Unveiling the structural and theoretical properties of 6-(2-fluoro-3-methylpyridin-4-yl)-2-(4-methoxyphenyl)-N-phenylquinoline-4-carboxamide compound as Sonic Hedgehog protein inhibitor: Synthesis, SCXRD, HSA, DFT, Docking and ADMET studies

Shalini, V. and Kumar, D. C. V. and Darshini, G. and Chethan, B. S. and Harsha, K. B. and Rajesh, S. M. and Rangappa, K. S. (2025) Unveiling the structural and theoretical properties of 6-(2-fluoro-3-methylpyridin-4-yl)-2-(4-methoxyphenyl)-N-phenylquinoline-4-carboxamide compound as Sonic Hedgehog protein inhibitor: Synthesis, SCXRD, HSA, DFT, Docking and ADMET studies. Journal of Molecular Structure, 1330. ISSN 0022-2860

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Abstract

The Hedgehog (Hh) pathway, when constitutively activated, can lead to tumour development in basal cell carcinomas and medulloblastomas. One of the effective ways for limiting tumour growth and preventing illness recurrence following surgery, radiation treatment, or chemotherapy is the inhibition of the Hedgehog signalling pathway. Inhibitors of the hedgehog pathway are therefore a significant class of anti-cancer medications. Owing to this, the present study aimed to synthesis the 6-(2-fluoro-3-methylpyridin-4-yl)-2-(4-methoxyphenyl)-N-phe- nylquinoline-4-carboxamide (QCA)- compound using Suzuki coupling reaction method, later the compound was confirmed using various spectroscopic characterization like LCMS, 1H NMR, 13C NMR and FTIR spectroscopy. In addition, the obtained crystal was subjected to the single crystal X-ray diffraction method, which shows the molecule crystallizes in the triclinic crystal system of P1 space group. Further, the molecular structure of QCA compound forms inter and intramolecular hydrogen bond interactions, which are results in the formation of S(6) self-motif, R2 1(7) graph-set ring motif, C-H⋅⋅⋅π weak hydrogen bond interactions respectively. These interactions in the crystal network were further corroborated using Hirshfeld surface and 2D fingerprint plot analysis, and later through Bader’s quantum theory of atoms in molecules (QTAIM). For the interpretation of results, computational methods currently make a strong supplement to experimental data. Hence, the DFT approach was used to optimize the geometry of the compound to its ground state. The computed energies demonstrated the stability and reactivity of the QCA compound for the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO). Using the same theoretical framework, a representation of the molecular electrostatic potential (MEP) was drawn to show the molecule’s charge distribution and chemical reactivity. Several physicochemical properties of the QCA molecule are examined and found that QCA compound has an optimal range of physicochemical and ADMET properties hence indicating adherence to Lipinski’s rule of five for favorable safety profiles with favourable pharmacokinetics. The molecular docking simulation of the synthesized QCA molecule with Sonic Hedgehog protein and was carried out using MGL tools 1.5.6 with AutoDock Vina. The docking studies revealed that the molecule might possess potential anticancer activity against Sonic Hedgehog protein, which is compared to the standard drug Glasdegib.

Item Type:	Article
Uncontrolled Keywords:	QCA, XRD, DFT, QTAIM, Docking, ADMET,
Subjects:	C Chemical Science > Chemistry
Divisions:	Department of > Chemistry
Depositing User:	Ms Varalakshmi
Date Deposited:	27 Oct 2025 06:14
Last Modified:	27 Oct 2025 06:14
URI:	http://eprints.uni-mysore.ac.in/id/eprint/17867

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