Polyaromatic Bis(indolyl)methane Derivatives with Antiproliferative and Antiparasitic Activity

Abstract

Bis(indolyl)methanes (BIMs) are a class of compounds that have been recognized as an important core in the design of drugs with important pharmacological properties, such as promising anticancer and antiparasitic activities. Here, we explored the biological activity of the BIM core functionalized with different (hetero)aromatic moieties. We synthesized substituted BIM derivatives with triphenylamine, N,N-dimethyl-1-naphthylamine and 8-hydroxylquinolyl groups, studied their photophysical properties and evaluated their in vitro antiproliferative and antiparasitic activities. The triphenylamine BIM derivative 2a displayed an IC₅₀ of 3.21, 3.30 and 3.93 μM against Trypanosoma brucei, Leishmania major and HT-29 cancer cell line, respectively. The selectivity index demonstrated that compound 2a was up to eight-fold more active against the parasites and HT-29 than against the healthy cell line MRC-5. Fluorescence microscopy studies with MRC-5 cells and T. brucei parasites incubated with derivative 2a indicate that the compound seems to accumulate in the cell's mitochondria and in the parasite's nucleus. In conclusion, the BIM scaffold functionalized with the triphenylamine moiety proved to be the most promising antiparasitic and anticancer agent of this series.

Keywords: African trypanosomiasis; antiproliferative agent; antiprotozoal agent; bis(indolyl)methane derivatives; leishmaniasis.

Figure 1

Structures of arundine, vibrindole A, arsindoline A and arsindoline B.

Scheme 1

Synthesis of bis(indolyl)methane derivatives 2a–c.

Figure 2

Fluorescence microscopy of MRC-5 cells treated with compound 2a. Cells were incubated with 5 μM of compound 2a (green channel) for 30 min (A) and 2 h (B). The mitochondria stain is represented in the red channel, and the nuclear stain is represented in the blue channel. The negative control is displayed in row (C). Scale bar: 20 μm.

Figure 3

Fluorescence microscopy of parasites T. brucei treated with compound 2a. Parasites were incubated with 5 μM of compound 2a (green channel) for 30 min (A); 1 h (B); and 2 h (C). The mitochondria stain is represented in the red channel, and the nuclear stain is represented in the blue channel. The negative control is displayed in row (D). Scale bar: 10 μm.