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Grafting of niclosamide or salicylanilide onto polyurethane (PU) was executed to develop antifungal effectiveness and barnacle repelling capability in seawater compared with underivatized PU. The PU surface was simultaneously modified to improve the surface hydrophilicity by inserting dimethylolpropionic acid into PU frame or by grafting recycled polyols onto PU. Surface modifications of PU significantly affected its properties, such as cross-link density, tensile and shape memory properties, and flexibility under freezing conditions relative to the unmodified PU. The modification of PU surface also notably influenced the glass transition and the melting and crystallization related to soft segments. The breaking tensile stress and the shape recovery were enhanced significantly after the grafting of polyol due to chemical cross-linking, whereas the breaking tensile strain was not reduced. Some PU samples demonstrated complete antifungal effectiveness against a mixture of fungi, and barnacle growth on PU films was limited in the specifically modified PUs. [ABSTRACT FROM AUTHOR]

Based on the presence of carbamate moiety, twenty salicylanilide N -monosubstituted carbamates concomitantly with their parent salicylanilides and five newly prepared 4-chlorophenyl carbamates obtained from isocyanates were investigated using Ellman’s method for their in vitro inhibitory activity against acetylcholinesterase (AChE) from electric eel and butyrylcholinesterase (BChE) from equine serum. The carbamates and salicylanilides exhibited mostly a moderate inhibition of both cholinesterase enzymes with IC 50 values ranging from 5 to 235 µM. IC 50 values for AChE were in a narrower concentration range when compared to BChE, but many of the compounds produced a balanced inhibition of both cholinesterases. The derivatives were comparable or superior to rivastigmine for AChE inhibition, but only a few of carbamates also for BChE. Several structure-activity relationships were identified, e.g., N -phenethylcarbamates produce clearly favourable BChE inhibition. The compounds also share convenient physicochemical properties for CNS penetration. [ABSTRACT FROM AUTHOR]

Enterococci are commensal micro-organisms present in the gastrointestinal tract of humans. Although normally innocuous to the host, strains of enterococcus exhibiting resistance to vancomycin (VRE) have been associated with high rates of infection and mortality in immunocompromised patients. Decolonization of VRE represents a key strategy to curb infection in highly-susceptible patients. However, there is a dearth of decolonizing agents available clinically that are effective against VRE. The present study found that niclosamide, an anthelmintic drug, has potent antibacterial activity against clinical isolates of vancomycin-resistant Enterococcus faecium (minimum inhibitory concentration 1–8 µg/mL). E. faecium mutants exhibiting resistance to niclosamide could not be isolated even after multiple (10) serial passages. Based upon these promising in-vitro results and the limited permeability of niclosamide across the gastrointestinal tract (when administered orally), niclosamide was evaluated in a VRE colonization-reduction murine model. Remarkably, niclosamide outperformed linezolid, an antibiotic used clinically to treat VRE infections. Niclosamide was as effective as ramoplanin in reducing the burden of vancomycin-resistant E. faecium in the faeces, caecal content and ileal content of infected mice after only 8 days of treatment. Linezolid, in contrast, was unable to decrease the burden of VRE in the gastrointestinal tract of mice. The results obtained indicate that niclosamide warrants further evaluation as a novel decolonizing agent to suppress VRE infections. [ABSTRACT FROM AUTHOR]

[Display omitted] Obesity is a growing global health problem and is associated with increased prevalence of many metabolic disorders, including diabetes, hypertension and cardiovascular disease. Pancreatic lipase (PL) has been validated as a key target for developing anti-obesity agents, owing to its crucial role in lipid digestion and absorption. In the past few decades, porcine PL (pPL) is always used as the enzyme source for screening PL inhibitors, which generate numerous pPL inhibitors but the potent inhibitors against human PL (hPL) are rarely reported. Herein, a series of salicylanilide derivatives were designed and synthesized, while their anti-hPL effects were assayed by a fluorescence-based biochemical approach. To investigate the structure–activity relationships of salicylanilide derivatives as hPL inhibitors in detail, structural modifications on three rings (A, B and C) of the salicylanilide skeleton were performed. Among all tested compounds, 2t and 2u were found possessing the most potent anti-PL activity, showing IC 50 values of 1.86 μM and 1.63 μM, respectively. Inhibition kinetic analyses suggested that both 2t and 2u could effectively inhibit hPL in a non-competitive manner, with the k i value of 1.67 μM and 1.70 μM, respectively. Fluorescence quenching assays suggested that two inhibitors could quench the fluorescence of hPL via a static quenching procedure. Molecular docking simulations suggested that 2t and 2u could tightly bind on an allosteric site of hPL. Collectively, the structure–activity relationships of salicylanilide derivatives as hPL inhibitors were carefully investigated, while two newly identified reversible hPL inhibitors (2t and 2u) could be used as promising lead compounds to develop novel anti-obesity drugs. [ABSTRACT FROM AUTHOR]

Tuberculosis is caused by Mycobacterium tuberculosis , an intracellular pathogen that can survive in host cells, mainly in macrophages. An increase of multidrug-resistant tuberculosis qualifies this infectious disease as a major public health problem worldwide. The cellular uptake of the antimycobacterial agents by infected host cells is limited. Our approach is to enhance the cellular uptake of the antituberculars by target cell-directed delivery using drug-peptide conjugates to achieve an increased intracellular efficacy. In this study, salicylanilide derivatives (2-hydroxy- N -phenylbenzamides) with remarkable antimycobacterial activity were conjugated to macrophage receptor specific tuftsin based peptide carriers through oxime bond directly or by insertion of a GFLG tetrapeptide spacer. We have found that the in vitro antimycobacterial activity of the salicylanilides against M. tuberculosis H 37 Rv is preserved in the conjugates. While the free drug was ineffective on infected macrophage model, the conjugates were active against the intracellular bacteria. The fluorescently labelled peptide carriers that were modified with different fatty acid side chains showed outstanding cellular uptake rate to the macrophage model cells. The conjugation of the salicylanilides to tuftsin based carriers reduced or abolished the in vitro cytostatic activity of the free drugs with the exception of the palmitoylated conjugates. The conjugates degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond-linked salicylanilide-amino acid fragment as the smallest active metabolite. [ABSTRACT FROM AUTHOR]

Inhibiting osteoclastogenesis is a promising therapeutic target for treating osteoclast-related diseases. Herein, we synthesized a series of modified salicylanilides and their corresponding 3-phenyl-2 H -benzo[ e ][1,3]oxazine-2,4(3 H )-dione and 10-phenyldibenzo[ b,f ][1,4]oxazepin-11(10 H )-one derivatives, and investigated the effects of such compounds on RANKL-induced osteoclast formation. Among them, a salicylanilide derivative ( A04) and its 3-phenyl-2 H -benzo[ e ][1,3]oxazine-2,4(3 H )-dione derivative ( B04 ) markedly suppressed RANKL-induced osteoclast differentiation and showed no significant cytotoxic effects at doses higher than that required to inhibit osteoclast formation. Both compounds reduced osteoclast formation and bone resorptive activity of osteoclasts in a dose-dependent manner. Further, the anti-osteoclastogenic effects of A04 and B04 may operate through reducing the RANKL-induced nuclear translocation of NFATc1. Accordingly, we present the potent anti-osteoclastogenic compounds A04 and B04 as promising candidates for further optimization as anti-resorptive agents. [ABSTRACT FROM AUTHOR]

Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 μM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 μM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 μM). Results from molecular docking studies suggest that carbamate compounds, especially N,Ndiphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization. [ABSTRACT FROM AUTHOR]

ABSTRACT [ABSTRACT FROM AUTHOR]

In the Mycobacterium genus over one hundred species are already described and new ones are periodically reported. Species that form colonies in a week are classified as rapid growers, those requiring longer periods (up to three months) are the mostly pathogenic slow growers. More recently, new emerging species have been identified to lengthen the list, all rapid growers. Of these, Mycobacterium abscessus is also an intracellular pathogen and it is the most chemotherapy-resistant rapid-growing mycobacterium. In addition, the cases of multidrug-resistant Mycobacterium tuberculosis infection are also increasing. Therefore there is an urgent need to find new active molecules against these threatening strains. Based on previous results, a series of salicylanilides, salicylanilide 5-chloropyrazinoates and carbamates was designed, synthesized and characterised. The compounds were evaluated for their in vitro activity on M. abscessus , susceptible M. tuberculosis H 37 Rv, multidrug-resistant (MDR) M. tuberculosis MDR A8, M. tuberculosis MDR 9449/2006 and on the extremely-resistant Praha 131 (XDR) strains. All derivatives exhibited a significant activity with minimum inhibitory concentrations (MICs) in the low micromolar range. Eight salicylanilide carbamates and two salicylanilide esters exhibited an excellent in vitro activity on M. abscessus with MICs from 0.2 to 2.1 μM, thus being more effective than ciprofloxacin and gentamicin. This finding is potentially promising, particularly, as M. abscessus is a threateningly chemotherapy-resistant species. M. tuberculosis H 37 Rv was inhibited with MICs from 0.2 μM, and eleven compounds have lower MICs than isoniazid. Salicylanilide esters and carbamates were found that they were effective also on MDR and XDR M. tuberculosis strains with MICs ≥1.0 μM. The in vitro cytotoxicity (IC 50 ) was also determined on human MonoMac-6 cells, and selectivity index (SI) of the compounds was established. In general, salicylanilide derivatives substituted by halogens on both salicyl and aniline rings showed better activity, than 4-benzoylaniline derivatives. The ester or carbamate bond formation of parent salicylanilides mostly retained or improved antimycobacterial potency with moderate selectivity. [ABSTRACT FROM AUTHOR]

Based on the previously described antimicrobial activity of salicylanilide derivatives, we designed and synthesized novel 2-(phenylcarbamoyl)phenyl 4-substituted benzoates. The most active salicylanilides were selected for esterification by various 4-substituted benzoic acids. These compounds were evaluated in vitro against Mycobacterium tuberculosis , including multidrug-resistant strains, nontuberculous mycobacteria ( Mycobacterium avium and Mycobacterium kansasii ), and eight bacterial and fungal strains. We also investigated the cytostatic and cytotoxic actions of the esters. The minimum inhibitory concentrations (MICs) against mycobacteria ranged from 0.125 to 8 μM. Interestingly, the drug-resistant strains exhibited the highest susceptibility without any cross-resistance with established drugs. 4-Bromo-2-[4-(trifluoromethyl)phenylcarbamoyl]phenyl 4-nitrobenzoate showed the most potent inhibition with MIC values ranging from 0.25 to 2 μM. Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus , were inhibited by two derivatives with MIC values of at least 0.49 μM, whereas Gram-negative bacteria and most of the tested fungi did not display any marked susceptibility. Benzoates exhibited no cytotoxicity at concentrations up to 50 μM but most caused significant cytostasis with IC 50 values lower than 10 μM. Some cytotoxicity-based selectivity indexes for drug-susceptible and drug-resistant M. tuberculosis as well as Staphylococci were higher than 100. These values indicate that some of these derivatives are promising candidates for future research. [ABSTRACT FROM AUTHOR]

A new series of 27 diethyl 2-(phenylcarbamoyl)phenyl phosphorothioates (thiophosphates) was synthesized, characterized by NMR, IR and CHN analyses and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium avium and two strains of Mycobacterium kansasii. The best activity against M. tuberculosis was found for O-{4-bromo-2-[(3,4-dichlorophenyl)carbamoyl]phenyl} O,O-diethyl phosphorothioate (minimum inhibitory concentration of 4 μM). The highest activity against nontuberculous mycobacteria was exhibited by O-(5-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}- phenyl) O,O-diethyl phosphorothioate with MIC values from 16 μM. Prepared thiophosphates were also evaluated against acetylcholinesterase from electric eel and butyrylcholinesterase from equine serum. Their inhibitory activity was compared to that of the known cholinesterases inhibitors galanthamine and rivastigmine. All tested compounds showed a higher (for AChE inhibition) and comparable (for BChE inhibition) activity to that of rivastigmine, with IC50s within the 8.04 to 20.2 μM range. [ABSTRACT FROM AUTHOR]

Abstract: A series of 27 salicylanilide diethyl phosphates was prepared as a part of our on-going search for new antimicrobial active drugs. All compounds exhibited in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium strains, with minimum inhibitory concentration (MIC) values of 0.5–62.5μmol/L. Selected salicylanilide diethyl phosphates also inhibit multidrug-resistant tuberculous strains at the concentration of 1μmol/L. Salicylanilide diethyl phosphates also exhibited mostly the activity against Gram-positive bacteria (MICs ⩾1.95μmol/L), whereas their antifungal activity is significantly lower. The IC50 values for Hep G2 cells were within the range of 1.56–33.82μmol/L, but there is no direct correlation with MICs for mycobacteria. [Copyright &y& Elsevier]

Rafoxanide is an effective treatment for the control of fluke infections in animals, but it is currently not permitted for treating animals whose milk is intended for human consumption. In this study, the persistence of rafoxanide residues in milk, and their migration to dairy products, was investigated following the treatment of six lactating dairy cows with Curafluke 10% oral drench. The highest concentration of rafoxanide residues detected in the individual cows milk ranged from 249 to 627 μg kg−1and occurred at 2–3 days post-treatment. At 2 and 23 days post-treatment (representing high and low residue concentrations) the milk was pooled into two independent aliquots, each containing the full day’s milk produced by three cows. Milk products were made from pasteurised and unpasteurised milk. Pasteurisation appeared to have little impact on the stability of the residues. Rafoxanide concentrated sixfold in the cheese (week 0) compared to the starting milk (2070 vs. 349 μg kg−1) but was four times lower in whey (75 μg kg−1). Rafoxanide residues were up to 14 times higher in butter (week 0) than in the starting milk (5468 vs. 376 μg kg−1). Residues were found to further concentrate in butter and cheese at longer storage and ripening times, respectively. Skim-milk powder was manufactured from skim milk, and residues were 10-fold higher than in the starting skim milk (5468 vs. 376 μg kg−1) despite the 185°C temperature required for the process. Rafoxanide residues were stable in this skim-milk powder when stored at ambient temperature for at least 1 year. Results showed that detectable rafoxanide residues were excreted in milk for 47 days, and concentrated in the fat-based products. The analytical ranges of the UHPLC-MS/MS method used were 1.0–200 μg kg−1(milk and whey) and 10–2000 μg kg−1(other dairy products). [ABSTRACT FROM PUBLISHER]

Abstract: A series of salicylanilides was synthesized based on a high-throughput screening hit against Mycobacterium tuberculosis. A free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure–activity relationship of the aniline ring is largely driven by the presence of electron withdrawing groups. We synthesized 94 analogs exploring substitutions of both rings and the linker region in this series and we have identified multiple compounds with low micromolar potency. Unfortunately, cytotoxicity in a murine macrophage cell line trends with antimicrobial activity, suggesting a similar mechanism of action. We propose that salicylanilides function as proton shuttles that kill cells by destroying the cellular proton gradient, limiting their utility as potential therapeutics. [Copyright &y& Elsevier]

The increasing emergence especially of drug-resistant tuberculosis has led to a strong demand for new anti-tuberculosis drugs. Eighteen salicylanilide benzoates were evaluated for their inhibition potential against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii; minimum inhibitory concentration values ranged from 0.5 to 16 μmol/L. The most active esters underwent additional biological assays. Four benzoates inhibited effectively the growth of five multidrug-resistant strains and one extensively drug-resistant strain of M. tuberculosis at low concentrations (0.25-2 μmol/L) regardless of the resistance patterns. The highest rate of multidrug-resistant mycobacteria inhibition expressed 4-chloro-2-[4-(trifluoromethyl)- phenylcarbamoyl]phenyl benzoate (0.25-1 μmol/L). Unfortunately, the most potent esters were still considerably cytotoxic, although mostly less than their parent salicylanilides. [ABSTRACT FROM AUTHOR]

Searching for novel antimicrobial agents still represents a current topic in medicinal chemistry. In this study, the synthesis and analytical data of eighteen salicylanilide esters with 4-(trifluoromethyl)benzoic acid are presented. They were assayed in vitro as potential antimycotic agents against eight fungal strains, along with their parent salicylanilides. The antifungal activity of the presented derivatives was not uniform and moulds showed a higher susceptibility with minimum inhibitory concentrations (MIC) ≥ 0.49 μmol/L than yeasts (MIC ≥ 1.95 μmol/L). However, it was not possible to evaluate a range of 4-(trifluoromethyl)benzoates due to their low solubility. In general, the most active salicylanilide was N-(4-bromophenyl)-4-chloro-2-hydroxybenzamide and among esters, the corresponding 2-(4-bromophenylcarbamoyl)-5-chlorophenyl 4-(trifluoromethyl) benzoate exhibited the lowest MIC of 0.49 μmol/L. However, the esterification of salicylanilides by 4-(trifluoromethyl)benzoic acid did not result unequivocally in a higher antifungal potency. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel sulfonamides containing 5-chloro-2-hydroxybenzaldehyde or 5-chloro-2-hydroxybenzoic acid scaffolds were designed, synthesized and characterized by IR, 1H NMR and 13C NMR. All ten target synthesized derivatives and starting sulfonamides were evaluated in vitro for the activity against Gram-positive and Gram-negative bacteria, fungi, Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium kansasii. The most active compound against methicillin-sensitive and methicillin-resistant Staphyloccoccus aureus was 5-chloro-N-{4-[N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenyl}-2-hydroxybenzamide with MIC 15.62–31.25 μmol/L. 4-Amino-N-(thiazol-2-yl)benzenesulfonamide and 4-(5-chloro-2-hydroxybenzylideneamino)-N-(thiazol-2-yl)benzenesulfonamide have shown the best activity against M. kansasii at the concentrations of 1–4 μmol/L. The efficacy against other strains was weaker and the studied derivatives exhibited almost none antifungal potency. [Copyright &y& Elsevier]

Abstract: The FT-IR and FT-Raman spectra of 5-chloro-2-(3-chlorophenylcarbamoyl)phenylacetate were studied. The vibrational wave numbers and corresponding vibrational assignments were examined theoretically using the Gaussian 03 set of quantum chemistry codes and the normal modes are assigned by Potential Energy Distribution calculations. The synthesis, elemental analysis and NMR values are presented. The red shift of the NH stretching wave number in the infrared spectrum from the computed wave number indicates the weakening of the NH bond resulting in proton transfer to the neighboring oxygen atom. The first hyperpolarizability, infrared intensities and Raman activities are reported. The calculated first hyperpolarizability is comparable with the reported values of similar derivatives and is an attractive object for future studies of nonlinear optics. The geometrical parameters of the title compound are in agreement with that of similar reported derivatives. [Copyright &y& Elsevier]

Abstract: In the present study salicylanilide was reacted with 2,4,6-trichloro-1,3,5-triazine producing reactive salicylanilide at a yield of 45% according to reaction conditions set. The reactive salicylanilide was confirmed structurally through FT-IR analysis. Pristine viscose fabric was treated with active salicylanilide to impart permanent antibacterial and antifungus properties to the fabric. Covalently attached reactive salicylanilide, as revealed, was quantitatively assessed through spectrophotometric and nitrogen elemental analysis. The antibacterial and antifungus capability of reactive salicylanilide treated viscose fabric; fastness and washing reproduction were examined and evaluated. [Copyright &y& Elsevier]

[image omitted] A highly efficient protocol for the preparation of aromatic amides is described by the direct reactions between salicyclic acid and aromatic amines in the presence of phosphorous trichloride under microwave irradiation. The method has several advantages over the conventional methods, including operational simplicity, good yield, and reduced reaction time. [ABSTRACT FROM AUTHOR]

Abstract: To identify new transglycosylase inhibitors with potent anti-methicillin-resistant Staphylococcus aureus (MRSA) activities, a high-throughput screening against Staphylococcus aureus was conducted to look for antibacterial cores in our 2M compound library that consists of natural products, proprietary collection, and synthetic molecules. About 3600 hits were identified from the primary screening and the subsequent confirmation resulted in a total of 252 compounds in 84 clusters which showed anti-MRSA activities with MIC values as low as 0.1μg/ml. Subsequent screening targeting bacterial transglycosylase identified a salicylanilide-based core that inhibited the lipid II polymerization and the moenomycin-binding activities of transglycosylase. Among the collected analogues, potent inhibitors with the IC50 values below 10μM against transglycosylase were identified. The non-carbonhydrate scaffold reported in this study suggests a new direction for development of bacterial transglycosylase inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Eleven halogenated (S)-2-(phenylcarbamoyl)phenyl 2-acetamido-3-phenylpropanoates (3a–3k) were designed and synthesized as potential antimicrobial agents. They were evaluated in vitro against some mycobacterial, bacterial and fungal strains. These compounds were active against drug-sensitive and atypical mycobacterial strains with general MIC values from 0.25 to 16 μmol/L. The most active compounds were (S)-4-chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl 2-acetamido-3-phenylpropanoate (3i) and (S)-4-bromo-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl 2-acetamido-3-phenylpropanoate (3k) which exhibited activity against MDR and XDR-TB strains with MICs from 1 to 2 μmol/L. 3k was shown to be less cytotoxic with higher IC50. Some compounds exhibited low MICs on Gram-positive bacteria (MICs ≥ 0.98 μmol/L) and on fungi (MICs ≥ 3.9 μmol/L). [ABSTRACT FROM AUTHOR]

Abstract: The absorption and emission spectra of salicylanilide (SAN) in methanol show strong blue-shift compared with those in cyclohexane. To make clear this phenomenon, the ground (S0) and excited state (S1) proton transfer reactions in cyclohexane and in methanol solutions were investigated, respectively. In cyclohexane, the intramolecular mechanism was carried out for the isolated SAN. Whereas in methanol solution, the role of the methanol molecule in proton transfer reaction was supposed that it directly participated the reaction path, called methanol-assisted mechanism. The computational results show that barrier height for the ground state proton transfer is too high to happen, but is energetically favored in S1 for both isolated SAN and methanol-assisted system. In addition, it indicates that the hydrogen-bonding between SAN and methanol molecule can dramatically lower the barrier by methanol-assisted mechanism in S1. Herein, we also have applied a combination of the continuum dielectric and the explicit solvent model to study the spectra of SAN in methanol, which exhibit that the interaction between SAN and one methanol molecule yields a hydrogen-bonding complex responsible for the blue-shifted wavelength of absorption and emission spectra in methanol solvent. [Copyright &y& Elsevier]

Abstract: FT-IR and FT-Raman spectra of 4-chloro-2-(3,4-dichlorophenylcarbamoyl)phenyl acetate were recorded and analyzed. Synthesis and elemental analysis are also reported. The vibrational wavenumbers of the compound have been computed on the basis of density functional theory using B3LYP/6-31G* basis set. The predicted infrared intensities and Raman activities are reported. [Copyright &y& Elsevier]

Abstract: Interleukin (IL)-12p40, a subunit component of both IL-12 and IL-23, is being widely studied for its role in inflammatory disease. As part of an effort to profile cellular signaling pathways across different cell types, we report salicylanilide inhibitors of IL-12p40 production in stimulated dendritic cells. Based on a hypothesis that a desirable therapeutic profile is one that could block IL-12p40 but not IL-6 production, we engaged in directed analoging. This resulted in salicylanilides with similar IL-12p40 related potency but enhanced selectivity relative to IL-6 production. [Copyright &y& Elsevier]

Salicylanilide was detected on glass plates precoated with a 0.50 mm layer of silica gel 60 F254 (E.Merck, # 1.05744) and with a 0.25 mm layer of silica gel 60 F254 (E.Merck, # 1.05715), as well as on aluminum plates precoated with a 0.20 mm layer of silica gel 60 F254 (E.Merck, # 1.05554), silica gel 60 (E.Merck, # 1.05553), and a mixture of silica gel 60 and kieselguhr F254 (E.Merck, # 1.05567), with and without the use of brilliant green as a visualizing reagent. Spectrodensitograms of salicylanilide, with and without the use of brilliant green, on the particular chromatographic sorbents were presented. The limit of detection (detectability), detection index, broadening index, modified contrast index, densitometric visualizing index, and linearity range were used to evaluate the visualizing effects of salicylanilide. It was stated that the proposed new parameter within work, namely the densitometric visualizing index, is the objective parameter describing the visualizing effect of detected salicylanilide. [ABSTRACT FROM AUTHOR]

Abstract: Novel benzoxazepines were prepared upon esterification of biologically active salicylanilides with some N-protected amino acids. While the desired conjugates of the salicylanilides with the amino acids were obtained when sterically more demanding amino acids were used, benzoxazepines were formed as a result of a seven-exo-trig cyclization in the case of N-protected glycine and alanine. The structures of the products were confirmed by 2D NMR methods, and further transformations of the acyclic conjugates provided additional support for the proposed mechanism of cyclization. [Copyright &y& Elsevier]

Redox-active drugs are the mainstay of parasite chemotherapy. To assess their repurposing potential for eumycetoma, we have tested a set of nitroheterocycles and peroxides in vitro against two isolates of Madurella mycetomatis, the main causative agent of eumycetoma in Sudan. All the tested compounds were inactive except for niclosamide, which had minimal inhibitory concentrations of around 1 µg/mL. Further tests with niclosamide and niclosamide ethanolamine demonstrated in vitro activity not only against M. mycetomatis but also against Actinomadura spp., causative agents of actinomycetoma, with minimal inhibitory concentrations below 1 µg/mL. The experimental compound MMV665807, a related salicylanilide without a nitro group, was as active as niclosamide, indicating that the antimycetomal action of niclosamide is independent of its redox chemistry (which is in agreement with the complete lack of activity in all other nitroheterocyclic drugs tested). Based on these results, we propose to further evaluate the salicylanilides, niclosamide in particular, as drug repurposing candidates for mycetoma. [ABSTRACT FROM AUTHOR]

[Display omitted] Zika virus has emerged as a potential threat to human health globally. A previous drug repurposing screen identified the approved anthelminthic drug niclosamide as a small molecule inhibitor of Zika virus infection. However, as antihelminthic drugs are generally designed to have low absorption when dosed orally, the very limited bioavailability of niclosamide will likely hinder its potential direct repurposing as an antiviral medication. Here, we conducted SAR studies focusing on the anilide and salicylic acid regions of niclosamide to improve physicochemical properties such as microsomal metabolic stability, permeability and solubility. We found that the 5-bromo substitution in the salicylic acid region retains potency while providing better drug-like properties. Other modifications in the anilide region with 2′-OMe and 2′-H substitutions were also advantageous. We found that the 4′-NO 2 substituent can be replaced with a 4′-CN or 4′-CF 3 substituents. Together, these modifications provide a basis for optimizing the structure of niclosamide to improve systemic exposure for application of niclosamide analogs as drug lead candidates for treating Zika and other viral infections. Indeed, key analogs were also able to rescue cells from the cytopathic effect of SARS-CoV-2 infection, indicating relevance for therapeutic strategies targeting the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics—a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine—have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system. [ABSTRACT FROM AUTHOR]

The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N -monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis H 37 Ra, H 37 Rv including multidrug- and extensively drug-resistant strains, Mycobacterium avium , Mycobacterium kansasii , Mycobacterium aurum and Mycobacterium smegmatis as representatives of nontuberculous mycobacteria (NTM) and for their cytotoxic and cytostatic properties in HepG2 cells. Since salicylanilides are multi-targeting compounds, we determined also inhibition of mycobacterial isocitrate lyase, an enzyme involved in the maintenance of persistent tuberculous infection. The minimum inhibitory concentrations were from ≤0.5 μM for both drug-susceptible and resistant M. tuberculosis and from ≤0.79 μM for NTM with no cross-resistance to established drugs. The presence of halogenated salicylanilide scaffold results into an improved activity. We have verified that isocitrate lyase is not a key target, presented carbamates showed only moderate inhibitory activity (up to 18% at a concentration of 10 μM). Most of the compounds showed no cytotoxicity for HepG2 cells and some of them were without cytostatic activity. Cytotoxicity-based selectivity indexes of several carbamates for M. tuberculosis , including resistant strains, were higher than 125, thus favouring some derivatives as promising features for future development. Image 1 • Salicylanilide N -monosubstituted carbamates are highly active against mycobacteria. • MIC against multidrug-resistant mycobacteria are from 0.5 μM. • Salicylanilide carbamates are mild inhibitors of mycobacterial isocitrate lyase. • The majority of carbamates are non-cytotoxic and selective for mycobacteria. [ABSTRACT FROM AUTHOR]