7035-71-4Relevant academic research and scientific papers
Intramolecular hydrogen bonding in medicinal chemistry
Kuhn, Bernd,Mohr, Peter,Stahl, Martin
supporting information; experimental part, p. 2601 - 2611 (2010/08/05)
The formation of intramolecular hydrogen bonds has a very pronounced effect on molecular structure and properties. We study both aspects in detail with the aim of enabling a more rational use of this class of interactions in medicinal chemistry. On the basis of exhaustive searches in crystal structure databases, we derive propensities for intramolecular hydrogen bond formation of five- to eight-membered ring systems of relevance in drug discovery. A number of motifs, several of which are clearly underutilized in drug discovery, are analyzed in more detail by comparing small molecule and protein-ligand X-ray structures. To investigate effects on physicochemical properties, sets of closely related structures with and without the ability to form intramolecular hydrogen bonds were designed, synthesized, and characterized with respect to membrane permeability, water solubility, and lipophilicity. We find that changes in these properties depend on a subtle balance between the strength of the hydrogen bond interaction, geometry of the newly formed ring system, and the relative energies of the open and closed conformations in polar and unpolar environments. A number of general guidelines for medicinal chemists emerge from this study
Photoinduced molecular rearrangements. The photochemistry of some 1,2,4-oxadiazoles in the presence of nitrogen nucleophiles. Formation of 1,2,4-triazoles, indazoles, and benzimidazoles
Buscemi, Silvestre,Vivona, Nicolo,Caronna, Tullio
, p. 8397 - 8401 (2007/10/03)
The photochemistry of some 3,5-disubstituted 1,2,4-oxadiazoles in the presence of nitrogen nucleophiles [external, such as added amines or hydrazines, or internal, such as an o-aminophenyl moiety at C(3) of the oxadiazole ring] has been investigated. In the irradiation of 5-amino-(or 5-N-substituted amino) 3-phenyl-1,2,4-oxadiazoles in the presence of aliphatic primary amines (or ammonia), photolytic species arising from heterolytic cleavage of the ring O-N bond capture the nucleophilic reagent to give open-chain intermediates, which develop into 1,2,4-triazolin-5-ones. Similarly, irradiations of 3,5-diphenyl-, 3-methoxy-5-phenyl-, and 5-methyl-3-phenyl-1,2,4-oxadiazoles gave 1,2,4-triazoles. In the same context, irradiations of representative substrates in the presence of hydrazines have been also investigated. In the irradiation of 3-(o-aminophenyl)-5-methyl-, 3-[o-(methylamino)phenyl]-5-methyl-, and 3-(o-aminophenyl)-5-phenyl-1,2,4-oxadiazoles, concomitant formation of indazoles and benzimidazoles, presumably arising from a common photolytic species, has been observed. Some mechanistic aspects have been considered, and possible applications in synthesis have been pointed out.
