Lipophilic Guanylhydrazone Analogues as Promising Trypanocidal Agents: An Extended SAR Study

Abstract

In this report, we extend the SAR analysis of a number of lipophilic guanylhydrazone analogues with respect to in vitro growth inhibition of Trypanosoma brucei and Trypanosoma cruzi. Sleeping sickness and Chagas disease, caused by the tropical parasites T. brucei and T. cruzi, constitute a significant socioeconomic burden in low-income countries of sub-Saharan Africa and Latin America, respectively. Drug development is underfunded. Moreover, current treatments are outdated and difficult to administer, while drug resistance is an emerging concern. The synthesis of adamantane-based compounds that have potential as antitrypanosomal agents is extensively reviewed. The critical role of the adamantane ring was further investigated by synthesizing and testing a number of novel lipophilic guanylhydrazones. The introduction of hydrophobic bulky substituents onto the adamantane ring generated the most active analogues, illustrating the synergistic effect of the lipophilic character of the C1 side chain and guanylhydrazone moiety on trypanocidal activity. The n-decyl C1-substituted compound G8 proved to be the most potent adamantane derivative against T. brucei with activity in the nanomolar range (EC50=90 nM). Molecular simulations were also performed to better understand the structure-activity relationships between the studied guanylhydrazone analogues and their potential enzyme target.

Overcoming barriers with non-covalent interactions: supramolecular recognition of adamantyl cucurbit[n]uril assemblies for medical applications

“…11 The antiviral mode of action of simple adamantane amines consists of ion channel blocking of the viral transmembrane proteins, 17 effectively preventing further virus replication, 18 while the application as neuroactive compounds is based on a high lipophilicity of adamantane that enables efficient crossing of the molecules across the blood-brain barrier. 19 Over the years in our laboratory we also explored many adamantane-based compounds as potential bioactive molecules, ranging from applications in enzyme inhibition 20,21 and antitrypanosomal activity 22 to their liposome incorporation as a means for targeted compound delivery. [23][24][25] In recent times adamantane derivatives have started to attract focus as components of complex drug delivery systems and this exciting new research direction is the main topic of this review.…”