Diamine and aminoalcohol derivatives active against Trypanosoma brucei

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 1; pp. 440 - 443
• Main Authors: Olmo, Esther del, Diaz-González, Rosario, Escarcena, Ricardo, Carvalho, Luis, Bustos, Luis A., Navarro, Miguel, Feliciano, Arturo San
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-01-2012; Elsevier
• Subjects: African trypanosomiasis; Alcohols - chemistry; Aminoalcohols; Animals; Biological and medical sciences; Cell Death; cell growth; Cercopithecus aethiops; Chemistry, Pharmaceutical - methods; Cytology; Cytotoxicity; death; Diamines; Diamines - chemistry; Drug Design; Flagella; Humans; Medical sciences; Models, Chemical; Parasites; Pharmacology. Drug treatments; Phenotype; Sleeping sickness; Time Factors; Trypanocidal Agents - pharmacology; Trypanocide; Trypanosoma brucei; Trypanosoma brucei brucei - metabolism; Trypanosoma brucei gambiense; Trypanosoma gambiense; trypanosomiasis; Trypanosomiasis, African - parasitology; Vero Cells; Diamines; Aminoalcohols; Trypanocide; Sleeping sickness; Kinetoplastida; Protozoa; Protozoal disease; Aminoalcohol; Parasitosis; African sickness; Infection; Diamine; Trypanosoma brucei; Trypanosomiasis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.10.108

New agents inducing lethal alterations in the flagellar pocket structure of Trypanosome brucei are described.
Twenty compounds selected as representative members of three series of long-chain 1,2-diamines, 2-amino-1-alkanols and 1-amino-2-alkanols structurally related to dihydrosphingosin, were synthesized and tested in vitro for their ability to inhibit the sleeping sickness parasites Trypanosoma bruceirhodesiense and Trypanosoma brucei gambiense. Eight compounds showed EC50 values in the submicromolar range, with selectivity indexes up to 39 related to the respective cytotoxicity values for Vero cells. The parasite phenotype detected after treatment with the most potent compounds showed irreversible cell morphology alterations of the flagellar pocket that lead to inhibition of cell growth and parasite death.