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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)-N-1 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 (3a-e) was achieved by the three-component reactions of 1H-indole-3-carbaldehyde (1), ethyl 3-oxobutanoate, 5,5-dimethyl cyclohexane-1,3-dione (Dimidone), barbituric, thiobarbituric acid, and cyclohexanone (2a-e), respectively; and malononitrile in the presence of triethylamine. Compound (4) was afforded by fusing of compound (3a) with thiourea. Also, compounds (5a, b) were yielded by the grinding of compounds (3c, d) with formic acid. On the other side, one-pot synthesis of 7a-d has been achieved via three-component of 1H-indole-3-carbaldehyde (1), and malononitrile in the presence of amine derivatives (namely, 2,4-dinitroaniline, 3-nitroaniline, 3-bromoaniline, and 4-methoxyaniline) (6a-d), respectively, by condensation. Also, compounds (8, 9) were obtained by refluxing of compounds (7a, b) with formic acid. Compound (10) was afforded by condensing the mixture of 1H-indole-3-carbaldehyde (1) 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 (3a-e) using the three-component reactions of 1H-indole-3-carbaldehyde (1) with active methylene compounds namely: ethyl 3-oxobutanoate, 5, 5-dimethy cyclohexane-1, 3-dione (Dimidone), barbituric acid, thiobarbituric acid, and cyclohexanone (2a-e); and malononitrile in ethanol and triethylamine as catalyst were proceeded in one step. Also, compounds (3a, 3c, d) were reacted with thiourea/and formic acid, respectively, to give compounds (4 and 5a, b). The 3-indole derivatives (7a-d) were formed via condensation of the amine derivatives (6a-d) with indole aldehydes (1) and malononitrile. Compounds (8 and 9) were afforded by condensation of compounds (7b, c) with formic acid, 2-amino-chromene (10) was produced by reaction of resorcinol, 1H-indole-3-carbaldehyde (1), 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 in vivo and pharmacokinetic studies.
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Reference:
Indole alkaloid derivatives as building blocks of natural products from Bacillus thuringiensis and Bacillus velezensis and their antibacterial and antifungal activity study,
,Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles