ABSTRACT
A novel series of selective HCV NS5B RNA dependent RNA polymerase inhibitors has been disclosed. These compounds contain an appropriately substituted tetrahydrobenzothiophene scaffold. This communication will detail the SAR and activities of this series.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Thiophenes/chemistry , Thiophenes/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Caco-2 Cells , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Humans , Models, Chemical , Protein Structure, Tertiary , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Insights gained from a crystal structure of scytalone dehydratase led to the design of carboxamide inhibitors with a phenoxypropyl group substituted on the nitrogen atom Potent enzyme inhibitors were synthesized around this motif, the best of which provided excellent control of rice blast disease in greenhouse assays and outdoor field trials.
Subject(s)
Antifungal Agents/chemical synthesis , Hydro-Lyases/antagonists & inhibitors , Crystallography, X-Ray , Cyclopropanes/chemistry , Drug Design , Kinetics , Models, Chemical , Models, Molecular , Plant Diseases , Tyrphostins/chemistryABSTRACT
C9H12O3, Mr = 168.2, triclinic, P1, a = 5.5385 (6), b = 8.543 (1), c = 10.373 (1) A, alpha = 113.329 (9), beta = 100.78 (1), gamma = 99.82 (1) degree, V = 426.2 (2) A3, Dx = 1.31 g cm-3, Z = 2, Cu K alpha (lambda = 1.54178 A, graphite monochromator), mu = 8.2 cm-1, F(000) = 180, T = 293 K. Final R = 0.036, wR = 0.081 for 1559 reflections with I greater than 3 sigma(I). The relative configurations at the two chiral centers are (S,R). The dihedral angle between the five- and six-membered rings (O1--C4--C5--O3) is 69.9 (1) degree. The tetrahydropyran is in a chair conformation with the furanone ring equatorial.
