119158-00-8Relevant articles and documents
Arginine analogues incorporating carboxylate bioisosteric functions are micromolar inhibitors of human recombinant DDAH-1
Tommasi, Sara,Zanato, Chiara,Lewis, Benjamin C.,Nair, Pramod C.,Dall'Angelo, Sergio,Zanda, Matteo,Mangoni, Arduino A.
, p. 11315 - 11330 (2015/11/27)
Dimethylarginine dimethylaminohydrolase (DDAH) is a key enzyme involved in the metabolism of asymmetric dimethylarginine (ADMA) and N-monomethyl arginine (NMMA), which are endogenous inhibitors of the nitric oxide synthase (NOS) family of enzymes. Two isoforms of DDAH have been identified in humans, DDAH-1 and DDAH-2. DDAH-1 inhibition represents a promising strategy to limit the overproduction of NO in pathological states without affecting the homeostatic role of this important messenger molecule. Here we describe the design and synthesis of 12 novel DDAH-1 inhibitors and report their derived kinetic parameters, IC50 and Ki. Arginine analogue 10a, characterized by an acylsulfonamide isosteric replacement of the carboxylate, showed a 13-fold greater inhibitory potential relative to the known DDAH-1 inhibitor, L-257. Compound 10a was utilized to study the putative binding interactions of human DDAH-1 inhibition using molecular dynamics simulations. The latter suggests that several stabilizing interactions occur in the DDAH-1 active-site, providing structural insights for the enhanced inhibitory potential demonstrated by in vitro inhibition studies.
Substituted 2-Imino-5-arylidenethiazolidin-4-one Inhibitors of Bacterial Type III Secretion
Kline, Toni,Felise, Heather B.,Barry, Kathleen C.,Jackson, Stona R.,Nguyen, Hai V.,Miller, Samuel I.
experimental part, p. 7065 - 7074 (2009/11/30)
Diverse species of pathogenic Gram-negative bacteria use secretion systems to export a variety of protein toxins and virulence factors that help establish and maintain infection. Disruption of such secretion systems is a potentially effective therapeutic strategy. We developed a high-throughput screen and identified a trisaryl substituted 2-imino-5-arylidenethiazolidin-4-one, compound 1, as an inhibitor of the type III secretion system. Expansion of this chemotype enabled us to define the essential pharmacophore for type III secretion inhibition by this structural class. A synthetic diversity set helped us identify N-3 as the most permissive locus and led to the design of a panel of novel N-3-dipeptide-modified congeners with improved activity and physiochemical properties. We now report on the synthesis of these compounds, including a novel solid phase approach to the rapid generation of the dipeptide-thiazolidinone hybrids, and their in vitro characterization as inhibitors of type III secretion in Salmonella enterica serovar Typhimurium.
