Design, Synthesis, Biological Evaluation, 2D-QSAR Modeling, and Molecular Docking Studies of Novel 1 H-3-Indolyl Derivatives as Significant Antioxidants

Abstract

Novel candidates of 3-(4-(thiophen-2-yl)-pyridin/pyran/pyrimidin/pyrazol-2-yl)-1H-indole derivatives (2-12) were designed by pairing the pyridine/pyrane/pyrimidine/pyrazole heterocycles with indole and thiophene to investigate their potential activities as (2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) inhibitors. The purpose of these derivatives' modification is to create high-efficiency antioxidants, especially against ABTS, as a result of the efficiency of this set of key heterocycles in the inhibition of ROS. Herein, 2D QSAR modeling was performed to recommend the most promising members for further in vitro investigations. Furthermore, the pharmacological assay for antioxidant activity evaluation of the yielded indole-based heterocycles was tested against ABTS (2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid); by utilizing ascorbic acid as the standard. Candidate 10 showed higher antioxidant activity (IC₅₀ = 28.23 μg/mL) than ascorbic acid itself which achieved (IC₅₀ = 30.03 μg/mL). Moreover, molecular docking studies were performed for the newly designed and synthesized drug candidates to propose their mechanism of action as promising cytochrome c peroxidase inhibitors compared to ascorbic acid as a reference standard. Our findings could be promising in the medicinal chemistry scope for further optimization of the newly designed and synthesized compounds regarding the introduced structure-activity relationship study (SAR) in order to get a superior antioxidant lead compound in the near future.

Keywords: 2D-QSAR modeling; ABTS assay; antioxidant activity; ascorbic acid; docking studies; indole chalcones.

Figure 1

Rationale of the newly synthesized 1H-3-indolyl derivatives using molecular association.

Scheme 1

Synthesis of the starting candidate.

Scheme 2

Synthesis of functional pyrimidine ring by hetero-cyclization of chalcone 1.

Scheme 3

Synthesis of pyrazoles by cyclo-condensation reaction of chalcone 1 with hydrazines.

Scheme 4

Synthesis A six-membered ring (pyran/cyclohexenone/pyridone) from the mother candidate using various reagents.

Scheme 5

Formation of 2-amino-6-(1H-indol-3-yl)-4-(thiophen-2-yl)-4H-pyran-3-carbonitrile and its condensed derivatives.

Figure 2

ABTS radical scavenging effect of (thiophen-2-yl)-1H-indole derivatives with standard ascorbic acid.

Figure 3

Graphical presentation of considerable antioxidant activity of thiophen-2-ylindole candidates (2, 3, 4, 7, 8, 10, 12b, 12d, and 12e).

Figure 4

Structure-activity relationship study of the newly designed and synthesized derivatives tested biologically as antioxidants.

Figure 5

The correlation plot between predicted IC50 ($Pred.) values on the x-axis and IC50 values on the y-axis for compounds 2, 10, 3, 12b, 12d, 12e, and ascorbic acid. The plots give R² values equal to 0.6673.