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Palladium(II)-Salicylanilide complexes of the type [Pd(k2-Saln)2] (1), [Pd(k2-Saln)2(diphos)] (2-6) (diphos = dppe, dppp, dppb, dppf, and dppmS2) and [Pd(k2-Saln)2(m-dppm)] (7) were synthesized and characterized. The salicylanidate ligand (Saln-) was bonded as bidentate chelating through the O atoms of hydroxyl and carbonyl groups in complex (1), whereas coordinated as monodentate through the O atom of hydroxyl group in complexes (2-7), and the all diphosphine ligands except dppm bonded as bidentate chelating to afford a square planner geometry around the Pd(II) ion. The dppm ligand was coordinated as bidentate bridging to afford binuclear complex. The prepared complexes displayed respectable activity against the pathogen bacteria species. Complex (5) showed the highest inhibition value against all types of bacteria, compared to the other complexes and the free ligand. On the other hand, the complex [Pd(Saln)2], showed the lowest inhibition against all types of bacteria. And the inhibition sequence of complexes is as following:(5) > (4) > (2) > (3) > HSaln > (1)Calculations of density function theory (DFT) were performed at the B3LYP/6-311G(d,p) level involved in the Gaussian 09 program to inspect the optimized structures of the chelating agent and its complexes. Docking study of the ligand was performed against the proteins of bacterial strains Streptococcus pyogenes (ID: 5GOT), Escherichia coli (ID: 1C14), Staphylococcus aureus (ID: 3BL6), and Salmonella typhimurium (ID: 3V7F) by Schrodinger suite program using XP glide protocol.

The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide’s anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.

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 IC50 values ranging from 5 to 235 µM. IC50 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.

Palladium(II)-Salicylanilide complexes of the type [Pd(κ2-Saln)2] (1), [Pd(κ2-Saln)2(diphos)] (2-6) (diphos = dppe, dppp, dppb, dppf, and dppmS2) and [Pd(κ2-Saln)2(μ-dppm)] (7) were synthesized and characterized. The salicylanidate ligand (Saln−) was bonded as bidentate chelating through the O atoms of hydroxyl and carbonyl groups in complex (1), whereas coordinated as monodentate through the O atom of hydroxyl group in complexes (2-7), and the all diphosphine ligands except dppm bonded as bidentate chelating to afford a square planner geometry around the Pd(II) ion. The dppm ligand was coordinated as bidentate bridging to afford binuclear complex. The prepared complexes displayed respectable activity against the pathogen bacteria species. Complex (5) showed the highest inhibition value against all types of bacteria, compared to the other complexes and the free ligand. On the other hand, the complex [Pd(Saln)2], showed the lowest inhibition against all types of bacteria. And the inhibition sequence of complexes is as following: (5) > (4) > (2) > (3) > HSaln > (1) Calculations of density function theory (DFT) were performed at the B3LYP/6-311G(d,p) level involved in the Gaussian 09 program to inspect the optimized structures of the chelating agent and its complexes. Docking study of the ligand was performed against the proteins of bacterial strains Pseudomonas aeruginosa (ID: 3P3E), Escherichia coli (ID: 1C14), Staphylococcus aureus (ID: 3BL6), and Salmonella typhimurium (ID: 3V7F) by Auto-Dock tools to portend the best binding mode.

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 H37Rv 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.

Graphical abstract, 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’-NO2 substituent can be replaced with a 4’-CN or 4’-CF3 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.

Two series of novel salicylanilide analogues (4a-4 g) and (4h-4t) were designed, synthesized, and characterized, especially the structure of compound 4q was further confirmed by single X-ray diffraction. The inhibitory activity on polyphenoloxidase (PPO) from the cephalothorax of Chinese white shrimp (Fenneropenaeus chinensis) was evaluated. The result indicated that all the synthesized derivatives (except 4 g and 4t) exhibited moderate PPO inhibitory properties having IC50 values in the range of 0.21 ± 0.19 to 4.32 ± 0.53 mM, whereas reference inhibitor salicylic acid and 3a have IC50 values 3.93 ± 0.43 mM and 12.83 ± 0.51 mM, respectively. Specifically, 4-nitro-benzoic acid 3-(2‑hydroxy‑benzoylamino)- propyl ester (4q) exhibited the most potent PPO inhibitory activity with an IC50 value of 0.21 ± 0.19 mM. The kinetic studies of the compound (4q) demonstrated that the inhibitory effects of the compound on the PPO were belonging to competitive inhibitors. Meanwhile, the structure-activity relationship was discussed. Therefore, compound 4q could act as a PPO inhibitor with anti-browning and antimicrobial properties to be applied in the food industry.

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-2H-benzo[e][1,3]oxazine-2,4(3H)-dione and 10-phenyldibenzo[b,f][1,4]oxazepin-11(10H)-one derivatives, and investigated the effects of such compounds on RANKL-induced osteoclast formation. Among them, a salicylanilide derivative (A04) and its 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-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.

Cationic monofunctional platinum(II)-based anticancer agents with a general formula of cis -[Pt(NH 3 ) 2 (N-donor)Cl] + have recently drawn significant attention due to their unique mode of action, distinctive anticancer spectrum, and promising antitumor activity both in vitro and in vivo . Understanding the mechanism of action of novel monofunctional platinum compounds through rational drug design will aid in the further development of active agents. In this study, we synthesized and evaluated a monofunctional platinum-based anticancer agent SA–Pt containing a bulky salicylanilide moiety. The antiproliferative activity of SA–Pt was close to that of cisplatin. Mechanism studies revealed that SA–Pt entered HeLa cells more efficiently than cisplatin, blocked the cell cycle at the S-phase, and induced apoptosis. The compound bound to DNA as effectively as cisplatin, but did not block RNA polymerase II-mediated transcription as strongly as cisplatin, indicating that once the compound formed Pt-DNA lesions, the salicylanilide group was more easily recognized and removed. This study not only enriches the family of monofunctional platinum-based anticancer agents but also guides the design of more potent monofunctional platinum complexes.

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.

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 H37Ra, H37Rv 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.

The synthesis and biological evaluation of two series of salicylanilide derivatives on the EGFR and ErbB-2 tyrosine kinases inhibitory activities were conducted. Of the tested compounds those having an additional aryl group substituted on the anilino ring were active on the EGFR tyrosine kinase inhibition ( 7a – c and 13a , 13c , 13d , 13f ). The inhibitory activities were all in the low micromolar or submicromolar range. In addition, compound 13a was found to have dual inhibitory activities both on EGFR and ErbB-2 tyrosine kinases (1.654 ± 1.280 and 7.134 ± 1.265 μmol/L).

A series of novel sulfonamides containing 5-chloro-2-hydroxybenzaldehyde or 5-chloro-2-hydroxybenzoic acid scaffolds were designed, synthesized and characterized by IR, 1 H NMR and 13 C 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.

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 IC 50 . Some compounds exhibited low MICs on Gram-positive bacteria (MICs ≥ 0.98 μmol/L) and on fungi (MICs ≥ 3.9 μmol/L).

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 0.1 μg/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 IC(50) values below 10 μM against transglycosylase were identified. The non-carbonhydrate scaffold reported in this study suggests a new direction for development of bacterial transglycosylase inhibitors.

The preparation of new prodrug forms of anti-tuberculosis active salicylanilide esters with amino acids led to an unexpected rearrangement. The isolation and the structure determination of 2-(5-chloro-2-hydroxyphenyl)-3-(3-chlorophenyl)-5-substituted-3,5-dihydro-4H-imidazol-4-ones unambiguously confirm one of the two proposed reaction mechanisms.

A series of novel, highly antimicrobial salicylanilide esters of N -protected amino acids were synthesized and characterized. Their in vitro antimicrobial activity against eight fungal strains and Mycobacterium tuberculosis was determined. The compounds had the highest level of activity against Aspergillus fumigatus , Absidia corymbifera and Trichophyton mentagrophytes , and these levels were higher than that of the standard drug fluconazole. In addition, three compounds showed interesting antituberculosis activity, with inhibition ranging from 89% to 99%. ( S )-4-Chloro-2-(4-trifluoromethylphenylcarbamoyl)-phenyl 2-benzyloxy-carbonylamino-propionate had the highest level of both antifungal and antimycobacterial activity. The structure–activity relationships of the new compounds are discussed.

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.

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.

Salicylanilide and 37 of its analogs were applied topically to mice as candidate chemoprophylactic agents against Schistosoma mansoni cercarial penetration. The compounds were solubilized in absolute methanol, dimethyl sulfoxide, or isopropanol at concentrations not exceeding 1.25% W/V. The tails of the mice of each experimental group were treated by immersion for 5 min in the test compound solution or in the vehicle. The treated tails of 5 mice from each group were washed for 30 min in flowing tap water 3-4 hr after compound application. Tails of all mice were then exposed to approximately 100 cercariae by tail immersion for 1 hr, 24 hr after treatment. The portal veins were perfused 49 days after exposure and worm burdens were determined. The protective capacity of each compound was calculated by comparing the reduction of the mean worm burdens of the compound treated mice to the worm burdens of those treated with only the vehicle and expressing the resulting value as percentage protection. Of the 38 compounds tested, 20 provided 98% or better protection if the treated tails were not washed before exposure to cercariae. Of these 20 active compounds, 16 provided 98% or better protection from infection by S. mansoni cercariae even after the mouse tails were subjected to the 30 min wash.

The electronic absorption spectra of salicylanilide and eight of its derivatives (with substituents o -OCH 3 , o -Cl (a), m -OH, m -OCH 3 , p -Cl, p -OH, p -OCH 3 and p -CH 3 ) have been determined in various solvents and in buffers. It was found that the structure is dominated by the formation of intramolecular hydrogen bonding between the hydroxyl and the carbonyl groups rather than that between the hydroxyl and imino groups. For (a). an additional hydrogen bond occurs between the imino hydrogen and the chlorine in the 2′-position. Intramolecular charge transfer occurs through the non-bonding electrons on the imino group as donor, rather than through the aniline group, and the carbonyl group as acceptor. In strongly polar solvents, the enol structure occurs.

Summary One of the great problems in keeping petroleum products is their degradation by microorganism, particularly fungi, actinomycetes, and bacteria. In the presence of these microorganisms, in combination with organic materials and other impurities, are formed sludges. Petroleum products, especially those used in jet fuels, are required to be completely free from water and microbial sludges. The preferable microbial inhibitors, used in keeping petroleum products, are: 2,4-dimethoxy benzaldehyde, bromoacetic acid, dimethylamine borane, ethyldidene diacetate, tri-n-butyl borate, sodium tetraborate, sulphanilamide, iso-butyl, resorcinol, amyl resorcinol, hexyl resorcinol, octyl resorcinol p-chloro-m-cresol, salicylanilide, 2,4,5-trichlorophenol, 2,4,6-trichlorophenol, 3-methoxy propionaldehyde, 2-bromo-ethyl-l,2-propanediol or mixtures of these microbial inhibitors. Beside the addition of microbial inhibitors, tanks used in keeping petroleum products must be clean and furnished iniside with an inert material. Tanks are preferably kept in places of low relative humidity in order to avoid water.

Formation of an iron(III)—rafoxanide chelate provides the basis for a direct spectrophotometric method for the quantification of this halogenated salicylanilide in the concentration range 9.00 × 10 -4 –7.00 × 10 -3 M. The intense visible charge-transfer absorption band of the complex at 505 nm represents a general spectrophotometric characteristic that is useful for other substituted salicylanilides. The maximum absorption wavelength of the charge-transfer band shifts monotonically to higher energy in an order consistent with Hammett substituent constants.

Incorporation of 32Pi into organic phosphate by mitochondria of Cotugnia digonopora was supported maximally by malate. Fumarate and succinate induced lower but significant production of ATP. Pyruvate, alpha-ketoglutarate and oxalacetate proved to be poor substrates and citrate and isocitrate had no effect. A net phosphorylation of approximately 2 mol of ADP was observed for each mol of CO2 liberated from malate or succinate. In contrast, with pyruvate, in spite of a high rate of decarboxylation, the production of ATP was extremely low. 2,4-Dinitrophenol inhibited phosphorylation. All anthelmintics examined interfered with the mitochondrial phosphorylation of ADP, with maximum inhibition by salicylanilide compounds. The anticestodal activity of the latter group of compounds, niclosamide for example, may, therefore, be attributed to their ability to inhibit mitochondrial phosphorylation.

The examination of a comprehensive set of halogen substituted salicylanilides by infra-red and ultraviolet spectroscopy shows that the molecules substituted in the 2′ position of the anilide ring form a special sub-group of salicylanilides because of their intramolecular NH—Halogen bonding. Even so, G eiger 's suggested structures for the α and β forms are probably correct. The primary reason for the excessive steric hindrance which causes the breakage of the chelate ring is the bonding of the proton accepting solvent to the NH group. The probability factor for the breakage of the chelate ring depends on the acidity of the OH group and the bridge strengthening properties of the substituents on the anilide ring. A possible structure for the salicylanilide ion is suggested.

In studies on the production of salicylanilide an assay method for salicylanilide itself and methods for the identification and determination of impurities were required. In addition to the starting materials (aniline and salicylic acid) four impurities were isolated and identified : salicylsalicylanilide, ar -phosphonosalicylanilide, 4-hydroxybenzanilide, and the p -hydroxybenzoate of 4-hydroxybenzanilide. Salicylanilide was assayed by direct ultraviolet spectrophotometry in basic methanol solution. Salicylic acid and phosphonosalicylanilide were extracted from a salicyl-anilide-chloroform solution with dilute sodium bicarbonate solution. Aniline and salicylsalicylanilide were determined by passing a methanolic solution of salicylanilide through Dowex 2, acetate-form, resin. Aniline, and methyl salicylate resulting from alcoholysis of salicylsalicylanilide, were contained in the eluate. All impurity concentrations were determined by ultraviolet spectrophotometry.

The closely related complexing agents, salicylic acid, salicylaldehyde, ethylsalicylate, salicylamide, salicylanilide, salicylalcohol, salicylhydroxamic acid, salicyloylhydrazide, salicylaldoxime, salicylaldazone, salicylamidoxime, salicylamine, salicylnitrile, salicylanil and N-methylimine-salicylaldehyde, have been studied to evaluate the relation between the first stability constants for the complexes of Cu2+, Ni2+, Zn2+ and Mg2+ (ions of equally spaced electronegativities) with some of these reagents while of Cu2+ with all of them, and pkOH values corresponding to the dissociation of phenolic hydrogens of the reagents. The metal-ligand stability constants have been determined at 30° ± 0·1° by the Bjerrum-Calvin pH-titration technique as adapted by Irving and Rossotti. An aqueous-dioxane medium, 75% in dioxane by volume and 0·1 M in NaClO4, was used with concentrations of metal ion ∼10−3 M and reagent = 4 × 10−3 M.

Synthesis and germicidal activity in the presence of detergents are reported for halogenated derivatives of the following classes of compounds: salicylanilides, homologs of salicylanilide, salicylanilides with substituents other than halogen or alkyl groups, other amides of salicylic acid, anilides of other acids, and Schiff's bases of salicylaldehyde. The anilides were prepared by first halogenating the acid or aniline in the desired manner and then reacting these products to form the amide linkage. In some cases, when the position of the incoming halogen would be unambiguous, the anilides were further halogenated to form new products. Bactericidal effectiveness and skin substantivity of the products were evaluated using filter paper and skin disk substantivity tests in the presence of soap or detergent. High activity in soap was shown by salicylanilides halogenated in these positions: 4′,5; 2′,4′,5; 3,4′,5; 3′,4′,5; 4,4′,5; 2′,3,4′,5; 3,3′,4′,5; 2′,3,4′,5,5′. Certain homologs and nitro-derivatives also possessed high activity.

Thianaphthene-2-carboxylic acid, thianaphthene-2-carboxamide and nineteen substituted thianaphthene-2-carboxamides were prepared. All of the compounds were screened for their antifungal activity against Trichophyton rubrum and those compounds which appeared to be equal to or more active than undecylenic acid were tested against three other pathogenic fungi. The in vitro activity of the compounds was compared to the activity of three known antifungal agents: undecylenic acid, salicylanilide, and 5-chloro-8-hydroxyquinoline. Of all of the compounds tested, N-(2-methylpiperidyl)-thianaphthene-2-carboxamide, N-cyclohexylthianaphthene-2-carboxamide, and N-morpholinylthianaphthene-2-carboxamide were the most active against all four of the fungi.

The ultraviolet spectrum of salicylanilide reveals various absorption bands, with wavelength and intensity that vary considerably in different solvents. Such an effect is attributed to the occurrence of equilibrium between rotational isomers and ionization. On the basis of this interpretation and by comparing the spectrum with those of salicylic acid and of salicylamide, an assignment of the main bands is proposed.

The dissociation constant of salicylanilide has been determined from measurements on the ultraviolet absorption spectrum.

Ultraviolet energy of 360nm wavelength required to elicit threshold erythema varied from 1200–4000 mj/cm2 in three patients sensitive to 4'5-dibromsalicylanilide after bathing with the offending salicylanilide-containing soap. Calculations based on these values, previously determined action spectra, and representative solar emission spectra indicate a greatly shortened reaction time of sensitive patients in sunlight.

Liquid trypticase soy broth media was buffered with Prideaux and Ward's universal buffer to neutral and basic pH levels (pH 7 to 10 inclusive). Preservative solutions of various concentrations were added to tubes containing the media, After inoculation of the tubes with a slurry obtained from soil samples suspended in water, these preparations were examined for preservative effectiveness over a 6-month period. In most cases preservative effectiveness varied with pH alteration. The preservative activity ranged from negligible with cinnamic acid and some of its derivatives, the amides of bromal and dichloroacetaldehyde, sorbic acid and dehydroacetic acid-sodium, to fair in the case of parabens and salicylanilide, to good with cetrimide, chlorophenesin, vanillic acid esters, hexylresorcinol, hexachlorophene, and phenylethanol.

Carboxin (5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxanilide) was tested for its effect on the activities of mitochondria from several fungi, pinto beans and rat liver. Succinate oxidation by mitochondria from the sensitive fungus Ustilago maydis was inhibited by low concentrations of carboxin, the K i being 0.32 μM. The inhibition was of a noncompetitive nature. Succinate oxidation was also inhibited in the mitochondria from other sources but not to the extent as in those from U. maydis . Carboxin had little effect on the oxidation of reduced nicotinamide adenine dinucleotide. The dioxide of carboxin, oxycarboxin, was not as effective in inhibiting succinate oxidation as was carboxin, but was more effective than the monoxide. Carboxin did not appear to uncouple oxidative phosphorylation in the presence of succinate in tightly coupled rat liver mitochondria but did decrease the respiratory control ratio. Carboxin was ineffective in releasing oligomycin inhibition in coupled rat liver mitochondria while dinitrophenol and salicylanilide were effective in this respect. It is believed that carboxin inhibits mitochondrial respiration at or close to the site of succinate oxidation and does not greatly affect the remaining portion of the electron transport system or the coupled phosphorylation reactions.

A new anthelmintic, 3, 5-diiodo-3’-chloro-4’-(p-chlorophenoxy) salicylanilide, or rafoxanide, has been found highly effective in the treatment of Haemonchus contortus infections in sheep. The compound, given as a drench at 5 or 10 mg./kg., was highly effective when administered 8 days after experimental infection. When administered 22 days after experimental infection, a dosage of 10 mg./kg.—the only dosage tested—was highly effective. At either 8 or 22 days after infection, greater than 95% efficiency against a thiabendazole=tolerantHaemonchus (K-strain) was obtained with either 5 or 10 mg. of rafoxanide added to 44 mg. of thiabendazole per kg. of bodyweight. The new drug was fully compatible with thiabendazole.

SUMMARY A new anthelmintic, 1,5-diiodo-3’-chlro-4’-(p-chlorophenoxy)-salicylanilide, was virtually 100% effective in killing; immature (6-week-old) Fasciola hepatica in sheep, when given orally at a dosage of 10–15 mg./kg. No toxic effects were observed in the treated animals. The potency of the compound was markedly affected by the type of formulation used.

In sheep, 3-tert butyl 4’5 dicyano 6 methyl 2’ bromo salicylanilide was found to be active against mature Fasciola hepatica down to 0·2 mg/kg but was toxic at 1·5 mg/kg.