Search Results (13)

In this study, we developed an efficient strategy for constructing thieno[3,2-b]thiophene molecules from 3-nitrothiophenes, containing carbonyl fragments at the C-2 and C-5 atoms, by nucleophilic aromatic substitution of the nitro group in these substrates. It was shown that the reaction of 3-nitrothiophene-2,5-dicarboxylates with thiophenols, thioglycolates and 2-mercaptoacetone in the presence of K₂CO₃ proceeds rapidly via nucleophilic displacement of the nitro group with the formation of 3-sulfenylthiophene-2,5-dicarboxylates. Further treatment of the resulting thiophene-2,5-dicarboxylates, which have -SCH₂CO₂Alk or -SCH₂COMe moiety at C-3 atom, with sodium alcoholates afford obtaining 2,3,5-trisubstituted thieno[3,2-b]thiophene derivatives according to the Dieckman condensation. In turn, the reaction of methyl 5-formyl-4-nitrothiophene-2-carboxylate with methyl thioglycolate or 2-mercaptoacetone in the presence of K₂CO₃ proceeds to directly form 2,5-disubstituted thieno[3,2-b]thiophenes. Full article

The title compounds were synthesized by the reaction of 5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide with various aldehydes bearing aromatic and heterocyclic moieties and acetophenones, and their cytotoxicity was tested via MTT assay against human triple-negative breast cancer MDA-MB-231, human melanoma IGR39, human pancreatic carcinoma Panc-1, and prostate cancer cell line PPC-1. Furthermore, the selectivity of compounds towards cancer cells compared to fibroblasts was also investigated. Four compounds were identified as the most promising anticancer agents out of a series of pyrrolidinone-hydrazone derivatives bearing a diphenylamine moiety. These compounds were most selective against the prostate cancer cell line PPC-1 and the melanoma cell lines IGR39, with EC₅₀ values in the range of 2.5–20.2 µM against these cell lines. In general, the compounds were less active against triple-negative breast cancer MDA-MB-231 cell line, and none of them showed an inhibitory effect on the migration of these cells. In the ‘wound healing’ assay, N′-((5-nitrothiophen-2-yl)methylene)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide was identified as the most promising derivative that could be further developed as an antimetastatic agent. N′-(5-chloro- and N′-(3,4-dichlorobenzylidene)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazides most efficiently reduced the cell viability in IGR39 cell spheroids, while there was no effect of the investigated pyrrolidinone-hydrazone derivatives on PPC-1 3D cell cultures. Antioxidant activity determined via FRAP assay of N′-(1-(4-aminophenyl)ethylidene)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide was 1.2 times higher than that of protocatechuic acid. Full article

Miscellaneous imines and acyl hydrazones were prepared from 5-nitrofuraldehyde and 5-nitrothiophene-2-carboxaldehyde. Their activities against Toxoplasma gondii and Leishmania major parasites were evaluated. Promising antiparasitic effects and selectivities were observed for certain acyl hydrazones and imines. Cobalt(II) and copper(II) complexes conserved the high anti-Toxoplasma activities of 3-hydroxy-2-naphthoic carboxyl hydrazone (2a). In addition, sound activities against L. major promastigotes were observed for various analogs of 2a (2b and 2i) and pyrid-2-ylpyrazole-based imines (3g and 3h). Relatively low toxicities to kidney cells and macrophages indicate promising selectivity profiles for these compounds. Full article

The present study was designed to evaluate the in vitro and in silico potential of the Schiff bases (Z)-4-ethoxy-N-((5-nitrothiophen-2-yl)methylene)benzenamine (1) and (Z)-2,4-diiodo-6-((2-methyl-3-nitrophenylimino)methyl)phenol (2). These Schiff bases were synthesized according to a reported method using ethanol as a solvent, and each reaction was monitored on a TLC until completion of the reaction. The structures of both compounds were elucidated using spectroscopic techniques such as UV–Vis, FTIR, ¹H NMR and ¹³C NMR. Molecular structure was determined using single-crystal XRD, which revealed that compounds 1 and 2 were monoclinic and triclinic, respectively. Hirshfeld surface analysis (HS) and 2D fingerprint plots were used to determine the intermolecular interactions along the contact contribution in the crystalline molecules. The structures of both compounds were optimized through a hybrid functional method B3LYP using the 6-31G(d,p) basis set, and various structural parameters were studied. The experimental and theoretical parameters (bond angle and bond length) of the compounds were compared with each other and are in close agreement. The in vitro esterase potential of the synthesized compounds was checked using a spectrophotometric model, while in silico molecular docking studies were performed with AutoDock against two enzymes of the esterase family. The docking studies and the in vitro assessment predicted that such molecules could be used as enzyme inhibitors against the tested enzymes: acetylcholine esterase (AChE) and butyrylcholine esterase (BChE). Full article

The microbial, biofilm-based infections of chronic wounds are one of the major challenges of contemporary medicine. The use of topically administered antiseptic agents is essential to treat wound-infecting microorganisms. Due to observed microbial tolerance/resistance against specific clinically-used antiseptics, the search for new, efficient agents is of pivotal meaning. Therefore, in this work, 15 isoxazole derivatives were scrutinized against leading biofilm wound pathogens Staphylococcus aureus and Pseudomonas aeruginosa, and against Candida albicans fungus. For this purpose, the minimal inhibitory concentration, biofilm reduction in microtitrate plates, modified disk diffusion methods and antibiofilm dressing activity measurement methods were applied. Moreover, the cytotoxicity and cytocompatibility of derivatives was tested toward wound bed-forming cells, referred to as fibroblasts, using normative methods. Obtained results revealed that all isoxazole derivatives displayed antimicrobial activity and low cytotoxic effect, but antimicrobial activity of two derivatives, 2-(cyclohexylamino)-1-(5-nitrothiophen-2-yl)-2-oxoethyl 5-amino-3-methyl-1,2-oxazole-4-carboxylate (PUB9) and 2-(benzylamino)-1-(5-nitrothiophen-2-yl)-2-oxoethyl 5-amino-3-methyl-1,2-oxazole-4-carboxylate (PUB10), was noticeably higher compared to the other compounds analyzed, especially PUB9 with regard to Staphylococcus aureus, with a minimal inhibitory concentration more than x1000 lower compared to the remaining derivatives. The PUB9 and PUB10 derivatives were able to reduce more than 90% of biofilm-forming cells, regardless of the species, displaying at the same time none (PUB9) or moderate (PUB10) cytotoxicity against fibroblasts and high (PUB9) or moderate (PUB10) cytocompatibility against these wound cells. Therefore, taking into consideration the clinical demand for new antiseptic agents for non-healing wound treatment, PUB9 seems to be a promising candidate to be further tested in advanced animal models and later, if satisfactory results are obtained, in the clinical setting. Full article

The 1-(4-acetamidophenyl)-5-oxopyrrolidine carboxylic acid was applied for synthesizing derivatives bearing azole, diazole, and hydrazone moieties in the molecule. Modification of an acetamide fragment to the free amino group afforded compounds with two functional groups, which enabled to provide a series of 4-substituted-1-(4-substituted phenyl)pyrrolidine-2-ones. The resulted compounds 2 and 4–22 were subjected to the in vitro anticancer and antimicrobial activity determination. The compounds 18–22 exerted the most potent anticancer activity against A549 cells. Furthermore, compound 21 bearing 5-nitrothiophene substituents demonstrated promising and selective antimicrobial activity against multidrug-resistant Staphylococcus aureus strains, including linezolid and tedizolid-resistant S. aureus. These results demonstrate that 5-oxopyrolidine derivatives are attractive scaffolds for the further development of anticancer and antimicrobial compounds targeting multidrug-resistant Gram-positive pathogens. Full article

The compound EACC (ethyl (2-(5-nitrothiophene-2-carboxamido) thiophene-3-carbonyl) carbamate) was recently reported to inhibit fusion of autophagosomes with lysosomes in a reversible manner by inhibiting recruitment of syntaxin 17 to autophagosomes. We report here that this compound also provides a strong protection against the protein toxin ricin as well as against other plant toxins such as abrin and modeccin. The protection did not seem to be caused by inhibition of endocytosis and retrograde transport, but rather by inhibited release of the enzymatically active A-moiety to the cytosol. The TANK-binding kinase 1 (TBK1) has been reported to phosphorylate syntaxin 17 and be required for initiation of autophagy. The inhibitor of TBK1, MRT68601, induced in itself a strong sensitization to ricin, apparently by increasing transport to the Golgi apparatus. Importantly, MRT68601 increased Golgi transport of ricin even in the presence of EACC, but EACC was still able to inhibit intoxication, supporting the idea that EACC protects at a late step along the retrograde pathway. These results also indicate that phosphorylation of syntaxin 17 is not required for the protection observed. Full article

Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common β-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1–2 μg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 μM, MIC: 8.6 μM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure–activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile. Full article

Two new N′-heteroarylidene-1-carbohydrazide derivatives, namely; E-N′-[(pyridine-3-yl)methylidene]adamantane-1-carbohydrazide (1) and E-N′-[(5-nitrothiophen-2-yl)methylidene]adamantane-1-carbohydrazide (2), were produced via condensation of adamantane-1-carbohydrazide with the appropriate heterocyclic aldehyde. Both compounds were chemically and structurally characterized by ¹H-NMR, ¹³C-NMR, infrared and UV-vis spectroscopies, and single crystal X-ray diffraction. The study was complemented with density functional theory calculations (DFT). The results show an asymmetrical charge distribution in both compounds, with the electron density accumulated around the nitrogen and oxygen atoms, leaving the positive charge surrounding the N-H and C-H bonds in the hydrazine group. Consequently, the molecules stack in an antiparallel fashion in the crystalline state, although the contribution of the polar contacts to the stability of the lattice is different for 1 (18%) and 2 (42%). This difference affects the density and symmetry of their crystal structures. Both molecules show intense UV-Vis light absorption in the range 200–350 nm (1) and 200–500 nm (2), brought about by π → π* electronic transitions. The electron density difference maps (EDDM) revealed that during light absorption, the electron density flows within the π-delocalized system, among the pyridyl/thiophene ring, the nitro group, and the N′-methyleneacetohydrazide moiety. Interestingly, compounds 1 and 2 constitute broad-spectrum antibacterial candidates, displaying potent antibacterial activity with minimal inhibitory concentration (MIC) values around 0.5–2.0 μg/mL. They also show weak or moderate antifungal activity against the yeast-like pathogenic fungus Candida albicans. Full article

To learn more about the structure–activity relationships of (E)-3-(5-styryl-1,3,4-oxadiazol-2-yl)benzenesulfonamide derivatives, which in our previous research displayed promising in vitro anticancer activity, we have synthesized a group of novel (E)-5-[(5-(2-arylvinyl)-1,3,4-oxadiazol-2-yl)]-4-chloro-2-R¹-benzenesulfonamides 7–36 as well as (E)-4-[5-styryl1,3,4-oxadiazol-2-yl]benzenesulfonamides 47–50 and (E)-2-(2,4-dichlorophenyl)-5-(2-arylvinyl)-1,3,4-oxadiazols 51–55. All target derivatives were evaluated for their anticancer activity on HeLa, HCT-116, and MCF-7 human tumor cell lines. The obtained results were analyzed in order to explain the influence of a structure of the 2-aryl-vinyl substituent and benzenesulfonamide scaffold on the anti-tumor activity. Compound 31, bearing 5-nitrothiophene moiety, exhibited the most potent anticancer activity against the HCT-116, MCF-7, and HeLa cell lines, with IC50 values of 0.5, 4, and 4.5 µM, respectively. Analysis of structure-activity relationship showed significant differences in activity depending on the substituent in position 3 of the benzenesulfonamide ring and indicated as the optimal meta position of the sulfonamide moiety relative to the oxadizole ring. In the next stage, chemometric analysis was performed basing on a set of computed molecular descriptors. Hierarchical cluster analysis was used to examine the internal structure of the obtained data and the quantitative structure–activity relationship (QSAR) analysis with multiple linear regression (MLR) method allowed for finding statistically significant models for predicting activity towards all three cancer cell lines. Full article

Bacterial resistance towards the existing class of antibacterial drugs continues to increase, posing a significant threat to the clinical usefulness of these drugs. These increasing and alarming rates of antibacterial resistance development and the decline in the number of new antibacterial drugs’ approval continue to serve as a major impetus for research into the discovery and development of new antibacterial agents. We synthesized a series of d-/l-alaninyl substituted triazolyl oxazolidinone derivatives and evaluated their antibacterial activity against selected standard Gram-positive and Gram-negative bacterial strains. Overall, the compounds showed moderate to strong antibacterial activity. Compounds 9d and 10d (d- and l-alaninyl derivatives bearing the 3,5-dinitrobenzoyl substituent), 10e (l-alaninyl derivative bearing the 5-nitrofurancarbonyl group) and 9f and 10f (d- and l-alaninyl derivatives bearing the 5-nitrothiophene carbonyl moiety) demonstrated antibacterial activity (MIC: 2 µg/mL) against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and Moraxella catarrhalis standard bacterial strains. No significant differences were noticeable between the antibacterial activity of the d- and l-alaninyl derivatives as a result of the stereochemistry of the compounds. Full article

An electron-transfer chain reaction between 2-nitropropane anion and α-bromoketones derived from nitrobenzene and nitrothiophene was demonstrated by mechanistic study and a specific convenient synthetic protocol. Thus, 2-bromo-1-(5-nitrothiophen-2-yl)ethanone or 2-bromo-1-(4-nitrophenyl)ethanone were reacted with several cyclic nitronate anions to form α,β-unsaturated ketones via a S_RN1 mechanism. This new method can be used to synthesize a wide variety of chalcone analogues. Full article

Novel 3-acetyl-2-aminothiophenes were prepared from cyanoacetone and1,4-dithianyl-2,5-diols using a modified Gewald reaction. The syntheses of thecorresponding acetamides, as well as that of 3-acetyl-2-amino-5-nitrothiophene – aninteresting building-block for thiophene azo dyes – are reported. Detailed spectroscopicinvestigations (¹H-NMR, ¹³C-NMR, MS, IR) of the obtained compounds are presented. Full article