Indole-Acrylonitrile Derivatives as Potential Antitumor and Antimicrobial Agents-Synthesis, In Vitro and In Silico Studies

Abstract

A series of 2-(1H-indol-2-yl)-3-acrylonitrile derivatives, 2a-x, 3, 4a-b, 5a-d, 6a-b, and 7, were synthesized as potential antitumor and antimicrobial agents. The structures of the prepared compounds were evaluated based on elemental analysis, IR, ¹H- and ¹³NMR, as well as MS spectra. X-ray crystal analysis of the representative 2-(1H-indol-2-yl)-3-acrylonitrile 2l showed that the acrylonitrile double bond was Z-configured. All compounds were screened at the National Cancer Institute (USA) for their activities against a panel of approximately 60 human tumor cell lines and the relationship between structure and in vitro antitumor activity is discussed. Compounds of interest 2l and 5a-d showed significant growth inhibition potency against various tumor cell lines with the mean midpoint GI₅₀ values of all tests in the range of 0.38-7.91 μM. The prominent compound with remarkable activity (GI₅₀ = 0.0244-5.06 μM) and high potency (TGI = 0.0866-0.938 μM) against some cell lines of leukemia (HL-60(TB)), non-small cell lung cancer (NCI-H522), colon cancer (COLO 205), CNS cancer (SF-539, SNB-75), ovarian cancer ((OVCAR-3), renal cancer (A498, RXF 393), and breast cancer (MDA-MB-468) was 3-[4-(dimethylamino)phenyl]-2-(1-methyl-1H-indol-2-yl)acrylonitrile (5c). Moreover, the selected 2-(1H-indol-2-yl)-3-acrylonitriles 2a-c and 2e-x were evaluated for their antibacterial and antifungal activities against Gram-positive and Gram-negative pathogens as well as Candida albicans. Among them, 2-(1H-indol-2-yl)-3-(1H-pyrrol-2-yl)acrylonitrile (2x) showed the most potent antimicrobial activity and therefore it can be considered as a lead structure for further development of antimicrobial agents. Finally, molecular docking studies as well as drug-likeness and ADME profile prediction were carried out.

Keywords: ADME; antimicrobial activity; cell growth inhibition; indole-acrylonitrile derivatives; molecular docking.

Figure 1

Structures of heteroaryl-acrylonitriles reported and studied in this work.

Scheme 1

Synthesis of 2-(1H-indol-2-yl)-3-acrylonitriles 2a–x and N-(4-(dimethylamino)phenyl)-1H-indole-2-carbimidoyl cyanide (3).

Figure 2

Molecular structure of 2l. Displacement ellipsoids are shown at the 50% probability level.

Scheme 2

Synthesis of 2-(1H-indol-2-yl)-3-phenylpropanenitriles 4a–c.

Scheme 3

Synthesis of N-substituted 2-(1H-indol-2-yl)-3-acrylonitriles 5a–d, 6a–b, and 7.

Figure 3

Comparison of the mean GI₅₀ values per panel displayed by compounds 2l and 5a–d.

Figure 4

The highest-scored poses of compound 5c (cyan sticks) docked in the active site of: caspase-3 (p17 and p12 subunits in green and orange, respectively), (A), caspase-9 (B), and tubulin (α- and β-tubulin in green and orange, respectively), (C); graphic representation of compound 5c fitted into the ligand-based pharmacophore (D). Hydrogen bonds are indicated as black dotted lines. For clarity, only relevant amino acids are presented. (A–C) were prepared using PyMOL 1.5.0.3., and (D) was generated by BIOVA Discovery Studio Visualizer (for interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article).

Figure 5

The highest-scored poses of compound 2x (cyan sticks) docked in the active site of E. coli enzyme (green), PBP4 (A), and β-lactamase (B). Hydrogen bonds are indicated as black dotted lines. For clarity, only relevant amino acids are presented. The figure was prepared using PyMOL 1.5.0.3. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article).

Figure 6

Oral bioavailability radar charts for the studied compounds 2l, 2x, and 5a–d. In bioavailability radar, the pink area represents the optimal range for each physicochemical property of oral bioavailability (LIPO—lipophilicity, SIZE—size, POLAR—polarity, INSOLU—solubility, INSATU—saturation and FLEX—flexibility), while the red lines represent compounds: (A) 2l, (B) 2x, (C) 5a, (D) 5b, (E) 5c, and (F) 5d.

Figure 7

BOILED-Egg plot for the studied compounds 2l, 2x, and 5a–d.