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Moreover, current treatments are outdated and difficult to administer, while drug resistance is an emerging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.
Keywords: Adamantane, S-adenosylmethionine decarboxylase (AdoMetDC), guanylhydrazones, structure-activity relationships, trypanocidal
agents, kernel-based partial least squares regression, szmap, hydration analysis, docking-scoring calculations.
Release S. 2018-1: Schrödinger suite 2018-1 protein preparation wizard. Epik, Schrödinger, LLC, New York 2018.
Schrödinger Release. 2018-1: LigPrep. Schrödinger, LLC, New York, NY 2018.
Schrödinger Release. 2018-1: Glide. Schrödinger, LLC, New York, NY 2018.
Roy K, Kar S. SAR and QSAR in drug discovery and chemical
design-some examples. In: Understanding the Basics of QSAR for
Applications in Pharmaceutical Sciences and Risk Assessment. 2015; pp. 427-53.
Schrödinger Release. 2018-1: Canvas. Schrödinger, LLC, New York, NY 2018.
Majerski Z, Hameršak Z. Rearrangement of bridgehead alcohols to polycyclic ketones by fragmentation-cyclization: 4-protoadaman-tanone (tricycle-[4.3.1.03,8]decan-4-one). Org Synth 1988; 50: 958-62.
SZMAP. OpenEye Scientific Software Inc. Santa Fe, NM, USA 2015.
Rights & PermissionsPrintExport