Synthesis of diverse amide linked bis-indoles and indole derivatives bearing coumarin-based moiety: cytotoxicity and molecular docking investigations

• Published in: Medicinal chemistry research 2018-03, Vol.27 (3), p.796-806
• Main Authors: Halawa, Ahmed H., Abd El-Gilil, Shimaa M., Bedair, Ahmed H., Eliwa, Essam M., Frese, Marcel, Sewald, Norbert, Shaaban, Mohamed, El-Agrody, Ahmed M.
• Format: Article
• Language: English
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Catalysts; Cell Biology; Cervical carcinoma; Cervix; Chemical synthesis; Chlorides; Coumarin; Cytotoxicity; Derivatives; Griseofulvin; Indoles; Mass spectrometry; Mass spectroscopy; Matrix metalloproteinase; Metalloproteinase; Molecular docking; Neutrophil collagenase; NMR; Nuclear magnetic resonance; Original Research; Pharmacology/Toxicology; Toxicity; Tryptamine
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-017-2103-7

New amide linked bis-indoles 10a , b , and 12 have been synthesized by treatment of tryptamine ( 9 ) or 5-aminoindole ( 11 ) with oxalyl chloride or adipoyl chloride. In addition, a newly indole derivatives 14 – 16 incorporated or fused with coumarin moieties have been prepared through the reaction of 9 or 11 with 4-chloro-3-formylcoumarin ( 13a ) or 4-chloro-3-nitrocoumarin ( 13b ). Further, 13-(3-nitrophenyl)-6,13-dihydrochromeno[4,3- b ]pyrrolo[3,2- f ]quinolin-12(3 H )-one ( 20 ) has been produced via one-pot Mannish reaction of 11 , 4-hydroxycoumarin ( 17 ), and 3-nitrobenzaldehyde ( 18 ) in the presence of N -chlorosuccinimide (NCS) as a catalyst. A mixture of 3-[(3 H -indol-3-ylidene)methyl]-4-hydroxy-2 H -chromen-2-one ( 24A ), and 3-[(1 H -indol-3-yl)methylene]chroman-2,4-dione ( 24B ) has been obtained with ratio 1:1 through Knoevenagel condensation reaction of indole-3-carboxaldehyde ( 21 ) and 17 . Structures of the obtained compounds have been assigned by sophisticated spectroscopic techniques ( 1 H-NMR, 13 C-NMR, and 2D NMR) and mass spectrometry. All the synthesized compounds have been screened for their cytotoxic activity against the human cervix carcinoma cell line (KB-3-1), where compounds 14a , 16 , and 20 exhibit the highest potent activity (IC 50  = 1.8, 2.2, and 7.9 µM, respectively) in comparison with the positive control (+)-Griseofulvin (IC 50  = 19.2 µM), whereas the tautomeric mixture 24A , B show moderate activity (IC 50  = 71.3 µM). Moreover, molecular docking study of the synthesized compounds toward the matrix metalloproteinase-8 (MMP-8) (PDB ID: 1MNC) has also discussed.