Synthesis and bioactivity of β-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase

Journal of Medicinal Chemistry
René ChoforSerge Van Calenbergh

Abstract

Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the β-position of the hydroxamate analogue of 2. While direct addition of a β-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.

References

Apr 1, 1977·Journal of Medicinal Chemistry·J G Topliss
Feb 1, 1982·Antimicrobial Agents and Chemotherapy·T MurakawaM Nishida
Aug 17, 2002·Antimicrobial Agents and Chemotherapy·Jochen WiesnerHassan Jomaa
Jan 25, 2003·Antimicrobial Agents and Chemotherapy·Bertrand LellPeter Gottfried Kremsner
Jul 16, 2003·Biochemical and Biophysical Research Communications·Susanna Sauret-GüetoManuel Rodríguez-Concepción
Oct 2, 2003·Bioscience, Biotechnology, and Biochemistry·Yoshiko SakamotoMakari Yamasaki
Feb 21, 2004·The Journal of Infectious Diseases·Steffen BorrmannPeter G Kremsner
May 13, 2005·Journal of Medicinal Chemistry·Katrin SilberGerhard Klebe
Jan 28, 2006·Bioorganic & Medicinal Chemistry Letters·Timothy HaemersSerge Van Calenbergh
Jul 28, 2006·Antimicrobial Agents and Chemotherapy·Steffen BorrmannPeter G Kremsner
Dec 26, 2007·Bioorganic & Medicinal Chemistry·Timothy HaemersSerge Van Calenbergh
Dec 29, 2009·Current Opinion in Microbiology·Michael U Shiloh, Patricia A DiGiuseppe Champion
Jun 22, 2011·The Journal of Experimental Medicine·Sethu C NairBoris Striepen
Aug 27, 2011·Journal of Medicinal Chemistry·Christoph T BehrendtThomas Kurz
Jan 28, 2012·Acta Crystallographica. Section D, Biological Crystallography·Christofer BjörkelidT Alwyn Jones
Feb 23, 2012·Scientific Reports·Tomonobu UmedaKazuo T Nakamura
May 5, 2012·Natural Product Reports·Jan-Ytzen van der Meer, Anna K H Hirsch
Jun 27, 2012·Journal of Medicinal Chemistry·Karin BrücherThomas Kurz
Jul 4, 2013·Journal of Medicinal Chemistry·Anna M JanssonSherry L Mowbray
Dec 24, 2013·Bioorganic & Medicinal Chemistry Letters·Emily R JacksonCynthia S Dowd
Feb 26, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·René ChoforSerge Van Calenbergh
Sep 26, 2014·Journal of Medicinal Chemistry·Sarah KonzuchThomas Kurz

❮ Previous
Next ❯

Citations

Jan 19, 2016·Chemical Communications : Chem Comm·Ming GaoXiuling Cui
Dec 12, 2020·European Journal of Medicinal Chemistry·Sharyu Kesharwani, Sandeep Sundriyal
Oct 3, 2018·Biochimica Et Biophysica Acta. Proteins and Proteomics·Nikita K UssinMaksymilian Chruszcz
Sep 8, 2018·Chemical Reviews·Allie Y ChenSeth M Cohen
Oct 23, 2018·ACS Medicinal Chemistry Letters·Charlotte CourtensSerge Van Calenbergh
Sep 8, 2018·Journal of Medicinal Chemistry·Xu WangCynthia S Dowd

❮ 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.

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Biofilms

Biofilms are adherent bacterial communities embedded in a polymer matrix and can cause persistent human infections that are highly resistant to antibiotics. Discover the latest research on Biofilms here.

Antimalarial Agents

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

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.