Design, synthesis and inhibitory activity against Mycobacterium tuberculosis thymidine monophosphate kinase of acyclic nucleoside analogues with a distal imidazoquinolinone.
Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt) has been proposed as an attractive target in the search of new agents to fight against tuberculosis. We recently reported that thymine derivatives carrying a naphtholactam or naphthosultam moiety at position 4 of a (Z)-butenyl chain inhibit TMPKmt in the subμM range. Here we describe the replacement of the planar naphtholactam and naphthosultam rings in our identified hits by 5,6-dihydro-1H-imidazo[4,5,1-ij]quinolinones and a 5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3,2-ij]quinoline-2,2-dioxide where the planarity has been broken. Interestingly, these non-planar compounds were similarly potent against the target enzyme than their aromatic analogues, suggesting a bioisosteric behavior that may also be applied to other biologically active compounds. The synthesis of the different targeted imidazoquinolinones has been successfully performed via a hypervalent iodide mediated oxidative cyclization of N-methoxyureas catalized by bis(trifluoroacetoxy)iodobenzene (PIFA) expanding the reported use of this reagent for the synthesis of differently substituted imidazoquinolinones.
Familiar
Olga
O
Instituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.
Munier-Lehmann
Hélène
H
Aínsa
José Antonio
JA
Camarasa
María-José
MJ
Pérez-Pérez
María-Jesús
MJ
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009705:Nucleosides; D015363:Quinolones; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase