Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents.
A simple and efficient synthesis of 6-fluoro-4-oxopyrido[2,3-a]carbazole-3-carboxylic acids (13a-e) and a structurally related 6-fluoro-4-oxothieno[2',3':4,5]pyrrolo[3,2-h]quinoline (13f) was achieved via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. The ability of 13a-f to inhibit the activity of DNA gyrase and topoisomerase IV was also investigated. The thieno isostere (13f) emerged as the most active antibacterial, while the 9-fluoro derivative (13e) was the most potent against multidrug-resistant staphylococci. Compounds 13a, 13c-f displayed growth inhibition against MCF-7 breast tumor and A549 non-small cell lung cancer cells coupled with an absence of cytotoxicity toward normal human-derm fibroblasts (HuDe). Compound 13e was the most active anticancer against MCF-7 cells, with greater potency than ellipticine (IC(50) 0.8 and 1.6muM, respectively). The most active compounds in this series show promise as dual acting anticancer and antibacterial chemotherapeutics.
Al-Trawneh
Salah A
SA
Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan.
Zahra
Jalal A
JA
Kamal
Marwan R
MR
El-Abadelah
Mustafa M
MM
Zani
Franca
F
Incerti
Matteo
M
Cavazzoni
Andrea
A
Alfieri
Roberta R
RR
Petronini
Pier G
PG
Vicini
Paola
P
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D027081:DNA Gyrase / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy; D005260:Female; D024841:Fluoroquinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase