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Various acetyl aromatics when reacted with dimethylformamide dimethyl acetal gave 1‐aryl‐3‐dimethylamino‐2‐propen‐1‐ones. These intermediates are masked β‐ketoaldehydes and react with hydrazine hydrate or hydroxylamine at room temperature to give in good yields pyrazoles or isoxazoles.

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The design of a GPCR-targeted library, based on a scoring scheme for the classification of molecules into "GPCR-ligand-like" and "non-GPCR-ligand-like", is outlined. The methodology is a valuable tool that can aid in the selection and prioritization of potential GPCR ligands for bioscreening from large collections of compounds. It is based on the distillation of knowledge from large databases of GPCR and non-GPCR active agents. The method employed a set of descriptors for encoding the molecular structures and by training of a neural network for classifying the molecules. The molecular requirements were profiled and validated by using available databases of GPCR- and non-GPCR-active agents [5736 diverse GPCR-active molecules and 7506 diverse non-GPCR-active molecules from the Ensemble Database (Prous Science, 2002)]. The method enables efficient qualification or disqualification of a molecule as a potential GPCR ligand and represents a useful tool for constraining the size of GPCR-targeted libraries that will help speed up the development of new GPCR-active drugs.

Several compounds that specifically inhibited replication of the H1 and H2 subtypes of influenza virus type A were identified by screening a chemical library for antiviral activity. In single-cycle infections, the compounds inhibited virus-specific protein synthesis when added before or immediately after infection but were ineffective when added 30 min later, suggesting that an uncoating step was blocked. Sequencing of hemagglutinin (HA) genes of several independent mutant viruses resistant to the compounds revealed single amino acid changes that clustered in the stem region of the HA trimer in and near the HA2 fusion peptide. One of the compounds, an N-substituted piperidine, could be docked in a pocket in this region by computer-assisted molecular modeling. This compound blocked the fusogenic activity of HA, as evidenced by its inhibition of low-pH-induced cell-cell fusion in infected cell monolayers. An analog which was more effective than the parent compound in inhibiting virus replication was synthesized. It was also more effective in blocking other manifestations of the low-pH-induced conformational change in HA, including virus inactivation, virus-induced hemolysis of erythrocytes, and susceptibility of the HA to proteolytic degradation. Both compounds inhibited viral protein synthesis and replication more effectively in cells infected with a virus mutated in its M2 protein than with wild-type virus. The possible functional relationship between M2 and HA suggested by these results is discussed.