A Tiny Change Makes a Big Difference in the Anti-Parasitic Activities of an HDAC Inhibitor
Univ Grenoble Alpes, CNRS, CHU Grenoble Alpes, Grenoble INP, TIMC-IMAG, F-38000 Grenoble, France
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions & Immunity to Infection, INSERM U 1209, CNRS UMR 5309, Univ Grenoble Alpes, F-38000 Grenoble, France
Centre de Biochimie Structurale (CBS), INSERM, CNRS, Univ Montpellier, 34000 Montpellier, France
Institute of Research for the Development (IRD), Univ Montpellier, MiVegec, 34000 Montpellier, France
Institute of Research for the Development (IRD), Univ Montpellier, InterTryp, 34000 Montpellier, France
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(12), 2973; https://doi.org/10.3390/ijms20122973
Received: 21 May 2019 / Revised: 14 June 2019 / Accepted: 15 June 2019 / Published: 18 June 2019
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
We previously synthesized an hydroxamate derivative (N-hydroxy-4-[2-(3- methoxyphenyl)acetamido]benzamide) named 363 with potent anti-Toxoplasma gondii activity and histone deacetylase inhibitor (HDACi) effects. Here we show that 1-N-hydroxy-4-N- [(2-methoxyphenyl)methyl]benzene-1,4-dicarboxamide, a 363 isomer, does not have antiparasitic potency and has a 13-fold decrease in HDACi activity. The in silico modeling of T. gondii HDACs of the type II strain discloses identity varying from 25% to 62% on more than 250 residues for S8EP32_TOXG and A0A125YPH4_TOXGM. We observed a high conservation degree with the human HDAC2 (53% and 64% identity, respectively) and a moderate one with the human HDAC8 (30–40%). Two other TgHDACs, S8F6L4_TOXGM and S8GEI3_TOXGM, were identified as displaying a higher similarity with some bacterial orthologs (~35%) than with the human enzymes (~25%). The docking in parallel of the two compounds on the models generated allowed us to gain insights on the docking of these hydroxamate derivatives that guide their specificity and potency against T. gondii histone deacetylase. This information would constitute the rationale from which more specific derivatives can be synthetized.