Synthesis and evaluation of antiplasmodial activity of 2,4-diamonipyrimidine analogues as inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR) Kamogelo R. Butsi 1,2* , Charles B. de Koning 1, Amanda L. Rousseau 1,2 1 Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, South Africa, 2 WITS Research Institute for Malaria (WRIM), University of the Witwatersrand, South Africa Malaria, a disease caused by parasitic protists, remains life-threatening in many parts of the world. Antiplasmodial antifolates act by inhibiting essential enzyme-catalyzed reactions in the parasite’s folate metabolic pathway. Substituted 2,4-diaminopyrimidines 1 are antifolates as they act by mimicking the structure of dihydrofolate (DHF) at a molecular level. They inhibit the enzyme dihydrofolate reductase (DHFR), which reduces DHF to tetrahydrofolate (THF), by binding in the enzyme's active site. [1,2] Inhibition of the enzyme consequently halts DNA replication and therefore arrests cell replication [3] . Herein we report our progress on the synthesis of a series of substituted 2,4-diaminopyrimidine derivatives 1 and their biological activity against Plasmodium falciparum , and their inhibitory activity against Pf DHFR.
Scheme 1: i) MeCN, tBuOK, IPA, 2-MeTHF; ii) tBuOK, 2-MeTHF, 100W, 100°C; iii) HIO 3 , H 2 SO 4 /H 2 O; iv) Pd(PPh 3 ) 2 Cl 2 , CuI, DIPEA; v) H 2 , Pd/C, EtOH References 1. CH Sibley, JE Hyde, PFG Sims, CV Plowe, JG Kublin, EK Mberu, AF Cowman, PA Winstanley, WM Watkins and AM Nzila, Trends in Parasitology , 2001 , 12, 570-571 2. Y Minato, JM Thiede, SL Kordus, EJ Mcklveen, BJ Turman and AD Baughn, Antimicrobial Agents and Chemotherapy , 2015 , 59, 5097-5106 3. B Hajian, E Scocchera, S Keshipeddy, N G-Dayanandan, C Shoen, J Krucinska, S Reeve, M Cynamon, AC Anderson, DL Wright, PLoS One , 2016 , 11, 1–13.
P12F
© The Author(s), 2023
Made with FlippingBook Learn more on our blog