A one-pot electrochemical nickel-catalyzed decarboxylative sp2–sp3 cross-coupling reaction has been developed using redox-active esters prepared in situ from alkyl carboxylates and N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (PITU). This undivided cell one-pot method enables C–C bond formation using inexpensive, benchtop-stable reagents with isolated yields up to 95% with good functional group tolerance, which includes nitrile, ketone, ester, alkene and selectivity over other aromatic halogens.

West Nile Virus (WNV) is a potentially deadly mosquito-borne flavivirus which has spread rapidly throughout the world. Currently there is no effective vaccine against flaviviral infections. We previously reported the identification of pyrazole ester derivatives as allosteric inhibitors of WNV NS2B-NS3 proteinase. These compounds degrade rapidly in pH 8 buffer with a half life of 1-2h. We now report the design, synthesis and in vitro evaluation of pyrazole derivatives that are inhibitors of WNV NS2B-NS3 proteinase with greatly improved stability in the assay medium.West Nile virus (WNV) is a mosquito-borne pathogen of the genus, Flavivirus. 1 This genus also contains many other human pathogens, such as Dengue virus (Den), Japanese encephalitis virus (JE), and yellow fever virus (YF). First isolated in 1937 from Uganda, WNV has since been widely distributed around the world. 2 Infections in humans are usually asymptomatic or cause a mild flu-like illness for a few days called West Nile fever. However, recent infections of WNV have been associated with much higher fatality rates particularly among the senior population. 3 Since the identification of WNV in New York in 1999 the virus has distributed itself widely throughout North America, infecting over 28,000 people (see the Center for Disease Control and Prevention site on the World Wide Web at www.cdc.gov/ncidod/dvbid/westnile/index.htm). Currently there is no effective vaccine against flaviviral infections. 2 WNV has a single-stranded RNA genome, which encodes a single polyprotein. This consists of three structural (C, prM, and E) and seven nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins. Post translational processing of the polyprotein precursor is required to produce functional viral proteins. 4 In particular, the WNV NS2B-NS3 proteinase holds promise as a potential target for therapeutic intervention with small molecule drugs. [5][6][7][8][9] Thus the identification of potent small molecule inhibitors of WNV would be a highly useful starting point for drug discovery and development.We previously reported the discovery of pyrazole derivatives as allosteric inhibitors of WNV NS2B-NS3 proteinase identified by high-throughput screening (HTS) of a small molecule library through the NIH Molecular Libraries Initiative (MLI). 10 The structures and data for compounds were deposited to the PubChem database under AID 577 (http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=577&loc=ea_ras) and AID 653 (Figure 1). However, these pyrazolyl benzoic acid ester derivatives (1-3) were rapidly hydrolyzed in an aqueous buffer (pH = 8) to the corresponding pyrazol-3-ol in approximately 1-2 hours. Clearly these compounds, while potent, were of limited use as tools to investigate the biochemistry and enzymatic kinetics of WNV NS2B-NS3 proteinase in vitro because of their instability. We hypothesized that it might be possible to design and synthesize analogues of the hits which retain potency as inhibitors of WNV NS2B-NS3 proteinase and, in addition, exh...

The first continuous flow synthesis of imidazo[1,2-a]pyridine-2-carboxylic acids directly from 2-aminopyridines and bromopyruvic acid has been developed, representing a significant advance over the corresponding in-flask method. The process was applied to the multistep synthesis of imidazo [1,2-a]pyridine-2-carboxamides, including a Mur ligase inhibitor, using a two microreactor, multistep continuous flow process without isolation of intermediates.Over the past several years high-throughput chemical synthesis has become increasingly important because of its potential to positively impact the drug discovery process. [1][2][3] Two of the most common hurdles encountered in the development of high-throughput syntheses of libraries of complex molecules have been slow reaction times and reliance on harsh or inconvenient reaction conditions. Moreover, the optimization and purification of these reactions are often time consuming and inefficient. Automated microreactor-based (microfluidic chip) continuous flow systems have the potential to greatly accelerate the production of small molecule libraries. 4, 5 Advantages include efficient heat transfer, enhanced reagent mixing, small reaction volumes, and the potential to run multistep reactions in a single, uninterrupted microreactor sequence using continuous flow conditions. 6,7 We are developing flow chemistry methods for transformations that are either not possible or highly inefficient using in-flask chemistry. This will enable the rapid synthesis of highly functionalized, druglike small molecules in high purity and on a scale sufficient for evaluation in multiple biological The imidazo[1,2-a]heterocyclic scaffold is found in compounds with anticancer, antiviral and antimicrobial activities, and in modulators of the nervous system. 8, 9 Typically, the synthesis of imidazo[1,2-a]heterocycles requires long reaction times and high temperatures, limiting the accessibility of these biologically important structures. 10 Direct condensation of 2-bromopyruvic acid with 2-aminopyridines to generate imidazo[1,2-a]pyridine-2-carboxylic acids is inefficient due to competing decarboxylation of the product at high temperatures. Therefore, stepwise protocols are generally used for the formation of imidazopyridine carboxylic acid derivatives. For example, in a typical in-flask procedure, ethyl bromopyruvate is condensed with 2-aminopyridine (Scheme 1).The product ester is isolated and subjected to saponification to provide the product. 11 Naturally, each in-flask step involves work-up and purification of the intermediates. Herein we report the first continuous flow synthesis of imidazo[1,2-a]pyridine-2-carboxylic acids from 2-aminopyridines and bromopyruvic acid using a single microreactor to enable the rapid synthesis of these compounds. We further demonstrate the incorporation of this procedure into a continuous, two microreactor method for the highly efficient preparation of a diverse library of amide derivatives.Focusing initially on the flow synthesis of imidazo[1,2,a]h...

The modification of 3′-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior drug-like properties. These analogues are more potent than 1 in vitro, and are highly selective for mGluR2 vs. other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration. The benzisothiazol-3-one derivative 14 decreased cocaine self-administration in rats, providing proof-of-concept for the use of mGluR2 PAMs for the treatment of cocaine dependence. KeywordsMetabotropic glutamate receptors; agonist; positive allosteric modulators; BINA; cocaine selfadministration Cocaine addiction is a chronic relapsing disorder affecting more than 1.6 million Americans. 1 Relapse rates among cocaine users is in the range of 94-99%, the highest among all commonly abused drugs. 2 Chronic cocaine abuse can lead to severe neurotoxicity, psychosis, lethargy, depression, or potentially death through a fatal overdose. Currently there is no effective treatment for cocaine dependence, and therefore cocaine addiction constitutes a major public health problem. Consequently, there is a significant need to identify new therapeutic agents for the treatment of cocaine and other psychomotor stimulant addictions. Recent findings suggest that neuroadaptations in glutamatergic * Corresponding Author: To whom correspondence should be addressed. ncosford@sanfordburnham.org. † These authors contributed equally to this work. NIH Public AccessAuthor Manuscript J Med Chem. Author manuscript; available in PMC 2012 January 13. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript transmission produced by repeated exposure to cocaine or other drugs of abuse are likely to contribute to the maintenance of addictive behaviors including drug use, craving and relapse to drug taking in humans. 3 Specifically, it has been shown that repeated cocaine exposure alters the function of Group II metabotropic glutamate receptors (mGluRs). 4a The Group II mGluRs include the mGluR2 and mGluR3 subtypes, which couple to G i/o proteins to negatively regulate the activity of adenylyl cyclase. 4b Brain regions implicated in different aspects of drug abuse and drug dependence, including the cerebral cortex, hippocampus, striatum, amygdala, frontal cortex and nucleus accumbens display high levels of mGluR2 and mGluR3 binding, 5 suggesting a role for the mGluR2/3 subtypes in the development of cocaine dependence and as potential targets for therapeutic agents. 3a,3e,3f,6 Orthosteric (glutamate site) mGluR2/3 agonists such as LY379268 6g are constrained amino acid analogues that do not exhibit selectivity for mGluR2 versus mGluR3, presumably because of the high degree of sequence homology at the glutamate binding site for these two recept...