2. Academic Validation
  3. Novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives and their antitrypanosomal activities against T.brucei

Novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives and their antitrypanosomal activities against T.brucei

  • Bioorg Med Chem Lett. 2024 Sep 1:109:129825. doi: 10.1016/j.bmcl.2024.129825.
Annie E Taylor 1,  Moritz Hering 1,  Mark R J Elsegood 2,  Simon J Teat 3,  George W Weaver 2,  Randolph R J Arroo 4,  Marcel Kaiser 5,  Pascal Maeser 5,  Avninder S Bhambra 6
Affiliations

Affiliations

  • 1 Leicester School of Allied Health Sciences, De Montfort University, Leicester LE1 9BH, UK.
  • 2 Department of Chemistry, Loughborough University, Loughborough LE11 3TU, UK.
  • 3 Advanced Light Source, 1 Cyclotron Road, Lawrence Berkeley National Laboratory Berkeley, CA 94720-8229, United States.
  • 4 Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
  • 5 Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland; University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
  • 6 Leicester School of Allied Health Sciences, De Montfort University, Leicester LE1 9BH, UK. Electronic address: abhambra@dmu.ac.uk.
PMID: 38823730 DOI: 10.1016/j.bmcl.2024.129825
Abstract

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, Parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development.

Keywords

Antiparasitic; Antitrypanosomal; Kinetoplastid; Neglected tropical diseases; Pyrimidines; T.brucei.

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