Zhi, ChengxinLong, Zheng-yuManikowski, AndrzejBrown, Neal C.Tarantino, Paul M.Holm, Karsten A.Dix, Edward J.Wright, George E.Foster, Kimberly A.Butler, Michelle MarieLaMarr, William A.Skow, Donna J.Motorina, IrinaLamothe, SergeStorer, Richard2022-08-232022-08-232005-10-282008-10-16J Med Chem. 2005 Nov 3;48(22):7063-74. <a href="http://dx.doi.org/10.1021/jm050517r">Link to article on publisher's site</a>0022-2623 (Print)10.1021/jm050517r16250666https://hdl.handle.net/20.500.14038/34006Numerous 3-substituted-6-(3-ethyl-4-methylanilino)uracils (EMAU) have been synthesized and screened for their capacity to inhibit the replication-specific bacterial DNA polymerase IIIC (pol IIIC) and the growth of Gram+ bacteria in culture. Direct alkylation of 2-methoxy-6-amino-4-pyrimidone produced the N3-substituted derivatives, which were separated from the byproduct 4-alkoxy analogues. The N3-substituted derivatives were heated with a mixture of 3-ethyl-4-methylaniline and its hydrochloride to effect displacement of the 6-amino group and simultaneous demethylation of the 2-methoxy group to yield target compounds in good yields. Certain intermediates, e.g. the 3-(iodoalkyl) compounds, were converted to a variety of (3-substituted-alkyl)-EMAUs by displacement. Most compounds were potent competitive inhibitors of pol IIIC (K(i)s 0.02-0.5 microM), and those with neutral, moderately polar 3-substituents had potent antibacterial activity against Gram+ organisms in culture (MICs 0.125-10 microg/mL). Several compounds protected mice from lethal intraperitoneal (ip) infections with S. aureus (Smith) when given by the ip route. A water soluble derivative, 3-(4-morpholinylbutyl)-EMAU hydrochloride, given subcutaneously, prolonged the life of infected mice in a dose dependent manner.en-USJournal Articlehttps://escholarship.umassmed.edu/gsbs_sp/659651996gsbs_sp/659