4-[5-(4-Fluoro­phen­yl)-1H-imidazol-4-yl]pyridine

In the title compound, C14H10FN3, the imidazole ring makes dihedral angles of 28.2 (1) and 36.60 (9)° with the pyridine ring and the 4-fluoro­phenyl ring, respectively. The pyridine ring forms a dihedral angle of 44.68 (9)° with the 4-fluoro­phenyl ring. Inter­molecular N—H⋯N hydrogen bonds are observed in the crystal structure

3-Amino-2-methyl-4-oxo-3,4-dihydro­quinazolin-1-ium p-toluene­sulfonate monohydrate

In the title hydrated mol­ecular salt, C9H10N3O+·C7H7O3S−·H2O, the cation is protonated at a quinazolinone N atom and an intra­molecular N—H⋯O hydrogen bond occurs. In the crystal structure, inter­molecular N—H⋯O and O—H⋯O hydrogen bonds and C—H⋯O, C—H⋯π and weak aromatic π–π stacking inter­actions [centroid–centroid separations = 3.8648 (12) and 3.9306 (13) Å] help to establish the packing; a short S=O⋯π contact is also seen

Structural characterization of the Hepatitis C Virus NS3 protease from genotype 3a: The basis of the genotype 1b vs. 3a inhibitor potency shift

AbstractThe first structural characterization of the genotype 3a Hepatitis C Virus NS3 protease is reported, providing insight into the differential susceptibility of 1b and 3a proteases to certain inhibitors. Interaction of the 3a NS3 protease with a P2–P4 macrocyclic and a linear phenethylamide inhibitor was investigated. In addition, the effect of the NS4A cofactor binding on the conformation of the protease was analyzed. Complexation of NS3 with the phenethylamide inhibitor significantly stabilizes the protease but binding does not involve residues 168 and 123, two key amino acids underlying the different inhibition of genotype 1b vs. 3a proteases by P2–P4 macrocycles. Therefore, we studied the dynamic behavior of these two residues in the phenethylamide complex, serving as a model of the situation in the apo 3a protein, in order to explore the structural basis of the inhibition potency shift between the proteases of the genotypes 1b and 3a

Probing of Exosites Leads to Novel Inhibitor Scaffolds of HCV NS3/4A Proteinase

Hepatitis C is a treatment-resistant disease affecting millions of people worldwide. The hepatitis C virus (HCV) genome is a single-stranded RNA molecule. After infection of the host cell, viral RNA is translated into a polyprotein that is cleaved by host and viral proteinases into functional, structural and non-structural, viral proteins. Cleavage of the polyprotein involves the viral NS3/4A proteinase, a proven drug target. HCV mutates as it replicates and, as a result, multiple emerging quasispecies become rapidly resistant to anti-virals, including NS3/4A inhibitors.To circumvent drug resistance and complement the existing anti-virals, NS3/4A inhibitors, which are additional and distinct from the FDA-approved telaprevir and boceprevir α-ketoamide inhibitors, are required. To test potential new avenues for inhibitor development, we have probed several distinct exosites of NS3/4A which are either outside of or partially overlapping with the active site groove of the proteinase. For this purpose, we employed virtual ligand screening using the 275,000 compound library of the Developmental Therapeutics Program (NCI/NIH) and the X-ray crystal structure of NS3/4A as a ligand source and a target, respectively. As a result, we identified several novel, previously uncharacterized, nanomolar range inhibitory scaffolds, which suppressed of the NS3/4A activity in vitro and replication of a sub-genomic HCV RNA replicon with a luciferase reporter in human hepatocarcinoma cells. The binding sites of these novel inhibitors do not significantly overlap with those of α-ketoamides. As a result, the most common resistant mutations, including V36M, R155K, A156T, D168A and V170A, did not considerably diminish the inhibitory potency of certain novel inhibitor scaffolds we identified.Overall, the further optimization of both the in silico strategy and software platform we developed and lead compounds we identified may lead to advances in novel anti-virals

A total synthesis of zoapatanol

The novel structure and contragestational activity of zoapatanol, an oxepane ring containing diterpene make it an interesting synthetic target. Chapter Two describes the synthesis of a model compound, 2,2-dimethyl6E-(2-hydroxyethylidene)oxepan-3-ol. The alkylation of an anion equivalent of diethyl fumarate with a homoallylic halide and the acid catalysed cyclisation of an epoxy-diol to give, under optimised conditions, only the desired oxepane derivative were the key steps. Chapter Three is concerned with some attempted routes to zoapatanol, using geraniol as the starting material. Functionalisation at the 10-position was achieved by reaction with hypochlorous acid, terminal epoxidation or reaction with selenium dioxide. The ultimate failure of these approaches was due to a lack of stereospecificity in the onecarbon homologation at the 1-position. A successful synthesis of zoapatanol is the subject of Chapter Four. Carboalumination of 7-benzyloxy-6-methylhept-l-yne and quenching of the vinyl alane with ethylene oxide produced the key homoallylic alcohol. By the use of a similar sequence of reactions to that employed in the model compound synthesis, this alcohol was transformed into an epoxydiol which was cyclised to give an oxepane derivative with a functionalised side chain. Further elaboration afforded the title compound.</p