title: Novel biologically active nonpeptidic inhibitors of myristoylCoA:protein N-myristoyltransferase.
abstract: A new class of biologically active nonpeptidic inhibitors of Candida albicans NMT has been synthesized starting from the octapeptide ALYASKLS-NH2 (2). The synthetic strategy entailed the preparation of novel protected Ser-Lys mimics 9 and 12 from (S)- or (R)-3-iodotyrosine and then grafting key enzyme recognition elements in a stepwise manner. Like 2, compounds 16, 17, and 18 are competitive Candida NMT inhibitors that bind to the peptide recognition site of the enzyme. Moreover, 16-18 have an affinity comparable to that of 2 even though they are devoid of peptide bonds. In contrast to 2, these nonpeptidic inhibitors exhibit antifungal activity.
authors.affiliation: Department of Medicinal and Structural Chemistry, G. D. Searle and Company, St. Louis, Missouri 63198, USA.
authors.forename: B
authors.initials: B
authors.lastname: Devadas
authors.forename: S K
authors.initials: SK
authors.lastname: Freeman
authors.forename: C A
authors.initials: CA
authors.lastname: McWherter
authors.forename: N S
authors.initials: NS
authors.lastname: Kishore
authors.forename: J K
authors.initials: JK
authors.lastname: Lodge
authors.forename: E
authors.initials: E
authors.lastname: Jackson-Machelski
authors.forename: J I
authors.initials: JI
authors.lastname: Gordon
authors.forename: J A
authors.initials: JA
authors.lastname: Sikorski
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; C111359:N-(1-((3-(aminobutyl)-4-(cyclohexylethoxy)phenyl)methyl)-2-hydroxyethyl)-4-((2-methyl-1H-imidazol-1-yl)butyl)benzeneethanamine; C111360:N-(1-((3-(aminopropyl)-4-(cyclohexylethoxy)phenyl)methyl)-2-hydroxyethyl)-4-((2-methyl-1H-imidazol-1-yl)butyl)benzeneethanamine; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase