Preparation, biological evaluation and QSAR analysis of urea substituted 2,4-diamino-pyrimidine anti-malarials

  • RSC Med Chem. 2022 Oct 20;13(12):1587-1604. doi: 10.1039/d2md00218c.
Borvornwat Toviwek  1  2 ,  Jennifer Riley  3 ,  Nicole Mutter  3 ,  Mark Anderson  3 ,  Lauren Webster  3 ,  Irene Hallyburton  3 ,  Duangkamol Gleeson  4 ,  Kevin D Read  3 ,  M Paul Gleeson  1
Affiliations
  • 1. Department of Biomedical Engineering, School of Engineering, King Mongkut's Institute of Technology Ladkrabang Bangkok 10520 Thailand [email protected].
  • 2. Department of Chemistry, Faculty of Science, Kasetsart University Bangkok 0900 Thailand.
  • 3. Drug Discovery Unit, Divison of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee Dundee DD1 5EH UK.
  • 4. Applied Computational Chemistry Research Unit & Department of Chemistry, School of Science, King Mongkut's Institute of Technology Ladkrabang Bangkok 10520 Thailand.
PMID: 36561069 DOI: 10.1039/d2md00218c
Abstract

The synthesis and evaluation of twenty six new phenylurea substituted 2,4-diamino-pyrimidines against Plasmodium falciparum (Pf) 3D7 are reported. Compounds were prepared to improve both anti-malarial activity and selectivity of the series previously reported by our group. Additional properties have been determined to assess their potential as anti-malarial leads including; HepG2 cytotoxicity, solubility, permeability, and lipophilicity, as well as in vitro stability in human and rat microsomes. We also assess their inhibition profile against a diverse set of 10 human kinases. Molecular docking, cheminformatics and bioinformatics analyses were also undertaken. Compounds 40 demonstrated the best anti-malarial activity at Pf 3D7 (0.09 μM), good selectivity with respect to mammalian cytotoxicity (SI = 54) and low microsomal clearance. Quantitative structure activity relationship (QSAR) analyses point to lipophilicity being a key driver of improved anti-malarial activity. The most active compounds in the series suffered from high lipophilicity, poor aqueous solubility and low permeability. The results provide useful information to guide further chemistry iterations.