Bimetallic Iron–Palladium Catalyst System as a Lewis-Acid for the Synthesis of Novel Pharmacophores Based Indole Scaffold as Anticancer Agents

Abstract

The Friedel–Crafts reaction between substituted indoles as nucleophiles with chalcones-based benzofuran and benzothiophene scaffolds was carried out by employing a highly efficient bimetallic iron–palladium catalyst system. This catalytic approach produced the desired bis-heteroaryl products with low catalyst loading, a simple procedure, and with acceptable yield. All synthesized indole scaffolds 3a–3s were initially evaluated for their cytotoxic effect against human fibroblast BJ cell lines and appeared to be non-cytotoxic. All non-cytotoxic compounds 3a–3s were then evaluated for their anticancer activities against cervical cancer HeLa, prostate cancer PC3, and breast cancer MCF-7 cell lines, in comparison to standard drug doxorubicin, with IC50 values 1.9 ± 0.4 µM, 0.9 ± 0.14 µM and 0.79 ± 0.05 µM, respectively, and appeared to be moderate to weak anticancer agents. Fluoro-substituted chalcone moiety-containing compounds, 3b appeared to be the most active member of the series against cervical HeLa (IC50 = 8.2 ± 0.2 µM) and breast MCF-7 cancer cell line (IC50 = 12.3 ± 0.04 µM), whereas 6-fluroindol-4-bromophenyl chalcone-containing compound 3e (IC50 = 7.8 ± 0.4 µM) appeared to be more active against PC3 prostate cancer cell line.

The anti‐breast cancer potential of indole/isatin hybrids

“…The indole-benzofuran hybrid 71 (IC 50 : 12.37 µM) was somewhat less effective than doxorubicin (IC 50 : 0.79 µM) and additional structural modifications are required. [110] Indole-isatin hybrids 72 (IC 50 : 0.70-22.73 µM) exhibited strong activity against ZR-75 BC cells, with the SARs highlighting that (1) the activity was significantly impacted by substituents at N-1 position of isatin moiety, and the order of relative contribution was benzyl > methyl > hydrogen; (2) enhancement of the activity was observed in the presence of chloro and bromo halogen atoms at the C-5 position. [111] Notably, hybrids 72a,b (IC 50 : 0.74 and 0.70 µM) had a potency that was higher by ~11-folds than sunitinib (IC 50 : 8.31 µM).…”

“…The indole‐benzofuran hybrid 71 (IC 50 : 12.37 µM) was somewhat less effective than doxorubicin (IC 50 : 0.79 µM) and additional structural modifications are required. [ 110 ]…”

Insight into Indole‐Based Heterocyclic Scaffolds: A Medicinal Chemistry Perspective

“…Mohammad Shahidul Islam et al [28] developed a protocol for synthesis of new pharmacophores-based indole derivatives 36 (a-s). In this process, Friedel-Craft reaction was carried out between chalcones-based benzofuran and benzothiophene derivatives 34 (a-l) and substituted indole 35 (a-c) acting as nucleophile in the presence of methanol and FeÀ Pd bimetallic catalyst system at 60 °C.…”

“…Mohammad Shahidul Islam et al [28] . developed a protocol for synthesis of new pharmacophores‐based indole derivatives 36 (a–s) .…”