Procedures were developed for the synthesis of 3-methyl-5-phenylethynyl[1,2,4]triazine (4), 6-methyl-3-phenylethynyl[1,2,4]triazine (5), and 5-methyl-3-phenylethynyl[1,2,4]triazine (6a) as analogues of 2-methyl-6-(phenylethynyl)pyridine (2). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. The most potent of the three analogues was 6a. Twenty additional analogues of 6a were synthesized and evaluated for mGluR5 antagonist efficacy. The most potent compounds were 3-(3-methylphenylethynyl)-5-methyl[1,2,4]triazine (6b), 5-(3-chlorophenylethynyl)-5-methyl[1,2,4]triazine (6c), and 3-(3-bromophenylethynyl)-5-methyl[1,2,4]triazine (6d).
Two flavanones, hamiltones A (1) and B (2), an aurone, hamiltrone (3), a chalcone, hamilcone (4), and a tetrahydroxanthene, hamilxanthene (5), were isolated from Uvaria hamiltonii extracts guided initially by fractionation based on DNA strand-scission and/or 9KB cytotoxicity assays. Compounds 2-5 have not been reported previously, while 1 is new as a natural product. Structural assignments were made based on extensive spectroscopic measurements. Compounds 1-3 were inactive in the 9KB cytotoxicity assay, with compounds 4 and 5 having weak activity. In the DNA strand-scission assay, 3 was the most active compound found in the DNA strand-scission assay, being 10 times more potent than 1 or 2. Compound 4 was only weakly active, and 5 was inactive.
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