ABSTRACT
The synthesis of 4',6'-dihydrospiro[piperidine-4,5'-pyrazolo[3,4-c]pyridin]-7'(2'H)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 tert-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues.
Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Acetyl-CoA Carboxylase/chemistry , Lactams/chemistry , Lactams/chemical synthesis , Piperidines/chemistry , Piperidines/chemical synthesis , Pyrazoles/chemistry , Pyridones/chemistry , Pyridones/chemical synthesis , Alkylation , Cyclization , Molecular Structure , StereoisomerismABSTRACT
Phosphopantetheine adenylyltransferase (PPAT) is an essential enzyme in Coenzyme A biosynthesis. Because bacterial PPAT and mammalian PPAT are dissimilar, this enzyme is an attractive antibacterial target. Based on the structure of the substrate, 4-phosphopantetheine, a dipeptide library was designed, synthesised and tested against Escherichia coli PPAT. The most potent inhibitor PTX040334 was co-crystallised with E. coli PPAT. With this structural information, a rational iterative medicinal chemistry program was initiated, aimed at increasing the number of inhibitor-enzyme interactions. A very potent and specific inhibitor, PTX042695, with an IC(50) of 6 nM against E.coli PPAT, but with no activity against porcine PPAT, was obtained.
Subject(s)
Dipeptides/pharmacology , Enzyme Inhibitors/pharmacology , Nucleotidyltransferases/antagonists & inhibitors , Coenzyme A/biosynthesis , Dipeptides/chemical synthesis , Dipeptides/chemistry , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Escherichia coli/drug effects , Escherichia coli/enzymology , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Nucleotidyltransferases/metabolismABSTRACT
A series of 2(Z)-2-benzylidene-6,7-dihydroxybenzofuran-3[2H]-ones was identified as potent inhibitors of bacterial chorismate synthase. The 2'-hydroxy-4'-pentoxy analogue 33 is a potent inhibitor of Streptococcus pneumoniae chorismate synthase.
