In Vitro and In Vivo Activities of Aminoadamantane and Aminoalkylcyclohexane Derivatives against Trypanosoma brucei

Abstract

We reported recently that the bloodstream form of the African trypanosome, Trypanosoma brucei, is sensitive to the anti-influenza virus drug rimantadine. In the present report we describe the trypanocidal properties of a further 62 aminoadamantane and aminoalkylcyclohexane derivatives. Seventeen of the compounds were found to be more active than rimantadine, with four inhibiting growth in vitro of T. brucei by >90% at concentrations of 1 M. The most active derivative (1-adamantyl-4-amino-cyclohexane) was about 20 to 25 times more effective than rimantadine. We observed a correlation between structural features of the derivatives and their trypanocidal properties; hydrophobic substitutions to the adamantane or cyclohexane rings generally enhanced activity. As with rimantadine, the activity in vitro varied with the pH. T. brucei was more sensitive in an alkaline environment (including a normal bloodstream pH of 7.4) and less sensitive under acidic conditions. Tests for activity in vivo were carried out with a mouse model of infection with a virulent strain of T. brucei. Although the parasitemia was not eliminated, it could be transiently suppressed by >98% with the most active compounds tested. These results suggest that aminoadamantane derivatives could have potential as a new class of trypanocidal agents.

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

“…In a follow-up study, a larger compound library of 62 aminoadamantane- and aminocyclohexane derivatives was screened against T. brucei in an in vitro assay. 356 Of the screened compounds, 17 were more active than rimantadine, some of which are depicted in Scheme 28. Increased hyrophobicity obviously enhances trypanocidal activity, and compound 188 was the most potent screened, being about 20–25 times more effective than rimantadine.…”

Cytotoxic, mutagenicity, and genotoxicity effects of guanylhydrazone derivatives

“…We evaluated their antifungal and anti-trypanosome activity, and the results suggest a more pronounced activity for 2,3-DMeB relative to 3,4-DMeB. Antifungal and anti-trypanosomal activity had already been demonstrated for guanylhydrazones [37,39,40]. Santos-Filho et al [38] suggested that the action mechanism for guanylhydrazone derivatives may include three different pathways: (a) interaction with the membranes of the organism, which are negatively charged; (b) interaction with some specific enzyme of the organism; and (c) interaction with the DNA of the organism.…”

Preparation of dendritic adamantane-based polymers/layered silicate nanocomposites

“…The combination of dendritic materials possessing an adamantane core, which has significant potential in biomedical applications , with the physical characteristics of inorganic montomorillonite clay, such as Nanofil, is anticipated to generate novel utilitarian composites. Toward this goal, the N ‐[[[2‐Hydroxy‐l,l‐bis(hydroxymethyl)ethyl]amino]carbonyl]adamantane (Adm), possessing three hydroxyl termini, was prepared .…”

“…Notably, the resulting Adm‐p‐MMA‐b‐gly/NC contained adamantane core, as a new functionality. Adamantane is a cage‐type hydrocarbon that has pharmaceutical significance, where its derivatives are used as antiviral agents in the treatment of various diseases . It is also highly thermally stable; therefore, incorporation of the adamantane moiety and glucose unit in the desired nanocomposites by using chitosan‐modified clay, as a nanofiller, was expected to create temperature‐resistant materials for biomedical applications.…”