Abstract
In the present study a series of Schiff bases of indoline-2,3-dione were synthesized and investigated for their Mtb gyrase inhibitory activity. Promising inhibitory activity was demonstrated with some of these derivatives, which exhibited IC50 values ranging from 50–157 μM. The orientation and the ligand-receptor interactions of such molecules within the Mtb DNA gyrase A subunit active site were investigated applying a multi-step docking protocol using Molecular Operating Environment (MOE) and Autodock4 docking software. The results revealed the importance of the isatin moiety and the connecting side chain for strong interactions with the enzyme active site. Among the tested compounds the terminal aromatic ring benzofuran showed the best activity. Promising new leads for developing a novel class of Mtb gyrase inhibitors were obtained from Schiff bases of indoline-2,3-dione.
Highlights
Infections caused by mycobacteria are the single largest cause of death worldwide.Fluoroquinolones have been used with limited success as part of a second-line chemotherapeutic regime against mycobacterial diseases
Maximum activity was shown with compound 18, we propose that it can be utilized as a lead structure for future chemical optimization studies for novel inhibitors of the Mycobacterium tuberculosis (Mtb) enzyme DNA gyrase
The modeling results showed the importance of the isatin moiety and the connecting side chain for strong interactions with the enzyme active site
Summary
Fluoroquinolones have been used with limited success as part of a second-line chemotherapeutic regime against mycobacterial diseases. With the global emergence of multidrug-resistant tuberculosis (MDRTB) and extensively drug-resistant tuberculosis (XDRTB) there is an urgent need to develop new anti-mycobacterials. Design of new inhibitors with greater efficacy against mycobacterial enzymes would facilitate the development of efficient anti-TB drugs [1]. Mycobacterium tuberculosis (Mtb), the aetiologic agent of tuberculosis, is unusual in that it possesses only one type II topoisomerase, DNA gyrase [2]. The Mtb DNA gyrase exhibits a different activity spectrum as compared to other DNA gyrases. Despite the fact that it supercoils DNA with an efficiency comparable to that of other DNA gyrases it shows enhanced relaxation, DNA cleavage, and decatenation activities [3]
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