Synthesis and biological evaluation of tetracyclic thienopyridones as antibacterial and antitumor agents

The novel tetracyclic compounds, synthesized as bioisosters of fluoroquinolones, exhibited potent activity against bacteria and cancer cell lines, together with absence of cytotoxicity against normal cells. A facile synthesis of model 4-oxopyrido[3′,2′:4,5]thieno[3,2- b]indole-3-carboxylic acids 9a–...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2011-04, Vol.19 (8), p.2541-2548
Main Authors: Al-Trawneh, Salah A., El-Abadelah, Mustafa M., Zahra, Jalal A., Al-Taweel, Samir A., Zani, Franca, Incerti, Matteo, Cavazzoni, Andrea, Vicini, Paola
Format: Article
Language:English
Subjects:
4-Oxopyrido[3′,2′:4,5]thieno[3,2- b]indole-3-carboxylic acids
4-Oxothieno[2,3- b]pyridines
acids
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - pharmacology
Antibacterial activity
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Anticancer activity
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Bacillus megaterium
Bacillus subtilis
Biological and medical sciences
breast neoplasms
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
chemistry
cytotoxicity
DNA topoisomerase (ATP-hydrolysing)
Dose-Response Relationship, Drug
Female
fluoroquinolones
General aspects
Gram-Negative Bacteria - drug effects
Gram-Positive Bacteria - drug effects
growth retardation
Haemophilus influenzae
Humans
inhibitory concentration 50
lung neoplasms
Medical sciences
microwave treatment
Pharmacology. Drug treatments
Staphylococcus
Thienopyridines - chemical synthesis
Thienopyridines - pharmacology
Topoisomerase II Inhibitors
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Summary:The novel tetracyclic compounds, synthesized as bioisosters of fluoroquinolones, exhibited potent activity against bacteria and cancer cell lines, together with absence of cytotoxicity against normal cells. A facile synthesis of model 4-oxopyrido[3′,2′:4,5]thieno[3,2- b]indole-3-carboxylic acids 9a– e was achieved via Stille arylation of 2-chloro-3-nitro-4-oxothieno[2,3- b]pyridine-5-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. Compounds 9a– c and 9e exhibited very high potency against Gram positive Bacillus subtilis and Bacillus megaterium at concentrations 0.000015–0.007 μg/mL. They also displayed excellent activity towards other Gram positive bacilli and staphylococci and Gram negative Haemophilus influenzae, being in most cases superior or equal to commercial fluoroquinolones. Both 9a and 9c were inhibitors of the DNA gyrase activity. As concerns antitumor properties, compounds 9b– e showed growth inhibition of MCF-7 breast tumor and A549 non-small cell lung cancer cells with IC 50 1.6–2.8 μM and 2.6–6.9 μM, respectively, coupled with absence of cytotoxicity towards normal cells. These compounds are promising as dual acting chemotherapeutics.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.03.018