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

Borvornwat Toviwek, Jennifer Riley, Nicole Mutter, Mark Anderson, Lauren Webster, Irene Hallyburton, Duangkamol Gleeson, Kevin D. Read, M. Paul Gleeson (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1587-1604
Pages (from-to)1587-1604
Number of pages18
JournalRSC Medicinal Chemistry
Volume13
Issue number12
Early online date20 Oct 2022
DOIs
Publication statusPublished - Dec 2022

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