Design, synthesis, molecular docking and biological evaluation of new carbazole derivatives as anticancer, and antioxidant agents

Abstract

Background: The carbazole skeleton is an important structural motif occurring naturally or synthesized chemically and has antihistaminic, antioxidant, antitumor, antimicrobial, and anti-inflammatory activities.

Objectives: This study aimed to design and synthesize a novel series of carbazole derivatives and evaluate their antiproliferative and antioxidant activities.

Methods: The synthesized compounds were characterized utilizing HRMS, ¹H-, and ¹³C_APT-NMR, and assessed for their anticancer, antifibrotic, and antioxidant effects utilizing reference biomedical procedures. In addition, the AutoDock Vina application was used to perform in-silico docking computations.

Results: A series of carbazole derivatives were synthesized and characterized in the current study. Compounds 10 and 11 were found to have a stronger antiproliferative effect than compounds 2-5 against HepG2, HeLa, and MCF7 cancer cell lines with IC₅₀ values of 7.68, 10.09, and 6.44 µM, respectively. Moreover, compound 9 showed potent antiproliferative activity against HeLa cancer cell lines with an IC₅₀ value of 7.59 µM. However, except for compound 5, all of the synthesized compounds showed moderate antiproliferative activities against CaCo-2 with IC₅₀ values in the range of 43.7-187.23 µM. All of these values were compared with the positive control anticancer drug 5-Fluorouracil (5-FU). In addition, compound 9 showed the most potent anti-fibrotic compound, and the cellular viability of LX-2 was found 57.96% at 1 µM concentration in comparison with the positive control 5-FU. Moreover, 4 and 9 compounds showed potent antioxidant activities with IC₅₀ values of 1.05 ± 0.77 and 5.15 ± 1.01 µM, respectively.

Conclusion: Most of the synthesized carbazole derivatives showed promising antiproliferative, antioxidant, and antifibrotic biological effects, and further in-vivo investigations are needed to approve or disapprove these results.

Keywords: Anticancer; Antifibrotic; Antioxidant; Carbazole; Doxorubicin; LX-2; Molecular docking.

Fig. 1

The structures of some carbazole alkaloids with anticancer activities

Scheme 1

(i) Ethyl bromoacetate, NaH, DMF; then, hydrazine hydrate (80%), ethanol, reflux, 24 h; (ii) sulfonyl chloride, Et₃N, THF, rt, 18 h; (iii) -Ph (or p-Cl-Ph) isothiocyanate, ethanol, reflux, 3 h; (iv) Ethyl bromoacetate, sodium acetate, ethanol, reflux, 3 h; (v) CDI, DMF, rt, 1d. (vi) 4-Fluorobenzoyl chloride, Et₃N, DMF, 4 h

Fig. 2

Cell viability percentages against HeLa, HepG2, and MCF-7 for all synthesized compounds versus Dox (positive control) and DMSO (negative control)

Fig. 3

The cell viability of the LX2 cell line after treatment with the synthesized 9–11 compounds and positive control 5-FU

Fig. 4

The percentage of inhibition against DPPH after treatment with different concentrations of synthesized compounds (2–5, 8–11) and positive control Trolox

Fig. 5

3D (a) and 2D (b) molecular docking results with Autodock Vina and cartone (c) and surface (d) forms with CB-Dock for 3 + XDH/PDB: 3UNI (A Chain)

Fig. 6

3D (a) and 2D (b) molecular docking results with Autodock Vina and cartone (c) and surface (d) forms with CB-Dock for 11 + PPARG/PDB: 3VSO (A Chain)

Fig. 7

The placement within XDH/PDB: 3UNI (A Chain) and PPARG/PDB: 3VSO (A Chain) of 3 and 11 molecules

Fig. 8

The bioavailability radars of 2–5 and 8–11 compounds

Fig. 9

The boiled-egg plots of compounds 2–5 and 8–11

Fig. 10

The RMSD/time plots presenting the molecular dynamics simulation trajectory of A 3UNI-Ligand 9 complex, B 3UNI-Ligand 10 complex, the red color represents the 3UNI protein backbone, the blue and green colors represent the ligands 9, and 10 respectively