Design, synthesis, molecular docking and biological activity evaluation of some novel indole derivatives as potent anticancer active agents and apoptosis inducers.

Reaction of 5-morphilinosulfonylisatin (1) with acetophenones (2a-e) afforded 3-hydroxy-3-substituted-2-oxoindoles 3a-e, when treated with acetic acid the expected 3-phenacylidene-2-oxoindoles 4a-d and 4-hydroxy-5'-(morpholinosulfonyl) spiro [chromene-2, 3'-indolin]-2'-one 6 were obtained. Isatin derivative (1) was stirred with cyano derivatives to produce the arylidines (7a-c), while under reflux condition, it gave pyrrolo[2,3-b]indoles (8, 9). Moreover, istain (1) reacted with pyrazolo-5-one or 3-substituted phenol in presence of malononitrile to afford spiroxindole derivatives (10a,b) and (11a,b). Also, compounds (10a,b) and (11a,b) were obtained through cyclization of (7a) with pyrazolo-5-one or 3-substituted phenol. The obtained compounds were identified by IR, 1H NMR, 13C NMR and elemental analysis. Anticancer activity against three cancer cell lines (HepG-2, HCT-116 and MCF-7) were evaluated using sulforhodamine B assay method. Compounds 4b, 4c, 7a, 7c and 9 showed broad spectrum anticancer activity on the three tested cell lines with IC50 values less than 10 µM. Cell cycle analysis was performed for the most promising derivatives, compounds 4b and 7c arrested HepG-2 cells at G2-M phase, while compounds 7a and 9 accumulated cells at G0-G1 phase, all of them induced apoptosis at priG1 phase in the range of (11.32-19.17%). Additionally compounds 4b, 7a and 9 showed more potent activity against EGFR than Lapatinib, their IC50 values are from 0.019 to 0.026 µM while IC50 of Lapatinib is 0.028 µM. Molecular docking studies were conducted to investigate the binding mode, amino acid interactions and free binding energy of these potent derivatives.

Design, synthesis, antiproliferative activity, molecular docking and cell cycle analysis of some novel (morpholinosulfonyl) isatins with potential EGFR inhibitory activity.

New series of 5-(morpholinosulfonyl) isatin derivatives were designed and synthesized. The new compounds were characterized on the basis of spectral and elemental analyses. They were examined for their cytotoxic effects using SRB assay on four cancer cell lines HepG2, HCT116, CACO and MCF-7 in addition to the non-cancerous human cell line. They were non cytotoxic towards the normal derived cell line (IC50 value > 130 µM). Compounds 3, 6, 10 and 11 showed IC50 values less than 10 µM on three of the tested cell lines HepG2, HCT116 and CACO. Compounds 2h, 5, and 7b showed IC50 values less than or nearly equal 10 µM on HepG2, CACO and HCT116 respectively. Compounds 3 and 6 revelaed IC50 values less than 12 µM on MCF7. These obtained IC50 values are comparable with that of doxrubicin as it has showed IC50 range from 4.5 to 8.28 µM on the tested cell lines. All these promising derivatives showed inhibitory activity against EGFR with IC50 values less than 2 µM. The most potent EGFR inhibitors 7b (IC50 = 46 nM) and 10 (IC50 = 23 nM) showed to cause cell cycle arrest at G2/M phase and induce apoptosis. Molecular docking studies also were simulated to put insight and make better understanding to their structural features.

New Imidazolidineiminothione, Imidazolidin-2-one and Imidazoquinoxaline Derivatives: Synthesis and Evaluation of Antibacterial and Antifungal Activities.

A series of new 5-imino-4-thioxo-2-imidazolidinone derivatives 3 with various halogenated and alkylated aromatic substituents at N1 and N3 was synthesized. Imidazolidineiminothione derivatives 3 were prepared from the reaction of N-arylcyanothioformamide derivatives with aryl isocyanates. These compounds were used as key synthons for the preparation of wide variety of new substituted imidazole compounds. Imine hydrolysis of 3 with ethanolic HCl produced the corresponding 4-thioxo-2,5-imidazolidindiones 4. Condensation of 3 with benzophenonhydrazone furnished the corresponding 4-azine derivatives 5. Monohydrazono and dihydrazono derivatives 6 and 8 were obtained upon treatment of imidazolidinone derivatives 3 with hydrazine hydrate. Finally, imidazolidinones 3 were reacted with o-phenylenediamines or pyrazol-5(4H)-ones and afforded the corresponding imidazoquinoxaline and imidazolidin-4-ylidenepyrazolone-5(4H)-one derivatives 11 and 12, respectively. Evaluation of the antibacterial and antifungal activities for the synthesized compounds was carried out to probe their activities. Most of the tested compounds showed significant activities. The best antimicrobial activity was observed for 1-(3-ethoxyphenyl)-6-methyl-1-phenyl-1H-imidazo[4,5-b]quinoxalin-2(3H)-ones (11c) followed by 5-imino-3-(3-methoxy- phenyl)-1-phenyl-4-thioxoimidazolidin-2-one (3f).