Muriel Gershon

Synergistic Mixtures of Fungitoxic Monochloro and Dichloro-8-Quinolinols against Five Fungi

Fourteen mono- and dichloro-8-quinolinols were tested against five fungi (Aspergillus niger, A. oryzae, Myrothecium verrucaria, Trichoderma viride, and Mucor circinelloides) and compared with the fungitoxicity of 8-quinolinol in Yeast Nitrogen Base containing1% D-glucose and 0.088% L-asparagine. All of the compounds were more fungitoxic than 8-quinolinol except for the surprising activity of 8-quinolinol against A. oryzae. Mixtures of the MICs of monochloro- and dichloro-8-quinolinols in which the halogens were in different positions of the quinoline ring showed synergism. Comparable mixtures in which one position of each compound was occupied by the same halogen showed additive activity. In a different study we showed that 3,5,6-, 3,5,7-, 4,5,7-, and 5,6,7-trichloro-8-quinolinols were not toxic to M. circinelloides, whereas the combinations of the correspondingly substituted mono- and dichloro-8-quinolinols as well as 3,6-dichloro- and5,7-dichloro-8-quinolinols were inhibitory. This indicated that a steric factor can be involved in affecting fungitoxicity.

Antifungal activity of substituted 8-quinolinol-5- and 7-sulfonic acids: a mechanism of action is suggested based on intramolecular synergism.

Abstract8-Quinolinol-5-sulfonic acid was nearly devoid of antimicrobial activity, due to what was believed to be an unfavorable partition coefficient. Since twenty six 8-quinolinol-5- and 7-sulfonic acids were available from our previous work, they were tested against six fungi. The 7-chloro and 7-bromo-5-sulfonic acids and the 5-chloro and 5-bromo-7-sulfonic acids showed fungal inhibition within one order of magnitude of that of 8-quinolinol. It is suggested that a nonchelating mechanism is in part responsible for this fungi toxicity. Five additional 5-sulfonic acids with chlorine in positions 3-, 6-, 3,6-, 3,7-, and 6,7- that were suitable for studies in synergism became available more recently. The enhanced activities of the dichlorosulfonic acids over the correspondingly substituted monochlorosulfonic acids is attributed to intramolecular synergism.

Reexamination of the thermolytic rearrangement of 4-halophenyl azides to 2-aminophenols and other products

SummaryThe halogenation of derivatives of 2-aminophenol with N-chloro- and N-bromosuccinimides at ambient temperatures in acetic acid was studied. With the necessary compounds available, a reexamination of the thermolytic rearrangement of 2-halophenyl azides to 2-aminophenols and other products was undertaken. It is certain that the rearrangement of 4-halophenyl azides to 2-aminophenols occurs but the products identified in this study differ significantly from those reported previously by Suschitzky et al. (1963, 1966).ZusammenfassungEs wurde die Halogenierung von 2-Aminophenol-Derivaten mit N-Chlor- und N-Bromsuccinimid bei Raumtemperatur in Essigsäure untersucht. Mit den zur Verfügung stehenden Verbindungen konnte eine Neuuntersuchung der thermolytischen Umlagerung von 4-Halogenphenylaziden zu 2-Aminophenolen und anderen Produkten unternommen werden. Diese Umlagerung findet sicherlich statt, allerdings differieren die dabei beobachteten Produkte signifikant von denen, die Suschitzky et al. 1963 und 1966 beschrieben.

Preparation and Fungitoxicity of Some Dichloro-8-Quinolinols

Summary. 2,5-, 3,5-, 3,7-, 4,5-, 5,6-, und 6,7-Dichloro-8-quinolinols were prepared and tested along with their 3,6- and 5,7-analogues against six fungi (Aspergillus niger, A.oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, and Trichophyton mentagrophytes) in Sabouraud dextrose broth. Most of the compounds were strongly antifungal, inhibiting five of the fungi below 1 μg/ml. This activity is attributed to intramolecular synergism. M. cirinelloides was inhibited less by these compounds.Zusammenfassung. 2,5-, 3,5-, 3,7-, 4,5-, 5,6-, und 6,7-Dichlor-8-chinolinole wurden dargestellt und zusammen mit ihren 3,6- und 5,7-Analoga gegenüber sechs Pilzen (Aspergillus niger, A. oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, and Trichophyton mentagrophytes) auf Sabouraud-Dextrose-Nährboden getestet. Die meisten Verbindungen zeigten starke fungistatische Wirkung mit einer Hemmkonzentration unterhalb 1 μg/ml. Diese Aktivität wird einer intramolekularen Synergie zugeschrieben. M. cirinelloides wurde durch diese Verbindungen weniger stark gehemmt.

Evidence of Steric Factors in the Fungitoxic Mechanisms of 8-Quinolinol and Its 2-, 3-, 4-, 5-, 6- and 7-Chloro and Bromo Analogues

SummaryA study was made of the fungitoxicity of 2-, 3-, 4-, 5-, 6- and 7-chloro and bromo-8-quinolinols againstAspergillus niger,A. oryzae,Myrothecium verrucaria,Trichoderma viride andTrichophyton mentagrophytes in Sabouraud dextrose broth and in Yeast Nitrogen Base supplemented with 1%D-glucose and 0.088%L-asparagine. Based on the presence or absence of synergism between pairs of substituted 8-quinolinols and reversal or nonreversal of toxicity byL-cysteine or N-acetyl-L-cysteine, the following conclusions were reached: (1) substituents on the quinoline ring change the site(s) of action of the toxicant; (2) the sites of action of the 5-, 6-, and 7-chloro-8-quinolinols are different from each other and from 8-quinolinol and its 2-, 3-, and 4-chloro analogues, and the same is true for the corresponding bromo compounds; (3) 8-quinolinol and its 3- and 4-chloro and bromo analogues appear to share common sites of action; (4) for good antifungal activity the 2 position of the ring must not be substituted by sterically bulky groups; (5) the geometry of the binding sites of action are not so constrained that they cannot accommodate the analogously substituted chloro- and bromo-8-quinolinols.ZusammenfassungEs wurde eine Studie der Fungitoxizität von 2-, 3-, 4-, 5-, 6- und 7-Chlor- und-Brom-8-chinolinol gegenüberAspergillus niger,A. oryzae,Myrothecium verrucaria,Trichoderma viride undTrichphyton mentagrophytes in Sabouraud Dextrose Nährmedium und in Hefe-N-Base mit 1%D-Glucose und 0.088%L-Asparagin unternommen. Auf der Basis des Zutreffens oder der Abwesenheit eines Synergismus zwischen Paaren von substituierten 8-Chinolinolen und der Umkehrung oder Nichtumkehrung der Toxizität durchL-Cystein oder N-Acetyl-L-cystein wurden folgende Schlußfolgerungen abgeleitet: (1) Substituenten am Chinolin-Ring ändern die Aktionsstelle(n) des Toxikans; (2) Die Angriffsstellen der 5-, 6- und 7-Chlor-8-chinolinole sind untereinander und von 8-Chinolinol und seinen 2-, 3- und 4-Chlor-Analogen verschieden, wobei das auch für die entsprechenden Brom-Verbindungen gilt; (3) 8-Chinolinol und seine 3- und 4-Chlor- und -Brom-Analogen scheinen gemeinsame Aktionsstellen zu teilen; (4) für eine gute antifungale Aktivität darf die 2-Position des Rings nicht mit sterisch anspruchsvollen Gruppen besetzt sein; (5) Die Geometrie des Bindungsstellen der Wirkung ist nicht so gespannt, daß nicht sowohl analoge Chlor- oder Brom-8-chinolinole Platz finden.

Preparation and fungitoxicity of 3,6-dichloro-and 3,6-dibromo-8-quinolinols

Summary3,6-Dichloro- and 3,6-dibromo-8-quinolinols were prepared by direct halogenation of 8-nitroquinoline by N-halosuccinimide in acetic acid or by halogenation of the corresponding 6-halo-8-nitroquinoline prepared via aSkraup reaction. The nitro group was reduced to amino and the amine was hydrolyzed to the phenol in 70% sulfuric acid at 220°C. The fungitoxicity of 3,6-dichloro- and 3,6-dibromo-8-quinolinols, as well as intermediates in their preparation, againstAspergillus niger, Aspergillus oryzae, Myrothecium verrucaria, Trichoderma viride, andMucor cirinelloides was determined. 3,6-dichloro-8-quinolinol is the most fungitoxic analogue of this class of compounds observed to date.Zusammenfassung3,6-Dichlor- und 3,6-Dibrom-8-chinoline wurden durch direkte Halogenierung von 8-Nitrochinolin mit N-Halogensuccinimid in Essigsäure oder durch Halogenierung der entsprechenden nachSkraup synthetisierten 6-Halogen-8-nitrochinoline hergestellt. Die Nitrogruppe wurde zum Amin reduziert und die Aminofunktion in 70% iger Schwefelsäure bei 220°C zum Phenol hydrolysiert. Die Fungitoxizität der 3,6-Dichlor- und 3,6-Dibrom-8-chinoline und jene der bei ihrer Herstellung auftretenden Zwischenstufen gegenAspergillus niger, Aspergillus oryzae, Myrothecium verrucaria, Trichoderma viride undMucor cirinelloides wurde bestimmt. 3,6-Dichlor-8-chinolin ist der derzeit stärkste bekannte fungitoxische Vertreter dieser Substanzklasse.

Antifungal activity of halophenols and halonitrophenols

SummaryThirty one compounds (phenol; its 12 possible monohalo analogues; 18 nitrophenols (2- and 4-nitrophenols, 4-, 5-, and 6-halo-2-nitrophenols, 3-halo-4-nitrophenols)) were tested for antifungal activity against six fungi (A. niger, A. oryzae, M. verrucaria, T. viride, M. cirinelloides, andT. mentagrophytes) inSabouraud dextrose broth. The two most fungitoxic compounds of those studied were 5-fluoro- and 5-iodo-2-nitrophenols which inhibited all the fungi at concentrations under 10 µg/ml. 6-Iodo-2-nitrophenol inhibited five fungi at a concentration below 10 µg/ml andM. cirinelloides at 10–100 µg/ml.Zusammenfassung31 Verbindungen (Phenol; seine 12 möglichen monohalogenierten Derivate; 18 Nitrophenole (2- und 4-Nitrophenole, 4-, 5- und 6-Halogen-2-nitrophenole, 3-Halogen-4-nitrophenole)) wurden gegenüber 6 Pilzstämmen (A. niger, A. oryzae, M. verrucaria, T. viride, M. cirinelloides, T. mentagrophytes) inSabouraud-Nähmedium auf ihre fungizide Aktivität untersucht. Am effizientesten waren dabei 5-Fluor- und 5-lod-2-nitrophenole (Hemmung aller Stämme bei Konzentrationen <10 µg/ml). 6-lod-2-nitrophenol war gegen 5 Pilze bei Konzentrationen <10 µg/ml und gegenüberM. cirinelloides zwischen 10 und 100 µg/ml aktiv.

Preparation and Fungitoxicity of Some Trichloro-, Tribromo-, Tetrachloro-, and Tetrabromo-8-Quinolinols

Summary. 3,5,6-, 3,5,7-, 4,5,7-, and 5,6,7-trichloro- and -tribromo-8-quinolinols as well as 3,5,6,7-tetrachloro- and -tetrabromo-8-quinolinols were prepared and tested against six fungi (Aspergillus niger, Aspergillus oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, and Trichophyton mentagrophytes) in Sabouraud dextrose broth. The compounds strongly inhibit five fungi but not M. cirinelloides. They are less active than the related dichloro-8-quinolinols which is attributed to steric hindrance.

Preparation of 6-Fluoro-8-quinolinol and Related 6-Fluoroquinolines

Summary. 6-Fluoro-8-quinolinol was prepared from 2-amino-5-fluorophenol by a Skraup synthesis. No synergism was observed between 5-fluoro- and 6-fluoro-8-quinolinols or between 6-fluoro- and 7-fluoro-8-quinolinols against any of the six fungi in our test system (Aspergillus niger, A. oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, and Trichophyton mentagrophytes) in Sabouraud dextrose broth. Unlike the fluoro-8-quinolinols, the 8-quinolinols comparably substituted with chlorine or bromine did form synergistic mixtures. This is attributed to steric factors.

Preparation and fungitoxicity of 3-bromo-6-chloro- and 6-bromo-3-chloro-8-quinolinols

Summary3-Bromo-6-chloro- and 6-bromo-3-chloro-8-nitro, -8-amino-, and -8-hydroxyquinolines along with 3-bromo- and 3-chloroquinolin-6,8-diols were prepared and tested for antifungal activity against six fungi (Aspergillus niger, A. oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, Trichophyton mentagrophytes) inSabouraud dextrose broth. Compounds with chlorine in the 3 position were generally more fungitoxic than the corresponding analogues with bromine. 6-Bromo-3-chloro-8-quinolinol inhibited four fungi at levels below 1 µg/ml andA. niger andM. cirinelloides at 2 µg/ml each.Zusammenfassung3-Brom-6-chlor- und 6-Brom-3-chlor-8-nitro-, -8-amino- und -8-hydroxychinoline sowie 3-Brom- und 3-Chlorchinolin-6,8-diole wurden hergestellt und gegen sechs Pilzstämme (Aspergillus niger, A. oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, Trichophyton mentagrophytes) inSabouraud-Dextrosenährmedium auf lhre fungizide Aktivität untersucht. Verbindungen mit Chlor in Position 3 sind durchwegs fungitoxischer als die entsprechenden Bromanalogen. 6-Brom-3-chlor-8-chinolinol hemmt das Wachstum von vier Pilzen bei Konzentrationen unter 1 µg/ml und das vonA. niger undM. cirinelloides bei einer Konzentration von jeweils 2 µg/ml.