Synthesis of aminophenylhydroxamate and aminobenzylhydroxamate derivatives and in vitro screening for antiparasitic and histone deacetylase inhibitory activity

Abstract

A series of aminophenylhydroxamates and aminobenzylhydroxamates were synthesized and screened for their antiparasitic activity against Leishmania, Trypanosoma, and Toxoplasma. Their anti-histone deacetylase (HDAC) potency was determined. Moderate to no antileishmanial or antitrypanosomal activity was found (IC50 > 10 μM) that contrast with the highly efficient anti-Toxoplasma activity (IC50 < 1.0 μM) of these compounds. The antiparasitic activity of the synthetized compounds correlates well with their HDAC inhibitory activity. The best-performing compound (named 363) express a high anti-HDAC6 inhibitory activity (IC50 of 0.045 ± 0.015 μM) a moderate cytotoxicity and a high anti-Toxoplasma activity in the range of known anti-Toxoplasma compounds (IC50 of 0.35–2.25 μM). The calculated selectivity index (10–300 using different human cell lines) of the compound 363 makes it a lead compound for the future development of anti-Toxoplasma molecules.

HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics

“…Further, the activity of SAHA and TST against T. gondii also showed IC 50 at the same range of pyrimethamine alone [0.12 μM] or when combined with sulfadiazine [0.067 μM] ( Dubar et al, 2011 ; Martins-Duarte, 2006 ). A previous study with another selective inhibitor for HDAC6 in mammals, N-hydroxy-4-[2-(3-methoxyphenyl) acetamido]benzamid , also showed activity against the RH strain at a nanomolar range of concentration [IC 50 0,35 μM and SI of 300 for the RH strain] ( Loeuillet et al, 2018 ), indicating that selective compounds for HDAC6 in mammals are active against T. gondii . This is very interesting as T. gondii does not have any homologues for HDAC6, which suggests TST may inhibit another TgHDAC or might even have off target activity.…”

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

“…Deacetylase activity of the recombinant HDAC1 enzyme confirms the lower potency of D16 as compared to 363 (Figure 1B). We previously documented the capacity of 363 to inhibit type I and II strains of T. gondii with IC 50 of 350 and 2270 nM, respectively [23] and reported that type I strains of T. gondii are 6-fold more susceptible than type II ones [23]. Here, we recorded an IC 50 below 1000 nM for type I (153 nM) or type II (853 nM) strains of T. gondii , that confirm that type I strains are 5.5 fold more susceptible than type II ones.…”

“…Compounds 363 (N-hydroxy-4-[2-(3-methoxyphenyl)acetamido]benzamide) and D16 (1-N-hydroxy-4-N-[(2-methoxyphenyl)methyl]benzene-1,4-dicarboxamide), represented in Figure 1A, were synthetized according to the general procedure previously described [23]. Synthetic schemes for D16 and 363 synthesis can be found in supplementary data Supplementary S1.…”

“…We recently synthetized hydroxamate derived compounds and investigated their anti-Trypanosomatids, anti- Toxoplasma gondii activities in link with their HDAC inhibitory potency [23]. Here, we further 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.…”

A Histone Deacetylase (HDAC) Inhibitor with Pleiotropic In Vitro Anti-Toxoplasma and Anti-Plasmodium Activities Controls Acute and Chronic Toxoplasma Infection in Mice

“…The passage from the bradyzoite to the tachyzoite state is controlled by epigenetic mechanisms involving histone deacetylases (HDACs) [ 24 ]. An increasing number of compounds potentially inhibiting histone deacetylases (HDACs) revealed high anti- T. gondii and/or anti- Plasmodium activity in vitro or animal models [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Therefore, these enzymes are relevant targets for treating cysts.…”