathway and apoptosis via GADD45A/JNK/P38. Full article

Aldehyde dehydrogenases (ALDHs) are a family of enzymes that aid in detoxification and are overexpressed in several different malignancies. There is a correlation between increased expression of ALDH and a poor prognosis, stemness, and resistance to several drugs. Several ALDH inhibitors have been generated due to the crucial role that ALDH plays in cancer stem cells. All of these inhibitors, however, are either ineffective, very toxic, or have yet to be subjected to rigorous testing on their effectiveness. Although various drug-like compounds targeting ALDH have been reported in the literature, none have made it to routine use in the oncology clinic. As a result, new potent, non-toxic, bioavailable, and therapeutically effective ALDH inhibitors are still needed. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin and indazole pharmacophore. Molecular docking studies and enzymatic tests revealed that among all of the synthesized analogs, compound 3 is the most potent inhibitor of ALDH1A1, ALDH3A1, and ALDH1A3, exhibiting 51.32%, 51.87%, and 36.65% inhibition, respectively. The ALDEFLUOR assay further revealed that compound 3 acts as an ALDH broad spectrum inhibitor at 500 nM. Compound 3 was also the most cytotoxic to cancer cells, with an IC₅₀ in the range of 2.1 to 3.8 µM for ovarian, colon, and pancreatic cancer cells, compared to normal and embryonic kidney cells (IC₅₀ 7.1 to 8.7 µM). Mechanistically, compound 3 increased ROS activity due to potent multi-ALDH isoform inhibition, which increased apoptosis. Taken together, this study identified a potent multi-isoform ALDH inhibitor that could be further developed as a cancer therapeutic. Full article

A series of eight 5-nitrofuran-tagged oxazolyl tetrahydropyrazolopyridines (THPPs) has been prepared in six stages with excellent regioselectivity. The testing of these compounds against pathogens of the ESKAPE panel showed a good activity of lead compound 1-(2-methoxyethyl)-5-(5-nitro-2-furoyl)-3-(1,3-oxazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] pyridine (13g), which is superior to nitrofurantoin. These results confirmed the benefit of combining a THPP scaffold with a nitrofuran warhead. Certain structure–activity relationships were established in the course of this study which were rationalized by the induced-fit docking experiments in silico. Full article

The treatment of urinary tract infections is usually empirical. For example, nitrofuran derivatives, mainly nitrofurantoin (but also furazidin), are used in Eastern Europe. A significant problem is the assessment of the usefulness of furazidin, as there are no standards for susceptibility testing. Additionally, a high percentage of strains resistant to nitrofurantoin should prompt caution when choosing furazidin in therapy. This study aimed to answer the question of whether it is possible to use nitrofurantoin susceptibility for furazidin drug susceptibility analyses and if there is any cross-resistance in the nitrofuran derivatives group. One hundred E. coli clinical isolates, obtained from the Central Teaching Hospital of the Medical University of Lodz, were cultured from positive urine samples. For susceptibility testing, microdilution and disk diffusion methods, following EUCAST guidelines, were used. The results showed that the MICs of furazidin were equal to or lower than those of nitrofurantoin in 89% of the tested strains. The MIC_50/90 values for furazidin were two times lower than those for nitrofurantoin. Positive correlations were found between MICs and growth inhibition zones for both antibiotics. Based on the obtained data and previous studies, it was assumed that the transfer of susceptibility testing results from nitrofurantoin to furazidin is acceptable due to cross-resistance in nitrofuran derivatives. Full article

Funding is often a constraint when planning research, especially in countries where basic research is underfunded. Researchers must take into account these limitations, e.g., in relation to the selection of appropriate reagents, the source of which may affect the study’s final results. The aim of this article was to compare the results of bacteria susceptibility testing using three different sources of antimicrobial: the pure powder available from the supplier and two tablet formulations with different excipients. The chosen substance was furazidin (nitrofuran derivative). The susceptibility was tested on a group of 45 uropathogenic Enterobacterales using both microdilution and disk diffusion methods. The obtained results indicated that despite the relatively higher price, the powder appeared to be the best substance for scientific purposes, especially for quantitative determinations. Full article

Furazolidone (FZD), a typical highly effective nitrofuran antibiotic, has been banned in aquaculture for its carcinogenicity and other adverse health effects, but it is still wildly used for its low cost and significant efficacy. Since FZD will be rapidly metabolized in living organisms, the traditional standard mass spectrometry method can quantitatively analyze trace amount of FZD by detecting its derivative. However, a rapid qualitative analysis method is more consistent with market demand in regular monitoring. In this study, high performance liquid chromatography (HPLC) was used to separate and purify FZD from the sea cucumber culture sediment, and the purified effluent was combined with a substrate of gold nanoparticles (Au NPs) for surface enhanced Raman spectroscopy (SERS) detection. The absolute detection limit of FZD by SERS is 1 ng, and the detection limit of FZD in actual sediment samples is less than 1 μg/kg. The cost and period of FZD analysis by HPLC-SERS are greatly reduced for the omission of derivatization compared with the traditional mass spectrometry method, which can better meet the requirements of practical applications. Full article

Nifuroxazide (NAZ), a nitrofuran derivative used to treat diarrhea, has been recently shown to possess anticancer activity. However, its pharmacokinetic profile is poorly known. The pharmacokinetic profile of NAZ was thus investigated in mice using a newly developed method based on high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). We determined the concentrations of NAZ in the plasma and brain tissue of mice treated with the drug. The method proved to be specific, reproducible, precise, and accurate. It also demonstrated high sensitivity, reaching an LOQ in the order of ppb for both matrices, using samples of 100 µL or 0.2 g. The new HPLC–MS/MS assay was successfully applied to study the pharmacokinetics of NAZ after chronic intraperitoneal administration in mice at a dose of 30 mg/kg. One hour after treatment, plasma concentrations of NAZ were in the range of 336–2640 ng/mL. Moreover, unlike the brains of healthy mice or those with healed mechanical injuries, we found that NAZ was able to cross the injured blood–brain barrier of tumor-infiltrated brains. Thus, following i.p. administration, NAZ reaches systemic levels suitable for testing its efficacy in preclinical models of glioblastoma. Overall, these pharmacokinetic data provide robust evidence supporting the repositioning of NAZ as an antitumor drug. Full article

The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIβ inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane ring present antiproliferative properties against neuroblastoma cell lines SK-N-SH and IMR-32. Likewise, quinoxalines with an arylethynyl group displayed promising antineoplastic properties against glioblastoma and lung cancer cell lines, U87-MG and A549 respectively. Here, 40 new quinoxaline derivatives bearing an oxirane ring were synthesized using a tetrakis(dimethylamino)ethylene (TDAE) strategy and a Sonogashira cross-coupling reaction. Each reaction with TDAE furnished a pair of diastereoisomers cis and trans. These new compounds formed two series according to the substitution of position 2 on the quinoxaline core, with chlorine or phenylacetylene respectively. Each of these isomers was evaluated for antiproliferative activity against neuroblastoma cell lines SK-N-SH and IMR-32 by MTT assay. All cell viability assay results were analyzed using R programming, as well as a statistical comparison between groups of compounds. Our evaluation showed no difference in drug sensitivity between the two neuroblastoma cell lines. Moreover, trans derivatives were observed to display better activities than cis derivatives, leading us to conclude that stereochemistry plays an important role in the antiproliferative activity of these compounds. Further support for this hypothesis is provided by the lack of improvement in antineoplastic activity following the addition of the phenylacetylene moiety, probably due to steric hindrance. As a result, compounds with nitrofuran substituents from the TDAE series demonstrated the highest antiproliferative activity with IC₅₀ = 2.49 ± 1.33 μM and IC₅₀ = 3.96 ± 2.03 μM for compound 11a and IC₅₀ = 5.3 ± 2.12 μM and IC₅₀ = 7.12 ± 1.59 μM for compound 11b against SK-N-SH and IMR-32, respectively. Furthermore, an in silico study was carried out to evaluate the mechanism of action of our lead compounds and predict their pharmacokinetic properties. Full article

Histoplasma capsulatum is a fungus that causes histoplasmosis. The increased evolution of microbial resistance and the adverse effects of current antifungals help new drugs to emerge. In this work, fifty-four nitrofurans and indoles were tested against the H. capsulatum EH-315 strain. Compounds with a minimum inhibitory concentration (MIC₉₀) equal to or lower than 7.81 µg/mL were selected to evaluate their MIC₉₀ on ATCC G217-B strain and their minimum fungicide concentration (MFC) on both strains. The quantification of membrane ergosterol, cell wall integrity, the production of reactive oxygen species, and the induction of death by necrosis–apoptosis was performed to investigate the mechanism of action of compounds 7, 11, and 32. These compounds could reduce the extracted sterol and induce necrotic cell death, similarly to itraconazole. Moreover, 7 and 11 damaged the cell wall, causing flaws in the contour (11), or changing the size and shape of the fungal cell wall (7). Furthermore, 7 and 32 induced reactive oxygen species (ROS) formation higher than 11 and control. Finally, the cytotoxicity was measured in two models of cell culture, i.e., monolayers (cells are flat) and a three-dimensional (3D) model, where they present a spheroidal conformation. Cytotoxicity assays in the 3D model showed a lower toxicity in the compounds than those performed on cell monolayers. Overall, these results suggest that derivatives of nitrofurans and indoles are promising compounds for the treatment of histoplasmosis. Full article

Four novel methyl 4-phenylpicolinoimidate derivatives of hydrazone have been synthesized and evaluated for their antimicrobial activity, including tuberculostatic activity. The compounds obtained are condensates of hydrazonamide or hydrazide with 5-nitro-2-furaldehyde or 5-nitro-2-thiophenecarboxaldehyde. The antimicrobial activity of the tested compounds varied. Compound 3b exhibited significant activity against the tested Gram-positive bacteria (7.8–250 µg/mL). The results of structural tests revealed that the compound is the only one obtained in the form of a Z isomer. Tuberculostatic activity tests showed higher activity of derivatives 3a and 4a containing nitrofuran systems (MICs 3.1–12.5 µg/mL). This research allowed us to identify hydrazone 3b as a starting point for further optimization in the search for antimicrobial drugs. Likewise, compound 4a appears to be a good guiding structure for use in future research on new anti-tuberculosis drugs. Full article

Fungal diseases affect more than 1 billion people worldwide. The constant global changes, the advent of new pandemics, and chronic diseases favor the diffusion of fungal pathogens such as Candida, Cryptococcus, Aspergillus, Trichophyton, Histoplasma capsulatum, and Paracoccidioides brasiliensis. In this work, a series of nitrofuran derivatives were synthesized and tested against different fungal species; most of them showed inhibitory activity, fungicide, and fungistatic profile. The minimal inhibitory concentration (MIC₉₀) values for the most potent compounds range from 0.48 µg/mL against H. capsulatum (compound 11) and P. brasiliensis (compounds 3 and 9) to 0.98 µg/mL against Trichophyton rubrum and T. mentagrophytes (compounds 8, 9, 12, 13 and 8, 12, 13, respectively), and 3.9 µg/mL against Candida and Cryptococcus neoformans strains (compounds 1 and 5, respectively). In addition, all compounds showed low toxicity when tested in vitro on lung cell lines (A549 and MRC-5) and in vivo in Caenorhabditis elegans larvae. Many of them showed high selectivity index values. Thus, these studied nitrofuran derivatives proved to be potent against different fungal species, characterized by low toxicity and high selectivity; for these reasons, they may become promising compounds for the treatment of mycoses. Full article

In our research, we used nicotinic acid as a starting compound, which was subjected to a series of condensation reactions with appropriate aldehydes. As a result of these reactions, we were able to obtain a series of twelve acylhydrazones, two of which showed promising activity against Gram-positive bacteria (MIC = 1.95–15.62 µg/mL), especially against Staphylococcus epidermidis ATCC 12228 (MIC = 1.95 µg/mL). Moreover, the activity of compound 13 against the Staphylococcus aureus ATCC 43300 strain, i.e., the MRSA strain, was MIC = 7.81 µg/mL. Then, we subjected the entire series of acylhydrazones to a cyclization reaction in the acetic anhydride, thanks to which we were able to obtain twelve new 3-acetyl-2,5-disubstituted-1,3,4-oxadiazoline derivatives. Obtained 1,3,4-oxadiazolines were also tested for antimicrobial activity. The results showed high activity of compound 25 with a 5-nitrofuran substituent, which was active against all tested strains. The most promising activity of this compound was found against Gram-positive bacteria, in particular against Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538 (MIC = 7.81 µg/mL) and ATCC 43300 MRSA strains (MIC = 15.62 µg/mL). Importantly, the best performing compounds did not show cytotoxicity against normal cell lines. It seems practical to use some of these compounds or their derivatives in the future in the prevention and treatment of infections caused by some pathogenic or opportunistic microorganisms. Full article