New systematically active antimycotics from the beta-blocker category

• Published in: Mycoses Vol. 38; no. 7-8; pp. 251 - 264
• Main Authors: Hänel, H., Kirsch, R., Schmidts, H.-L., Kottmann, H.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.1995; Blackwell
• Subjects: Adrenergic beta-Antagonists - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; antifungal activity; Antifungal agents; Antifungal Agents - pharmacology; Biological and medical sciences; Candida albicans; Candida albicans - drug effects; Candida albicans - enzymology; Candida albicans - growth & development; Candida albicans - pathogenicity; Candidiasis - drug therapy; Candidiasis - mortality; Candidiasis - pathology; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - metabolism; fungicidal activity; HeLa Cells; Humans; Male; Medical sciences; Mice; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; mouse model; Pharmacology. Drug treatments; Phospholipases - antagonists & inhibitors; Phospholipases - metabolism; Candida albicans; Mycosis; Rodentia; In vitro; Biological activity; Fungi; Infection; In vivo; Vertebrata; Antifungal agent; Experimental disease; Mammalia; Mouse; Animal; Fungi Imperfecti; Comparative study; Thallophyta; Beta blocking agent
• ISSN: 0933-7407; 1439-0507
• DOI: 10.1111/j.1439-0507.1995.tb00404.x

Beta‐blocker Summary. Candida albicans secretes phospholipases, which are considered to be one of the mediators of cell penetration. It is known that other phospholipases from mammalian cells can be inhibited by lipophilic beta‐blocking structures. As the result of a synthesis programme of several years' duration, structures deriving from β‐hydroxyethylamines were introduced. In vitro and in vivo results with these compounds are presented in comparison with standard antimycotics. In combination with fluconazole, several of the compounds can prevent death in mice infected with lethal inocula of C. albicans. Histological examinations confirm the inhibitory effect of the beta‐blocker‐like scructures on tissue penetration. The structures therefore constitute new antimycotics that are endowed with extensive in vitro effectiveness against fungi and also definite in vivo effects in the animal model. Zusammenfassung. Candida albicans sezerniert Phospholipasen, der als Vermittler der Zellpenetration diskutiert werden. Von anderen Phospholipasen aus Säugerzellen ist bekannt, daß sie durch lipophile β‐blockierende Strukturen hemmbar sind. Als Ergebnis eines mehrjährigen Synthese‐programms werden Strukturen vorgestellt, die sich von β‐Hydroxyethylaminen ableiten. In vitro und in vivo Ergebnisse mit diesen Verbindungen werden im Vergleich zu Standardantimykotika vorgestellt. In Kombination mit Fluconazol führen einzelne der Verbindungen zum Überleben von Mäusen, die mit letalen Inokula von C. albicans infiziert worden waren. Histologische Untersuchungen bestätigen den hemmenden Einfluß der β‐Blocker‐artigen Strukturen auf die Gewebepenetration. Die Strukturen stellen somit neue Antimykotika dar, die über eine breite in vitro Wirksamkeit gegenüber Pilzen wie auch über deutliche in vivo Wirkungen im Tiermodell verfügen.