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

Mohammad Shahidul Islam,Sammer Yousuf,Abdullah Saleh Alamary,Abdullah Mohammed Al-Majid,Assem Barakat,Muhammad Iqbal Choudhary,M Ali,Saeed Alshahrani

doi:10.3390/molecules26082212

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.

Highlights

Nitrogen heterocycles are key components of several biochemical, and possess interesting biological properties
We describe the synthesis of the new hits based on indole/
The achiral Friedel–Crafts reaction was explored with the chalcones-based benzofuran or thiophene analogues and the substituted indole by employing Fe-Pd bimetallic catalyst system [23] in MeOH at 60 ◦ C to afford the Friedel–Crafts adducts

Summary

Introduction

Nitrogen heterocycles (natural and synthetic) are key components of several biochemical, and possess interesting biological properties. Indoles are one such class of organic heterocyclic compounds that occur frequently as a privileged structural motif in many synthetic and natural products with versatile pharmacological activities [1]. In many cases they have widespread uses as cholesterol lowering agents, antiviral, antibacterial, antifungal, and as anticancer compounds [2]. Ajmalicine is an anti-hypertensive alkaloid [10], asperazine has an unusual profile of cytotoxicity [11,12], and dragmacidin exhibits anti-tumor activity against P-388 cell lines with IC50 value of 15 μg/mL, and IC50 of 1–10 μg/mL against MDAMB (human mammary), HCT-8 (human colon) and A-549

Methods

Results

Conclusion