Substituted salicylanilides. III. New salicylanilides and related compounds with antimicrobial activity.
Explore the source record for details and available documents.
Analgesics↗
SEARCH · PubMed Health
Results for “Salicylanilides”
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Search for new chemotherapeutics. I. Determination of the bacteriostatic and fungistatic effects of salicylanilide and certain substituted salicylanilides by means of a diffusion method in solid media with and without horse blood added.
Explore the source record for details and available documents.
Aniline Compounds↗
5-(Alkylsulfonyl)salicylanilides as potential dental antiplaque agents.
A series of 22 5-(alkylsulfonyl)salicylanilides was synthesized and evaluated for in vitro antibacterial and antiplaque activity against Actinomyces viscosus and Streptococcus mutans, adherent microorganisms implicated in periodontal disease and dental caries. The minimum inhibitory concentrations of 25 salicylanilides (including 5-acyl-, 5-alkyl-, and 5-(alkylsulfonyl)-4'-bromo- and -4'-(trifluoromethyl)salicylanilides) were found to correlate (r = 0.94) with estimated log D values. Several salicylanilides, such as 5-(decylsulfonyl)- and 5-(dodecylsulfonyl)-4'-(trifluoromethyl)salicylanilides (15 and 19) were found to exhibit high levels of in vitro antibacterial and antiplaque activity against A. viscosus and S. mutans.
Actinomyces↗
Structural requirements of salicylanilides for uncoupling activity in mitochondria: quantitative analysis of structure-uncoupling relationships.
The uncoupling activities of more than 20 salicylanilides were measured in rat liver mitochondria. The activities, expressed as the minimum concentrations required for full release of state-4 respiration, ranged over three orders of magnitude. The acid dissociation constant, pKA, and the partition coefficient between octanol and water (Poct) of some of the salicylanilides were determined. These two parameters were found to be well expressed in terms of the Hammett constant, sigma, and the hydrophobic substituent coefficient, II, respectively. The pKA and log Poct values of all the salicylanilides were predicted according to these relationships. Furthermore, the capacity factor, k', on high-performance liquid chromatography was determined on glyceryl-coated-controlled pore glass (gly-CPG). Values of log k' correlated well with those of log Poct. The uncoupling activities of the salicylanilides were analyzed in terms of these three parameters. Both hydrophobic and electron-withdrawing properties were found to be essential for induction of potent uncoupling activity. The correlations using log k' were better than those using log Poct.
Animals↗
A comparison of the metabolism and elimination of benzanilide and salicylanilide in the rat.
1. The metabolism and elimination of benzanilide and salicylanilide in rats were compared. 2. For both compounds, greater than 70% dose was excreted in urine with 20% in faeces, in 3 days. 3. With [14C]benzanilide and [14C]salicylanilide, 40% and 35% respectively of the 14C was excreted in the bile in 24 h. 4. Benzanilide was metabolized to 4'-hydroxybenzanilide (24%), 2-hydroxybenzanilide (salicylanilide, 19%) and 2'-hydroxybenzanilide (13%), with small amounts of 4-hydroxybenzanilide. 5. Salicylanilide was excreted unchanged (56%) with small amounts of the 5-hydroxy and 4'-hydroxy-derivatives. 6. All metabolites were present as glucuronide conjugates; the free aglycones were not found.
Anilides↗
The pharmacology of halogenated salicylanilides and their anthelmintic use in animals.
The halogenated salicylanilides are a large group of compounds developed mainly for their antiparasitic activity in animals. Several halogenated salicylanilides with potent antiparasitic activity have been synthesised of which only closantel, niclosamide, oxyclozanide, rafoxanide and resorantel are commercially available. Closantel and rafoxanide, which represent the most important drugs in the group, are used extensively for the control of Haemonchus spp. and Fasciola spp. infestations in sheep and cattle and Oestrus ovis in sheep in many parts of the world. Niclosamide is used extensively for its anticestodal activity in a wide range of animals. Antiparasitic activity of the halogenated salicylanilides has also been demonstrated against a large number of other internal parasites, in particular haematophagous helminths, and external parasites including ticks and mites, in a variety of animal species. Several cases of toxicity and mortality have been reported for closantel and rafoxanide in sheep and goats. Their unique pharmacokinetic behaviour appears to play an important role in the efficacy and safety of these compounds. The chemical and physical characteristics, mode of action, pharmacokinetics, antiparasitic activity and toxicity of the halogenated salicylanilides in animals are reviewed.
Animals↗
Glutathione S-transferases as markers of salicylanilide resistance in isolates of Fasciola hepatica.
A possible link between the level of glutathione S-transferase (GST, E.C. 2.5.1.18) activity and the development of salicylanilide resistance in Fasciola hepatica was investigated. Various isolates of F. hepatica with varying susceptibilities to salicylanilides were isolated and maintained in the laboratory. Individual flukes of these isolates were surveyed for their level of GST activity and a correlation between the level of GST activity and drug efficacy was found. In contrast to most other studies, a decrease in GST activity was associated with an increase in drug resistance. Evidence was collected to show that this may be a selective process since flukes which had survived exposure to rafoxanide and closantel in vivo (in sheep) had lower activity levels of GST than flukes from untreated sheep. Treatment with other flukicides (oxyclozanide, luxabendazole and triclabendazole) did not have this effect. Furthermore, in vivo treatment with closantel induced selection of particular isoenzymes in different isolates of F. hepatica having different degrees of susceptibility to closantel. However, no single isoenzyme or isoenzyme profile was associated with resistance and, in total, up to 8 different isoenzymes could be present in a single isolate. Thus, GST has some potential as a marker enzyme for salicylanilide resistance in F. hepatica. However, the precise role of GST in resistance is unclear and the extensive inter- and intra-isolate variation in activity levels and isoenzyme characteristics of this enzyme indicate the need for considerably more study before application in field situations.
Animals↗
Salicylanilides as inhibitors of the protein tyrosine kinase epidermal growth factor receptor.
A pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase and a putative binding mode of 4-anilinoquinazoline suggest that a salicylic acid function could serve as the pharmacophore replacement of a pyrimidine ring. Superpositions by CAMM of salicylanilides with the potent EGFR tyrosine kinase inhibitor 4-[(3'-chlorophenyl)amino]-6,7-dimethoxyquinazoline showed that salicylanilides should act as tyrosine kinase inhibitors. A series of salicylanilides was synthesized and their inhibitory activity against tyrosine kinases determined. Some of them indeed proved to be potent and selective EGFR tyrosine kinase inhibitors. The most potent ones being 28, 16, 20, 6, and 15, with IC(50) in the 23-71 nM range.
Enzyme Activation↗
[Salicylanilides: still a potential antibacterially active group].
The review presents a survey of potential biologically active salicylanilides, focusing particularly on their antibacterial activity. Emergence of bacterial resistance to a large number of antibacterial agents represents a major world-wide problem. On that account, perpetual attention is paid to the preparation of new bioactive antibacterial compounds. Salicylanilides belong to the group of compounds that have shown activity against gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, the strains representing the most significant problem in clinical practice. In 1998, a new mechanism of their action was proposed. Salicylanilides are inhibitors of two-component regulatory systems in bacteria. Electron-accepting substituents on the salicylic and hydrophobic groups on the anilide ring are most essential for the activity, but other electronic and structural parameters may also play an important role. Our aim, based on SAR analysis, is to develop new active drugs esterified by amino acid and later peptides. Furthermore, analogues carrying the hydroxybenzamide moiety may uncouple oxidative phosphorylation.
Anti-Bacterial Agents↗
Acryloylamino-salicylanilides as EGFR PTK inhibitors.
A series of acryloylamino-salicylanilides were synthesized as inhibitors of EGFR PTK. A strategy of pseudo six-membered ring formed through intramolecular hydrogen bonding in salicylanilides is employed to mimic the planar pyrimidine ring of quinazoline EGFR inhibitors. Acrylamido moiety is incorporated to target the Cys-773 of EGFR specifically. Some of the obtained compounds exhibited good activity as EGFR inhibitors.
Crystallography, X-Ray↗
Spectroscopic studies of cutaneous photosensitizing agents--XIV. The spin trapping of free radicals formed during the photolysis of halogenated salicylanilide antibacterial agents.
Several antibacterial halogenated salicylanilides, including 3,3',4',5-tetrachlorosalicylanilide (TCSA) and 3,4',5-tribromosalicylanilide (TBSA) are known to cause photoallergy. We have carried out photochemical and spin trapping studies to determine whether free radicals may be involved in the photoallergic response. Irradiation (lambda greater than 300 nm) of TCSA in buffered (pH 7.4) 50% ethanol resulted in the rapid loss of the 3-chloro atom, followed by the much slower release of 5- and then the 4'-chloro atoms to give 3'-chlorosalicylanilide as a stable photoproduct. Under the same conditions TBSA successively lost the 3-, 5- and 4'-bromine atoms to give salicylanilide. When TCSA or TBSA were irradiated (lambda = 356 nm) in buffered (pH 7.4) 50% ethanol containing 2-methyl-2-nitrosopropane (MNP) only solvent-derived free radicals were detected. However, irradiation (lambda = 356 nm) of TCSA and MNP in 0.1 N NaOH generated an ESR spectrum consisting of a broad triplet (aN = 15.6 G). This spectrum was attributed to the adduct formed by the reaction of MNP with the aryl radical generated by the loss of a chlorine atom from the sterically hindered 3-(or 4'-)-position. Under the same conditions TBSA initially generated a broad triplet (aN = 15.5 G) similar to that observed for TCSA. However, upon further irradiation a 21-line spectrum (aN = 14.4 G, a2H = 2.0 G and a2H = 0.9 G) appeared.(ABSTRACT TRUNCATED AT 250 WORDS)
Anti-Bacterial Agents↗
[Action of new class of substituted salicylanilides on ion conductivity of lipid membranes].
A new class of high-activity substituted salicylanilides has been studied in bilayer lipid membranes (BLM). Very low concentrations of these substances are shown to increase the BLM d. c. electroconductivity. Approximately Nernts value of transmembrane potential was measured when ten-fold pH gradient was produced. The experiments favour the opinion that these substituted salicylanilides act as protonophores. The obtained data suggest that DMSO facilitates its transport through the lipid bilayer. Furthermore, two different mechanisms are shown to take place in the H+ transport, when DMSO or water has been used as a solvent for these substances. The results suggest that other processes which are investigated now are involved.
Dimethyl Sulfoxide↗
[Biological effects of substances similar to salicylanilides. 3-aryl-2H, 4H-benz(e)(1,3)oxazine-2, 4-diones and thiosalicylanilides].
The review paper is the first collected communication about the biological activity of 3-aryl-2H,4H-benz(e)(1,3)oxazine-2,4-diones and thiosalicylanilides. The substances of the above mentioned structures show a number of biological activities (antibacterial, antituberculous, antimycotic, anthelmintic, molluscocidal, neuroleptic, analgesic and anti-inflammatory) which can be modelled by structural changes. Only very few of them have been hitherto introduced into practice as anthelmintic agents, or agents with a special purpose (destroying the sea lamprey in Canadian lakes). In the group of 3-aryl-2H,3H-benz(e)(1,3)-oxazine-2,4-diones, i.e. substances developed from salicylanilides by the action of alkyl-chloroformiates, antibacterial activity is reported in refs. 3-12, antituberculous activity in refs. 13, 14, antimycotic activity in refs. 5, 6, 9, 12, 15, 16, anthelmintic activity in refs. 6,917-20, molluscocidal activity in refs. 6, 21, analgesic and anti-inflammatory activity in refs. 22-24, herbicidal activity in refs. 25, 26, allergenic activity in ref. 27. In the group of salicylanilides, antibacterial activity is reported in refs. 28-37, antimycotic activity in refs. 28-36, antiprotozoal activity in ref. 35, anthelmintic activity in refs. 28-40, 49, molluscocidal activity in refs. 7, 28-36. The present paper furthermore sums up the papers concerned with the toxicities of the above-mentioned agents. Though the peak of research of the groups of the above-mentioned structure was in the 1960s and 1970s, papers investigating their biological activity can be encountered also at present.
Analgesics↗
Photocontact dermatitis to halogenated salicylanilides and related compounds. Our experience between 1967 and 1975.
We evaluated the role of the halogenated salicylanilides and related compounds in the development of photocontact dermatitis between 1967 and 1975 as seen at the University of California, San Francisco clinic. During this period positive photopatch tests to at least one of these chemicals were detected in 98 patients. Prior to 1967, tetrachlorosalicylanilide and the brominated salicylanilides were the most common offenders. Declines occurred in number of patients with positive photopatch tests and patch tests to these agents as well as the number of patients tested to these agents during this period; ie, almost three times as many people were tested and four times as many had positive photopatch tests in the last six months of 1967 as compared to the first nine months of 1975. The most striking reduction in numbers of patients with positive tests occurred after 1968, but the most notable reduction in the total number of positive photopatch tests occurred after 1970. We concluded that these results were most likely due to removal from the market of the more potent photosensitizing chemicals and increased physician familiarity with the disease process.
Adult↗
Relationship between the structure and antimycobacterial activity of substituted salicylanilides.
A series of 143 salicylanilides substituted in positions 4 and 5 and in positions 3' and 4' was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. To describe the structure-antimycobacterial activity relationships (QSARs), an approach based on the combination of the Free-Wilson and Hansch methods was employed (the substituent constants were used in the case of the substituents on the phenyl ring; indicator parameters were used for the substituents on the acyl moiety). The relationships between the antimycobacterial activity and physico-chemical parameters of all substituents were also explored. The quadratic representation of lipophilicity parameters did not lead to significant correlations.
Anti-Bacterial Agents↗
Synthesis of furo-salicylanilides and their heterocyclic derivatives with anticipated molluscicidal activity.
The synthesis of new furo-salicylanilides and their heterocyclic derivatives is described. Twenty-three compounds were screened for their molluscicidal activity against Biomphalaria alexandrina snails, the intermediate host of Schistosoma mansoni. Five of the tested compounds showed no activity, while eighteen compounds showed strong to moderate activity using bayluscide as a reference.
Animals↗
The oriented development of antituberculotics: salicylanilides.
On the basis of our previous results 22 salicylanilides were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. The Free-Wilson method was used to evaluate structure-antimycobacterial activity relationships. 4-Chloro-N-(4-propylphenyl)salicylamide and 5-chloro-N-(4-propylphenyl)salicylamide were selected for preclinical studies.
Antitubercular Agents↗
Cinnamoylnitrile-, pyran-, and pyranopyrazole-derivatives containing the salicylanilide moiety with anticipated molluscicidal activity.
The reaction of new cinnamonitriles containing the salicylyl moiety with active methylene reagents leads to the formation of the corresponding heterocycles. Their reaction with aniline yields the corresponding salicylanilide derivatives. The obtained pyrans and anilides were tested for molluscicidal activity.
Acrylonitrile↗