N-Alkyl isatin crystal packing, interaction energies and in-silico antiviral profiling: Single-crystal, PIXEL, QTAIM/NCI and docking studies of two 1-Alkylindole-2,3-diones

Nchioua, Intissar, Jana, Bidhan Chandra, Allah, Abderrazzak El Moutaouakil Ala, Dey, Pratik, Seth, Saikat Kumar, Said, Musa A., Al-Kaff, Nadia S., Kariuki, Benson ORCID: https://orcid.org/0000-0002-8658-3897 and Ramli, Youssef 2026. N-Alkyl isatin crystal packing, interaction energies and in-silico antiviral profiling: Single-crystal, PIXEL, QTAIM/NCI and docking studies of two 1-Alkylindole-2,3-diones. Journal of Molecular Structure 1372 , 146636. 10.1016/j.molstruc.2026.146636

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Abstract

Two N-alkylated isatin derivatives, 1-propylindole-2,3-dione (1) and 1-ethylindole-2,3-dione (2), were synthesised and structurally characterised by single-crystal X-ray diffraction. Compound (1) crystallises in the orthorhombic space group P 2₁2₁2₁, whereas compound (2) adopts a triclinic P–1 lattice with two crystallographically independent molecules in the asymmetric unit. In the solid state, both molecules assemble through weak C–H···O hydrogen bonds, lone-pair···π contacts, and π···π stacking into extended one- and two-dimensional supramolecular networks. Hirshfeld surface analysis, decomposed 2D fingerprint plots, and enrichment ratios quantify the relative importance of H···H, O···H/H···O, C···C, and C···H/H···C contacts in directing crystal packing. PIXEL calculations provide pairwise interaction and lattice energies, showing that dispersion provides the major stabilising contribution (≈54–55%) with a significant electrostatic component in both crystals, while QTAIM and NCI analyses confirm the closed-shell, weakly attractive nature of the key intermolecular contacts. Molecular docking against SARS-CoV-2 main protease (Mpro, PDB: 6LU7) and vaccinia virus thymidylate kinase (TMPK, PDB: 2V54) shows that compounds (1) and (2) preserve the isatin pharmacophore of Methisazone and achieve comparable binding energies at the poxvirus TMPK pocket (≈ −5.9 kcal/mol for both), while exhibiting moderate affinity for Mpro (−5.4 and −5.5 kcal/mol, respectively), lower than Methisazone (−6.1 kcal/mol) and the reference inhibitor N3 (−7.8 kcal/mol).. In-silico ADMET profiling indicates drug-like pharmacokinetics and manageable predicted toxicity, identifying N-alkyl isatins as computationally attractive candidates for poxvirus-directed antiviral investigation, pending experimental validation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Chemistry
Additional Information:	License information from Publisher: LICENSE 1: Title: This article is under embargo with an end date yet to be finalised.
Publisher:	Elsevier
ISSN:	0022-2860
Date of Acceptance:	22 May 2026
Last Modified:	02 Aug 2026 19:44
URI:	https://orca.cardiff.ac.uk/id/eprint/187366

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