New Trypanosoma brucei acting derivatives incorporating 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane†

Abstract

In this work, we describe the design, synthesis and evaluation of novel functionalised 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane derivatives. Based on previous findings, we incorporated a phenyl ring between the adamantane core and the pharmacophoric side chain to enhance the activity and selectivity index (SI). The aromatic imidazolines 1a–d and the linear amidines 2a,b and 3a,b exhibited notable activity against T. brucei. The 1-(4-phenyl)adamantane 1-(4-phenoxyphenyl)adamantane core was further functionalized with the aminoguanylhydrazone and thiosemicarbazone moieties. 2-[(E)-4-(1-adamantyl)benzylidene]hydrazine-1-carbothioamide 4c emerged as a promising trypanocidal agent with an EC₅₀ of 0.16 μM and an SI of 17. Future studies will focus on optimizing the length and the distance of the side chain between the aromatic ring and the chromophores to further enhance the activity and selectivity of these molecules.