@article{3021070,
    title = "Lipophilic guanylhydrazone analogues as promising trypanocidal agents: An extended sar study",
    author = "Pardali, V. and Giannakopoulou, E. and Balourdas, D.-I. and Myrianthopoulos, V. and Taylor, M.C. and Šekutor, M. and Mlinarić-Majerski, K. and Kelly, J.M. and Zoidis, G.",
    journal = "Current Pharmaceutical Design",
    year = "2020",
    volume = "26",
    number = "8",
    pages = "838-866",
    publisher = "Bentham Science Publishers",
    issn = "1381-6128",
    doi = "10.2174/1381612826666200210150127",
    keywords = "2 (10,11 dihydro 5h dibenzo[a,d][7]annulen 5 ylidene)guanylhydrazone;  2 (4 phenylcyclohexylidene)guanylhydrazone;  2 (9h fluoren 9 ylidene)guanylhydrazone;  adamantane derivative;  adamantane [1,2 a] inden 11 ylidene guanylhydrazone;  amidinohydrazone;  antitrypanosomal agent;  tricyclo [3.3.1.13,7] decan 1 yl (phenyl)methylene guanylhydrazone;  tricyclo [3.3.1.13,7] decan 2 yl (phenyl)methylene guanylhydrazone;  unclassified drug;  antitrypanosomal agent;  mitoguazone, animal cell;  carbon nuclear magnetic resonance;  chemical modification;  controlled study;  drug cytotoxicity;  drug design;  drug structure;  drug synthesis;  epimastigote;  growth inhibition;  in vitro study;  L6 cell line;  molecular docking;  molecular dynamics;  nonhuman;  priority journal;  proton nuclear magnetic resonance;  quantitative structure activity relation;  rat;  Review;  trypanocidal activity;  Trypanosoma brucei;  Trypanosoma cruzi;  drug effect;  structure activity relation;  Trypanosoma brucei brucei;  Trypanosoma cruzi, Mitoguazone;  Structure-Activity Relationship;  Trypanocidal Agents;  Trypanosoma brucei brucei;  Trypanosoma cruzi",
    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 Cha-gas 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 under-funded. Moreover, current treatments are outdated and difficult to administer, while drug resistance is an emerging concern.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. © 2020 Bentham Science Publishers."
}