Potent antimalarial activity of histone deacetylase inhibitor analogues.

Antimicrobial Agents and Chemotherapy
Katherine T AndrewsDavid P Fairlie

Abstract

The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from l-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.

References

Aug 20, 1976·Science·W Trager, J B Jensen
Nov 12, 1996·Proceedings of the National Academy of Sciences of the United States of America·S J Darkin-RattrayD M Schmatz
Apr 4, 1997·Journal of Molecular Biology·G JonesR Taylor
Apr 24, 1999·Molecular and Biochemical Parasitology·M B JoshiC Syin
Jun 17, 2000·International Journal for Parasitology·K T AndrewsP G Parsons
Aug 10, 2001·Current Opinion in Microbiology·A ScherfL H Freitas-Junior
Oct 31, 2001·Trends in Cell Biology·B R Cairns
Feb 14, 2002·Chemistry & Biology·Christina M Grozinger, Stuart L Schreiber
Oct 9, 2002·Nature·Laurence FlorensDaniel J Carucci
Sep 17, 2003·The Journal of Pharmacology and Experimental Therapeutics·Erding HuMichael Jaye
May 28, 2004·Journal of Medicinal Chemistry·Matthew P GlennDavid P Fairlie
Jun 3, 2004·Nature Reviews. Drug Discovery·David A FidockSolomon Nwaka
Jan 8, 2005·Proceedings of the National Academy of Sciences of the United States of America·J S UngerstedtP A Marks
Sep 24, 2005·Current Medicinal Chemistry. Anti-cancer Agents·Oscar MoradeiArkadii Vaisburg
Nov 3, 2005·Tropical Medicine & International Health : TM & IH·D NdiayeD F Wirth
Nov 18, 2005·Gene·Michele A GlozakEdward Seto
Aug 4, 2006·Journal of Medicinal Chemistry·Takayoshi SuzukiNaoki Miyata
Feb 3, 2007·Nature Reviews. Drug Discovery·Steven GrantPeter Kirkpatrick

❮ Previous
Next ❯

Citations

Jul 31, 2010·Journal of Medicinal Chemistry·Sandra C MwakwariAdegboyega K Oyelere
Nov 30, 2011·Immunology and Cell Biology·Katherine T AndrewsMalcolm K Jones
Sep 27, 2012·Proceedings of the National Academy of Sciences of the United States of America·Nicholas A MalmquistMatthew J Fuchter
Jan 11, 2012·Antioxidants & Redox Signaling·Paul V LicciardiTom C Karagiannis
Apr 18, 2012·Antimicrobial Agents and Chemotherapy·Subathdrage D M SumanadasaKatherine T Andrews
Jul 23, 2008·Antimicrobial Agents and Chemotherapy·Geoffrey S DowAlan P Kozikowski
Feb 19, 2009·Antimicrobial Agents and Chemotherapy·S Agbor-EnohM Jung
Jun 22, 2010·Eukaryotic Cell·Catherine J Merrick, Manoj T Duraisingh
Jun 3, 2014·Analytical Biochemistry·Christian MeynersFranz-Josef Meyer-Almes
Feb 14, 2015·International Journal of Molecular Sciences·Mohamed A Abdallah ElbadawiTalal Ahmed Awad
Sep 30, 2014·FEBS Letters·Amornrat Naranuntarat JensenLaran T Jensen
Jan 20, 2016·Drug Discovery Today·Tina S Skinner-AdamsKatherine T Andrews
Sep 25, 2012·Trends in Parasitology·Wieteke A M HoeijmakersRichárd Bártfai
Jul 23, 2015·International Journal for Parasitology. Drugs and Drug Resistance·Jessica A EngelKatherine T Andrews
Apr 28, 2016·International Journal for Parasitology. Drugs and Drug Resistance·Andrew C KotzeDavid P Fairlie
Nov 26, 2015·Journal of Molecular Graphics & Modelling·Jelena MelesinaWolfgang Sippl
May 18, 2016·ACS Medicinal Chemistry Letters·Jesus M OntoriaSteven Harper
Dec 27, 2008·Molecular and Biochemical Parasitology·Paul HorrocksRichard D Emes
Oct 22, 2008·Trends in Parasitology·David A FidockSteven R Meshnick
Jul 9, 2009·Journal of Cellular and Molecular Medicine·Fraczek JoannaRogiers Vera
Jul 19, 2008·Cellular Microbiology·Bradley I Coleman, Manoj T Duraisingh
Jan 12, 2012·The Journal of Asthma : Official Journal of the Association for the Care of Asthma·Simon G Royce, Tom C Karagiannis
Oct 1, 2008·Current Opinion in Microbiology·J Carl Craft
Feb 11, 2015·Nature Reviews. Microbiology·Christian DoerigAndrew B Tobin
Feb 10, 2017·Medicinal Research Reviews·Chiara ZagniAntonio Rescifina
Feb 24, 2017·PLoS Neglected Tropical Diseases·Felipe Leite de OliveiraMarcia Cury El-Cheikh
Feb 28, 2017·Journal of Medicinal Chemistry·Gebremedhin S HailuAntonello Mai
Nov 30, 2011·Memórias do Instituto Oswaldo Cruz·Raymond John PierceEmmanuel Roger
Jun 1, 2011·Pharmaceuticals·Brian T Grimberg, Rajeev K Mehlotra
Dec 14, 2017·Assay and Drug Development Technologies·Hermann A M Mucke
May 8, 2010·Organic & Biomolecular Chemistry·Rohan A DavisRoger G Shivas
Nov 4, 2009·Expert Review of Anti-infective Therapy·Donald L GardinerKatharine R Trenholme
Dec 4, 2012·Expert Review of Anti-infective Therapy·Laura VanagasSergio O Angel
Sep 7, 2017·Current Medicinal Chemistry·Anna Caroline AguiarRafael V C Guido
May 10, 2019·Communications Biology·Tina S Skinner-AdamsKatherine T Andrews

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

CRISPR Screens in Drug Resistance

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of CRISPR-Cas system in high-throughput genome-wide screens to identify genes that may confer drug resistance.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.