Molecular Insights of 7‑Azaindole Drugs and Their Intercalation in the Confined Space of Montmorillonite.

Two derivatives of the group of 7-azaindoles, 1-benzyl-3-(piperidin-1-ylmethyl)-1H-pyrrolo [2,3-b] pyridine, and 1-benzyl-5-methoxy-3-(piperidin-1-ylmethyl)-1H-pyrrolo [2,3-b] pyridine as mono-oxalate salts are studied in this work as potential neuroprotective drugs for the treatment of Alzheimer's disease. Previously, we studied the use of a natural montmorillonite clay mineral as a candidate for a drug delivery system, finding that these drugs can be intercalated into the confined interlayer space of montmorillonite and subsequently released in a human medium for therapeutic use. However, some aspects of this study could not be explained. This work has studied this process at the atomic and molecular levels by using the Interface force field (FF). Initially, this methodology was validated in this work, reproducing the experimental crystal structure of these 7-azaindole drugs. Then, this FF was applied to calculate the intercalation of these drugs by cation exchange into montmorillonite according to the experimental results. Our calculations have reproduced this intercalation at the cation exchange capacity at the molecular level, finding that the experimental structure can only be justified with the intercalation of five drug molecules per 4 × 2 × 1 supercell of clay mineral inside the confined interlayer space. In addition, this intercalation does not produce a monolayer disposition postulated initially from experiments. On the contrary, our molecular dynamics simulations show that the intercalated molecules adopt a disordered disposition with a certain tendency to form a bilayer configuration in the confined interlayer space of montmorillonite. Besides, the spectroscopic infrared properties are useful for monitoring the preparation and encapsulation processes of pharmaceutical drugs. Then, these properties were studied experimentally and calculated theoretically. The calculated frequencies of the crystal structure of these 7-azaindole drugs allowed assignments of the experimental FT-IR spectra. This collaborative work with experimental and theoretical research enhances the knowledge for a promising drug delivery system for anti-Alzheimer therapy.