title: Synthesis and antibacterial activity of 3-substituted-6-(3-ethyl-4-methylanilino)uracils.
abstract: Numerous 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.
authors.affiliation: GLSynthesis Inc., One Innovation Drive, Worcester, MA 01605, USA.
authors.forename: Chengxin
authors.initials: C
authors.lastname: Zhi
authors.forename: Zheng-yu
authors.initials: ZY
authors.lastname: Long
authors.forename: Andrzej
authors.initials: A
authors.lastname: Manikowski
authors.forename: Neal C
authors.initials: NC
authors.lastname: Brown
authors.forename: Paul M
authors.initials: PM
authors.lastname: Tarantino
authors.forename: Karsten
authors.initials: K
authors.lastname: Holm
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Dix
authors.forename: George E
authors.initials: GE
authors.lastname: Wright
authors.forename: Kim A
authors.initials: KA
authors.lastname: Foster
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Butler
authors.forename: William A
authors.initials: WA
authors.lastname: LaMarr
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Skow
authors.forename: Irina
authors.initials: I
authors.lastname: Motorina
authors.forename: Serge
authors.initials: S
authors.lastname: Lamothe
authors.forename: Richard
authors.initials: R
authors.lastname: Storer
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D000900:Anti-Bacterial Agents; D014498:Uracil; D004258:DNA Polymerase III