56018-32-7Relevant articles and documents
Discovery and structure-activity relationships of pyrrolone antimalarials
Murugesan, Dinakaran,Mital, Alka,Kaiser, Marcel,Shackleford, David M.,Morizzi, Julia,Katneni, Kasiram,Campbell, Michael,Hudson, Alan,Charman, Susan A.,Yeates, Clive,Gilbert, Ian H.
, p. 2975 - 2990 (2013/05/23)
In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC50 ～ 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.
5,10-Methylenetetrahydro-5-deazafolic Acid and Analogues: Synthesis and Biological Activities
Gangjee, Aleem,Patel, Jasmin,Kisliuk, Roy L.,Gaumont, Yvette
, p. 3678 - 3685 (2007/10/02)
The synthesis of 5,10-methylene-5-deazatetrahydrofolic acid (2), a stable, rigid analogue of 5,10-methylenetetrahydrofolate (1), is reported as a potential inhibitor of thymidylate synthase.The target compound was obtained by a Fisher-indole type cyclization of the hydrazone 16 from 2-amino-6-hydrazino-4-oxopyrimidine (10) and diethyl N--L-glutamate (15) followed by catalytic reduction of the product 17.Similarly, modification of the Fisher-indole type cyclization of the appropriate hydrazone precursors 11 and 12 afforded the nonclassical analogues 3-amino-7,8,9-trimethyl-2H-pyrrolopyridopyrimidin-1-one (4) and 3-amino-8-benzyl-7,9-dimethyl-2H-pyrrolopyridopyrimidin-1-one (5), respectively.The target compound 2, its aromatic precursor 18, and the nonclassical analogue 4 were evaluated as inhibitors of the growth of Manca human lymphoma cells and also as inhibitors of human dihydrofolate reductase, human thymidylate synthase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase.Compound 18 showed weak inhibition of lymphoma cell growth (IC50 = 42 μM) and of AICAR formylTF (IC50 = 17 μM).Compounds 2 and 4 did not inhibit lymphoma cell growth or thymidylate synthase.The inactivity of 2 was attributed to its lack of flexibility leading to its inability to bind to thymidylate synthase.
