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Conformational stabilization mediated by hydrogen bonds can play an important role in the drug-target recognition process. Non-classical hydrogen bonding is receiving great attention, where C–H⋯Y hydrogen bonds are found in some biological systems and are important for molecular recognition, leading to the possibility of exploration of this interaction in drug design projects. Studies that identify and characterize new non-classical interactions in different systems can assist in the rational application of these interactions. In this paper, we describe the serendipitous identification and characterization of a new non-classical hydrogen bond donor moiety found in 3-acyl-substituted furan. We applied a theoretical and experimental approach in the study of several N-acylhydrazones containing 3-acyl-substituted furan, where we describe the presence of a hydrogen bond between the C(2)–H bond of 3-acyl-substituted furan with the imine nitrogen in the syn conformer of the N-acylhydrazone moiety. In addition, we evaluated the strength of this interaction with intermolecular models. Thus, we believe that the 3-acyl-substituted furan moiety can be rationally explored as a hydrogen bond donor moiety in drug design projects.

Sigma-hole (σ-hole) bonds are interactions that are gaining special attention in medicinal chemistry. This type of interaction, initially assigned to the halogens (group 17 of the periodic table), has been extended to atoms of groups 14, 15 and 16. Sulfur atoms have been outstanding for describing these interactions at the intramolecular level (to induce conformational stability) and the intermolecular level (participating in molecular recognition of bioactive compounds by their respective targets). Thus, this work describes the theoretical and experimental characterization of a 1,4-N⋯S σ-hole intramolecular interaction in the N-acylhydrazone cardioactive prototype LASSBio-294 (1), which leads to conformational stabilization and has a direct influence on the molecular properties of this inotropic prototype compared to a negative control for the interaction, LASSBio-897 (2), which is the regioisomer at the thiophene ring. Our theoretical results were reached using the B3LYP/6-311G(d) level of theory, including analysis of conformational, orbital and electrostatic properties. We performed experimental studies using IR, Raman, UV and NMR spectroscopies, which corroborated our theoretical data, showing significant differences between LASSBio-294 (1) and LASSBio-897 (2) in relation to the bond strength of the groups involved in the N⋯S interaction (S–C and NC bonds), the energies of the orbitals associated with the S lone pair (Lp(S)) and the antibonding NC π bond (π*(NC)), as well as the 15N chemical shifts in both systems. Together, our results show how this unusual interaction can influence the molecular properties of some organic compounds.