A detailed analysis of the molecular and crystal packing of a series of pharmaceutically active triazolothiadiazole derivatives is reported. The most notable feature from the analysis of the supramolecular motifs is the presence of inversion dimers due to the formation of strong S•••N chalcogen bonds. This has been unequivocally established via inputs from energy calculations from PIXEL, the topological analysis using the approach of QTAIM from AIMALL, an analysis of the molecular electrostatic potentials plotted on Hirshfeld surfaces, and the analysis of the 3D-deformation densities obtained using Crystal Explorer. The total interaction energy for this contact is in the range of 28−33 kJ/mol in the molecules under investigation, and the electrostatic (Coulombic + polarization) contribution toward the total stabilization energy is more than 70%, indicating that such interactions are principally electrostatic in origin. The results from the analysis of the molecular ESP depict that this interaction exists between a strongly electropositive σ-hole on the sulfur atom and an electronegative region on the nitrogen. 3D-deformation density (DD) maps reveal the presence of a charge depletion (CD) region on the sulfur atom which is directed toward the charge concentration (CC) region on the nitrogen atom facilitating formation of such contacts in the crystal. These are further invesigated by QTAIM based calculations which establish the closed-shell nature of these contacts. The crystal packing is further stabilized by the presence of significantly important π•••π stacking interactions, wherein the interaction energies, calculated by the PIXEL method, reveal that some of these interactions in crystals have significant contributions from electrostatic components, with a lesser contribution from dispersion forces that normally dominate such interactions. The existence of a contribution of ∼48% from electrostatics between stacked rings owing to their unique electrostatic complementarity is a rare supramolecular feature observed in crystal packing in these solids. In addition, the existence of C−H•••O, C−H•••N, C−H•••F, and Cl•••N interactions is also characterized by a significant electrostatic component in their formation in crystals of these compounds.

Nicotinic acetylcholine receptors containing α9 subunits are essential for the auditory function and have been implicated, along with α7containing nicotinic receptors, as potential targets for the treatment of inflammatory and neuropathic pain. The study of α9-containing receptors has been hampered by the lack of selective agonists. The only α9-selective antagonists previously identified are peptide conotoxins. Curiously, the activity of α7 and α9 receptors as modulators of inflammatory pain appears to not rely strictly on ion channel activation, which led to the identification of α7 "silent agonists" and phosphocholine as an "unconventional agonist" for α9 containing receptors. The parallel testing of the α7 silent agonist p-CF 3 −diEPP and phosphocholine led to the discovery that p-CF 3 −diEPP was an α9 agonist. In this report, we compared the activity of α7 and α9 with a family of structurally related compounds, most of which were previously shown to be α7 partial or silent agonists. We identify several potent α9-selective agonists as well as numerous potent and selective α9 antagonists and describe the structural basis for these activities. Several of these compounds have previously been shown to be effective in animal models of inflammatory pain, an activity that was assumed to be due to α7 silent agonism but may, in fact, be due to α9 activity. The α9-selective conotoxin antagonists have also been shown to reduce pain in similar models. Our identification of these new α9 agonists and antagonists may prove to be invaluable for defining an optimal approach for treating pain, allowing for reduced use of opioid drugs.

A series of novel pyrazole–rhodanine derivatives was designed, synthesized, and biologically evaluated for their potential inhibitory effect on both aldehyde reductase (ALR1) and aldose reductase (ALR2).

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