Synthesis, crystal structure, DFT, Hirshfeld surface analysis, energy frameworks and in-Silico drug-targeting PFKFB3 kinase of novel triazolequinoxalin derivative (TZQ) as a therapeutic Strategy against cancer

Abstract

Overall, drug design is a dynamic and evolving field, with researchers constantly working to improve their understanding of molecular interactions, develop new computational methods, and explore innovative techniques for creating effective and safe medications. The process can involve steps such as the identification of targets, the discovery of lead compounds, lead optimization, preliminary testing, human trials, regulatory approval and finally post-marketing surveillance, all aimed at bringing a new drug from concept to market. In this article, the synthesis of the novel triazolequinoxalin (TZQ) 1-((1-hexyl-1H-1,2,3-triazol-5-yl)methyl)-3-phenylquinoxalin-2(1H)-one (4) is reported. The structure has been identified with a variety of spectroscopic methods (1H, 13C NMR, and LC-MS) and finally, the structure has been determined by X-ray diffraction (XRD) studies. The TZQ molecule has crystallized in the monoclinic space C2/c group with unit cell dimensions a = 41.201(2) Å, b = 10.6339(6) Å, c = 9.4997(4) Å, β = 93.904(4). The crystal structure is stabilized by intermolecular interactions (N-H ⋯ O and N-H … Cg) occurring within the molecule. The presence of these intermolecular interactions is evaluated through analysis of Hirshfeld surfaces (HS) and two-dimensional (2D) chemical fingerprints map. Additionally, energy frameworks were employed to identify the prevailing interaction energy influencing the molecular arrangement. Density Functional Theory (DFT) calculations were computed to establish concurrence between theoretical and experimental results. Furthermore, the HOMO-LUMO energy levels were determined using the B3LYP/6-31+G(d, p) level of theory. Finally, molecular docking was used to predict the anti-cancer activity of the compound (4) against PFKFB3 kinase and presented noticeable hydrophilic and hydrophobic interactions at the active site region.

Keywords: Anti-cancer docking studies; Energy framework; Hirshfeld surface; Triazolequinoxalin.

Scheme 1

Quinoxaline as a scaffold for many natural products.

Scheme 2

Reaction pathway for the synthesis of the title TZQ compounds (3 and 4).

Fig. 1

Molecular structure of compound (4) with anisotropic displacement ellipsoids drawn at 50 % probability level.

Fig. 2

Partial crystal packing of compound (4) showing the C–H⋅⋅⋅O, C–H⋅⋅⋅N and CO⋅⋅⋅π interactions. Symmetry codes: (i) x, y, −1+z; (ii) 3/2- x, −1/2+ y, 1/2- z, (iii) x, -y, ½+z.

Fig. 3

Frontier-molecular orbital HOMO-LUMO and energy gap of the title compound.

Fig. 4

(A) Hirshfeld surface mapped over d_norm, (a) Fingerprint plot of the compound from all the intermolecular contacts. (B), (C), (D) and (E) are the 2D fingerprint plots showing H–H, C–H, O–H, N–H contacts with the percentages contribution and (b), (c), (d) and (e) represent the associated d_norm Hirshfeld surfaces respectively.

Fig. 5

Two views (a, b) of the Hirshfeld surface mapped over d_norm for compound (4) over the range −0.2745 to 1.5767 a.u.

Fig. 6

Hirshfeld surface mapped over (a) shape index and (b) curvedness.

Fig. 7

The pictorial illustration of a) electrostatic coulomb interaction energy depicted in red, b) dispersion energy depicted in green, c) total interaction energy depicted in blue along different axes of the title compound.

Fig. 8

The pictorial representation of the compound (4), binded inside the cavity of pocket of PFKFB3 Kinase.