Design and Synthesis of 5‐Morpholino‐Thiophene‐Indole/ Oxindole Hybrids as Cytotoxic Agents

Abstract

A series of new 5‐morpholino‐thiophene‐indole/oxindole hybrids has been designed and synthesized using molecular hybridization approach. The synthesized compounds were evaluated for their in vitro cytotoxic potential against selected human cancer cell lines such as triple negative breast (MDA‐MB‐231), liver (SK‐Hep‐1), breast (MCF‐7), colon (HCT‐116) mouse melanoma (B16F10) and compared with normal human lung epithelial cell line (BEAS‐2B). Among the tested hybrids 11a–o and 13a–d, the compound 11f [(Z)‐N′‐((1‐Benzyl‐1H‐indol‐3‐yl)methylene)‐5‐morpholino‐4‐(p‐tolyl)thiophene‐2‐carbohydrazide] showed significant cytotoxic activity on HCT‐116 cancer cell line with IC50 value of 8.98 ± 0.6 μM. Cell cycle analysis revealed that compounds arrested the cell cycle in sub‐G1 phase. Moreover, JC‐1, acridine orange, DAPI nucleic acid, DCFDA staining studies suggest that one of the representative compound 11 f inhibited the cell proliferation through apoptosis. Further, molecular docking and relative viscosity studies of 11 f indicated the minor groove binding towards CT‐DNA.

Greener and Highly Efficient Synthesis, In Silico ADMET and Molecular Docking Studies of Potent Antimicrobial Thiophene Clubbed Pyrazole‐1,2,3‐Triazole Hybrids

“…[18][19][20][21][22][23][24][25][26] Moreover, compounds bearing thiophene in their structure have been found to possess potency towards a variety of biological activities such as antimicrobial, anticancer, antiinflammatory, anticonvulsant, antidiabetic, antiproliferative, and analgesic activities. [27][28][29][30][31][32][33][34][35] As per findings in the literature, pyrazole-1,2,3-triazole hybrids are potent pharmacologically active molecules. [1,9,12,13,[36][37][38] Even more, the pyrazole, thiophene, and 1,2,3-triazole rings have been found in various biologically utilized well-known synthetic drugs for the treatment of a variety of ailments (Figure 1).…”

The anti‐breast cancer potential of indole/isatin hybrids

“…[106] Mechanistically, these hybrids elevated ROS and caused cell damage leading to cell death. [108] Inducing apoptosis was the mechanism via which hybrid 69 suppressed cell proliferation. Isatin-furan hybrid 70 (IC 50 : 12.47 µM) was somewhat less effective than 5-fluorouracil (IC 50 : 5.20 µM) against MCF-7 cancer cells, with a median lethal dose (LD 50 ) of 250 mg/kg orally administered.…”

“…Replacement benzofuran by thiophene caused a decline in activity as indicated by the observation that hybrids 68 (IC 50 : 16.18–24.25 µM) exhibited lower activity than 5‐fluorouracil (IC 50 : 4.33 and 5.01 µM) against MCF‐7 and MDA‐MB‐231 cell lines, while replacement of isatin by indole seems had minimal impact on the activity, and hybrid 69 (IC 50 : 15.16 and 22.49 µM) was also effective against MCF‐7 and MDA‐MB‐231 BC cell lines. [ 108 ] Inducing apoptosis was the mechanism via which hybrid 69 suppressed cell proliferation. Isatin‐furan hybrid 70 (IC 50 : 12.47 µM) was somewhat less effective than 5‐fluorouracil (IC 50 : 5.20 µM) against MCF‐7 cancer cells, with a median lethal dose (LD 50 ) of 250 mg/kg orally administered.…”

Expedition of sulfur‐containing heterocyclic derivatives as cytotoxic agents in medicinal chemistry: A decade update

“…In addition to that, computational studies and relative viscosity analysis specified the minor groove binding towards CT-DNA. 145 The structures of various thiophene analogs supplemented by their SAR have been underlined in Figures 14 and 15. Additionally, Figure 16 displays a brief SAR with regard to the substitution pattern present on the rings and linkers, which may be favorable in designing novel thiophene scaffolds with potential antiproliferative activity.…”

“…The cell morphology and staining studies demonstrated that compound 103 inhibited cell proliferation through apoptosis. In addition to that, computational studies and relative viscosity analysis specified the minor groove binding towards CT‐DNA 145 …”