Polycyclic angular thieno, thiazeto, thiazolo and furobenzo[h]quiolines : design, synthesis, in vitro and in silico evaluation

Ahmed, Abeer Ahmed Abuelmagd (2012) Polycyclic angular thieno, thiazeto, thiazolo and furobenzo[h]quiolines : design, synthesis, in vitro and in silico evaluation. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Functionalized quinolines and their benzo/hetero-fused analogs are an important class of organic molecules that have attracted the attention of synthetic and medicinal chemists, because of their presence in numerous natural products and their wide range of biological activities. The quinolines, particularly those substituted at position 4, have marked antimalarial, antibacterial, anti-inflammatory, anticancer, and antiviral activities. -- The remarkable applications of these compounds have not only prompted many chemists to synthesize these types of compounds, they have also become an active research area of continuing interest. -- In this work a structure-based drug design was done using Hyperchem-3(TM) in order to develop a quinoline-originated Topoisomerase inhibitor with a potential anticancer and a better pharmacokinetic profile. The work involves the design and synthesis of many ring fused quinoline systems including thieno-, thiazeto-, thiazolo- and furobenzo[h] quinolines in order to clarify the structural requirements for the activity; the in-silico data determined in this work provides a deep understanding of the binding affinities of these types of derivatives. -- The results obtained in this study showed that the synthesized quinoline derivatives have good binding affinities to Human Topoisomerase II, particulary in the ATP binding region. Also, these derivatives were not able to chelate with Mg²⁺ which helped to account for the lack of cytotoxicity exihibited by these derivatives.

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