444810-96-2Relevant academic research and scientific papers
Interaction of α-Thymidine Inhibitors with Thymidylate Kinase from Plasmodium falciparum
Chen, Mengshen,Sinha, Kaustubh,Rule, Gordon S.,Ly, Danith H.
, p. 2868 - 2875 (2018/05/14)
Plasmodium falciparum thymidylate kinase (PfTMK) is a critical enzyme in the de novo biosynthesis pathway of pyrimidine nucleotides. N-(5′-Deoxy-α-thymidin-5′-yl)-N′-[4-(2-chlorobenzyloxy)phenyl]urea was developed as an inhibitor of PfTMK and has been reported as an effective inhibitor of P. falciparum growth with an EC50 of 28 nM [Cui, H., et al. (2012) J. Med. Chem. 55, 10948-10957]. Using this compound as a scaffold, a number of derivatives were developed and, along with the original compound, were characterized in terms of their enzyme inhibition (Ki) and binding affinity (KD). Furthermore, the binding site of the synthesized compounds was investigated by a combination of mutagenesis and docking simulations. Although the reported compound is indicated to be highly effective in its inhibition of parasite growth, we observed significantly lower binding affinity and weaker inhibition of PfTMK than expected from the reported EC50. This suggests that significant structural optimization will be required for the use of this scaffold as an effective PfTMK inhibitor and that the inhibition of parasite growth is due to an off-target effect.
DERIVATIVES OF PHENYL (THIO) UREA DEOXYTHYMIDINE AND USE THEREOF AS ANTIMALARIALS
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Page/Page column 13; 16; 17, (2013/03/26)
Deoxythymidine derivatives according to formula (I) are disclosed. wherein: X may be O or S; and R1, R2, R3, R4 and R5 may each be independently selected from H, halo, C1-C6 alkyl, C1-C6 haloalkyl, nitro, phenyl, heteroaryl, substituted heteroaryl wherein the substituents may be C1-C6 alkyl or C1-C6 haloalkyl, benzyl, -CH2OAr, -OR6 and six-membered ring heterocyclic groups containing 1 or more O and/or N heteroatoms wherein any N heteroatom may be C1-C6 alkyl-substituted; and R6 may be selected from C1-C6 alkyl, phenyl, six-membered ring heterocyclic groups containing at least one O heteroatom, benzyl and substituted benzyl wherein the substituents may be halo, C1-C6 alkyl or C1-C6 alkoxy; R7 may be H or C1-C6 alkyl; and the stereochemistry of the bond depicted as ? is either α or β. Such derivatives have shown good inhibitory activity against malaria-causing parasites, e.g. Plasmodium falciparum, but have shown low levels of toxicity to human cells.
Synthesis and evaluation of α-thymidine analogues as novel antimalarials
Cui, Huaqing,Carrero-Lérida, Juana,Silva, Ana P. G.,Whittingham, Jean L.,Brannigan, James A.,Ruiz-Pérez, Luis M.,Read, Kevin D.,Wilson, Keith S.,González-Pacanowska, Dolores,Gilbert, Ian H.
supporting information, p. 10948 - 10957 (2013/03/13)
Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea- α-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this
A convenient method for the conversion of β-thymidine to α-thymidine based on TMSOTf-mediated C1′-epimerization
Sato, Yuichi,Tateno, Gohsuke,Seio, Kohji,Sekine, Mitsuo
, p. 3251 - 3254 (2007/10/03)
A practically useful method for the synthesis of α-thymidine from β-thymidine was developed by trimethylsilyl triflate-mediated C1′-epimerization. When 5′-O-diphenylacetyl-3′-O-toluoylthymidine was trimethylsilylated and successively treated with TMSOTf in acetonitrile, the resulting α-thymidine derivative was crystallized and isolated without silica-gel column chromatography. Deprotection gave unprotected α-thymidine in an overall yield of 50% from β-thymidine.
