Design and Synthesis of Novel Anti-Plasmodial Histone Deacetylase Inhibitors Containing an Alkoxyamide Connecting Unit.
Despite recent declines in mortality, malaria remains an important global health problem. New therapies are needed, including new drugs with novel modes of action compared to existing agents. Among new potential therapeutic targets for malaria, inhibition of parasitic histone deacetylases (HDACs) is a promising approach. Homology modeling of PfHDAC1, a known target of some anti-plasmodial HDAC inhibitors, revealed a unique threonine residue at the rim of the active site in close proximity to the location of the cap group of vorinostat-type HDAC inhibitors. Aiming to obtain HDAC inhibitors with potent and preferential anti-plasmodial activity, we synthesized a mini-library of alkoxyamide-based HDAC inhibitors containing hydrogen bond acceptors in the cap group. Using a 5-step synthetic route, 12 new inhibitors were synthesized and assayed against Plasmodium falciparum asexual blood stage parasites (clones 3D7 and Dd2) and human cells (HepG2). The most active compound 6h (Pf3D7 IC50: 0.07 µM; PfDd2 IC50: 0.07 µM) was 25-fold more toxic against the parasite versus human HepG2 cells. Selected compounds were shown to cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more PfHDACs.
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
Leandro A
LA
Alves Avelar
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.
Jana
J
Held
Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
Jessica A
JA
Engel
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
Parichat
P
Sureechatchaiyan
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Leipzig University, Leipzig, Germany.
Finn K
FK
Hansen
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
Alexandra
A
Hamacher
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
Matthias U
MU
Kassack
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.
Benjamin
B
Mordmüller
Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
Katherine T
KT
Andrews
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
Thomas
http://orcid.org/0000-0002-9474-4224
T
Kurz
D000438:Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000438:Alcohols; D000577:Amides; D000962:Antimalarials; D056572:Histone Deacetylase Inhibitors; C059688:alkoxyl radical; D006655:Histone Deacetylases
Anti-plasmodial activity; Inhibitors; PfHDAC; Synthesis