5449-87-6Relevant articles and documents
Discovery and optimisation studies of antimalarial phenotypic hits
Mital, Alka,Murugesan, Dinakaran,Kaiser, Marcel,Yeates, Clive,Gilbert, Ian H.
supporting information, p. 530 - 538 (2015/10/12)
There is an urgent need for the development of new antimalarial compounds. As a result of a phenotypic screen, several compounds with potent activity against the parasite Plasmodium falciparum were identified. Characterization of these compounds is discussed, along with approaches to optimise the physicochemical properties. The in vitro antimalarial activity of these compounds against P. falciparum K1 had EC50 values in the range of 0.09e29 mM, and generally good selectivity (typically >100-fold) compared to a mammalian cell line (L6). One example showed no significant activity against a rodent model of malaria, and more work is needed to optimise these compounds.
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.
