In:
ChemMedChem, Wiley, Vol. 12, No. 19 ( 2017-10-09), p. 1627-1636
Abstract:
In this work we aimed to develop parasite‐selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease‐causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid‐based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC 50 : 8– 〉 51 μ m ), with 11 also having sub‐micromolar in vitro activity against drug‐sensitive (3D7) and multidrug‐resistant (Dd2) asexual blood‐stage P. falciparum parasites (IC 50 ≈0.1–0.5 μ m ). A subset of compounds were examined for activity against early‐ and late‐stage P. falciparum gametocytes and P. berghei exo‐erythrocytic‐stage parasites. While only moderate activity was observed against gametocytes (IC 50 〉 2 μ m ), the most active compound ( N 1 ‐((3,5‐dimethylbenzyl)oxy)‐ N 4 ‐hydroxyterephthalamide, 1 f ) showed sub‐micromolar activity against P. berghei exo‐erythrocytic stages (IC 50 0.18 μ m ) and 〉 270‐fold better activity for exo‐erythrocytic forms than for HepG2 cells. This, together with asexual‐stage in vitro potency (IC 50 ≈0.1 μ m ) and selectivity of this compound versus human cells (SI 〉 450), suggests that 1 f may be a valuable starting point for the development of novel antimalarial drug leads with low host cell toxicity and multi‐stage anti‐plasmodial activity.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201700360
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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