Exploring Highly Functionalized Tetrahydropyridine as a Dual Inhibitor of Monoamine Oxidase A and B: Synthesis, Structural Analysis, Single Crystal XRD, Supramolecular Assembly Exploration by Hirshfeld Surface Analysis, and Computational Studies

Abstract
Ethyl 4-(4-fluorophenylamino)-2,6-bis(4-(trifluoromethyl)phenyl)-1-(4-fluoro-phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (FTEAA) has been synthesized efficiently in an iodine-catalyzed five-component reaction of 4-fluoroaniline, 4-trifluoromethyl benzaldehyde, and ethyl acetoacetate in methanol at 55 °C for 12 h. Various spectro-analytical techniques such as 1H and 13C NMR and Fourier-transform infrared spectroscopy have validated the structure of FTEAA. Further confirmation of the structure of FTEAA has been established on the basis of single-crystal X-ray diffraction analysis. The supramolecular assembly of FTEAA in terms of strong and comparatively weak noncovalent interactions is fully investigated by Hirshfeld surface analysis, the interaction energy between pairs of molecules, and energy frameworks. The void analysis is conducted to explore the strength and stability of the crystal structure. Furthermore, molecular docking analysis was computationally performed to see the potential intermolecular interactions between the selected proteins and FTEAA. The binding interaction energies are found to be −8.8 and −9.6 kcal/mol for the proteins MAO-B (PDB ID: 2V5Z) and MAO-A (PDB ID: 2Z5X), respectively. These reasonably good binding energies (more negative values) indicate the efficient associations between the FTEAA and target proteins. The proteins and FTEAA were also analyzed for intermolecular interactions. FTEAA and proteins interact in a variety of ways, like conventional hydrogen bonds, carbon–hydrogen bonds, alkyl, π-alkyl, and halide interactions.

Citation
Khan, B. A., Ashfaq, M., Muhammad, S., Munawar, K. S., Tahir, M. N., Al-Sehemi, A. G., & Alarfaji, S. S. (2022). Exploring Highly Functionalized Tetrahydropyridine as a Dual Inhibitor of Monoamine Oxidase A and B: Synthesis, Structural Analysis, Single Crystal XRD, Supramolecular Assembly Exploration by Hirshfeld Surface Analysis, and Computational Studies. ACS Omega. https://doi.org/10.1021/acsomega.2c03909

Acknowledgements
B.A.K. is thankful to HEC Pakistan for the financial support (NRPU-6455). The authors from King Khalid University extend their appreciation to the Deanship of Scientific Research at King Khalid University, Saudi Arabia for funding this work through Small Groups RGP.1/318/43. For computer time, this research used the resources of the Supercomputing Laboratory at King Abdullah University of Science & Technology (KAUST) in Thuwal, Saudi Arabia.

Publisher
American Chemical Society (ACS)

Journal
ACS Omega

DOI
10.1021/acsomega.2c03909

Additional Links
https://pubs.acs.org/doi/10.1021/acsomega.2c03909

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