Polycyclic Quinolones (Part 1) — Thieno[2,3-b]benzo[h]quinoline Derivatives: Design, Synthesis, Preliminary in vitro and in silico Studies

Abstract

Heterocyclic systems with a quinoline nucleus represent the most spectacular example of privileged molecules in medicinal chemistry, as their biological activities are surely affected by changes in structural features. Quinoline derivatives have been shown to display a wide spectrum of biological activities such as antibacterial, antifungal, antiparasitic, antiviral, cytotoxic and anti-inflammatory activities. In this study, several 7-hydroxy-8-oxo-8,9-dihydrobenzo[h]thieno[2,3-b]quinoline-9-carboxylic acids were designed, synthesized, and were further subjected to chemical reactions such as alkylation and annelation. The synthesized compounds were also subjected to docking study and biological evaluation. This work was mainly designed to shed light on the requirements for the quinoline nucleus to act as an anticancer agent. Unexpectedly, the synthesized derivatives showed weak or no cytotoxicity against cancer cell lines and the increase in the extent of aromatic/condensed rings did not increase the affinity toward the double stranded DNA. Our virtual screening demonstrated that the chelation with Mg is a determining factor in the expected interaction with Topoisomerases. Key synthetic issues, crystallographic and docking studies have also been described. INTRODUCTION Quinoline derivatives represent a major class of heterocycles. The quinoline ring system occurs in various natural products, especially in alkaloids. Its skeleton is often used for the design of many synthetic compounds with diverse pharmacological properties. The 4(1H)-quinolone-3-carboxylic acid is one of the most studied quinoline-originated multivalent scaffold that has been used in constructing a diverse series of biologically active compounds such as antibacterials, anticancers and antiviral agents. HETEROCYCLES, Vol. 85, No. 1, 2012 103