Synthesis of new indole derivatives using one- pot multicomponent reaction with antiproliferative towards normal and cancer cell lines

Background and objectives
Indoles derivatives are natural products, which are well known for their anticancer activity due to its ability to induce cell death for many cancer cell lines. The aim of this study is to synthesize some new heterocyclic compounds derived from 1H-indole-3-carbaldehyde, malononitrile, and different reagents namely: active methylene derivatives, amine derivatives, and resorcinol. The newly synthesized derivatives were prepared and confirmed by their IR, Mass, and NMR spectra; and were also tested for their antiproliferative potency towards human breast cancer (MCF-7) and normal murine fibroblast (BALB/3T3) cell lines.
Materials and methods
The synthesis of new indole derivatives was achieved by the three-component reactions of 1H-indole-3-carbaldehyde , ethyl 3-oxobutanoate, 5,5-dimethyl cyclohexane-1,3-dione (Dimidone), barbituric, thiobarbituric acid, and cyclohexanone , respectively; and malononitrile in the presence of triethylamine. Compound was afforded by fusing of compound with thiourea. Also, compounds were yielded by the grinding of compounds with formic acid. On the other side, one-pot synthesis of has been achieved via three-component of 1H-indole-3-carbaldehyde , and malononitrile in the presence of amine derivatives (namely, 2,4-dinitroaniline, 3-nitroaniline, 3-bromoaniline, and 4-methoxyaniline) , respectively, by condensation. Also, compounds were obtained by refluxing of compounds with formic acid. Compound was afforded by condensing the mixture of 1H-indole-3-carbaldehyde with resorcinol in the presence of malononitrile and triethylamine. The newly synthesized derivatives were tested for their antiproliferative potency towards human breast cancer (MCF-7) and normal murine fibroblast (BALB/3T3) cell lines. Results indicated that they showed significant in-vitro antiproliferative activity.
Results and conclusion
A novel protocol for the preparation of indole derivatives using the three-component reactions of 1H-indole-3-carbaldehyde with active methylene compounds namely: ethyl 3-oxobutanoate, 5, 5-dimethy cyclohexane-1, 3-dione (Dimidone), barbituric acid, thiobarbituric acid, and cyclohexanone ; and malononitrile in ethanol and triethylamine as catalyst were proceeded in one step. Also, compounds ( were reacted with thiourea/and formic acid, respectively, to give compounds (. The 3-indole derivatives ( were formed via condensation of the amine derivatives with indole aldehydes and malononitrile. Compounds ( were afforded by condensation of compounds ( with formic acid, 2-amino-chromene ( was produced by reaction of resorcinol, 1H-indole-3-carbaldehyde , and malononitrile. The in-vitro study showed that most of the prepared compounds gave similar activity towards breast cancer cell line MCF-7 but did not reveal the cytotoxic potency against normal cell line. This means that most of these compounds kill cancer cells but have no or slight effects on normal cells. The newly synthesized derivatives were tested for their antiproliferative potency towards human breast cancer (MCF-7) and normal murine fibroblast (BALB/3T3) cell lines. The results showed that the in-vitro antiproliferative activity of the prepared compounds was significant and could thus be investigated for further and pharmacokinetic studies.