A Tiny Change Makes a Big Difference in the Anti-Parasitic Activities of an HDAC Inhibitor.

Corinne Loeuillet,Denis Sereno,Gilles Labesse,Bastien Touquet,Jean François Guichou

doi:10.3390/ijms20122973

Abstract

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.

Highlights

About one-third of the world’s human population is infected with Toxoplasma gondii [1]
Toxoplasma infection in humans occurs via the ingestion of tissue cysts with raw or undercooked meat or by consumption of oocysts with contaminated food, water, vegetables, fruits, etc
High odds ratios (ORs) of Toxoplasma infection are reported in HIV/AIDS patients in Asia and Africa and in cancer patients in Asia [3]

Summary

Introduction

About one-third of the world’s human population is infected with Toxoplasma gondii [1]. Like azithromycin, clarithromycin, spiramycin, atovaquone, dapsone, and cotrimoxazole (trimethoprim-sulfamethoxazole) have been used, with limited efficiency because these molecules have no effect on the bradyzoite form of the parasite [4] It appears that Toxoplasma drug resistance is ongoing, urging the search for novelIndt.rJu. Mgolt.aSrcig. DHeDrei,swcuesfsuirothner address the HDAC inhibitory potency of an isomer of our best performing compound to interfere with the multiplication of T. gondii in relation with its HDACi activity. For D16, the hydrogen bond frequently recorded for 363, is less often present and corresponds with a conformation of D16 that brings the oxygen atom of the methoxy group close to the oxygen of the amide group This unfavorable conformation would decrease the overall affinity of the compound, without interfering directly with the predicted affinity results that are based only on protein–ligand interactions. While the lower affinity for the putative targets can be predicted by similarity with the lower activity observed against human orthologs (see HDAC1) and the theoretical models discussed above, the low activity of D16 compared to the parent (363) can be due to a poorer cell penetration

General Procedures for the Synthesis of Derivatives

HDAC Assays

Comparative Modeling and Ligand Docking

Findings

Conclusions