Schiff Bases of Indoline-2,3-dione Potential Novel Inhibitors of Mycobacterium Tuberculosis (Mtb) DNA Gyrase 英文参考文献.docVIP

Molecules 2011, 16, 7864-7879; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Article Schiff Bases of Indoline-2,3-dione: Potential Novel Inhibitors of Mycobacterium Tuberculosis (Mtb) DNA Gyrase ? Tarek Aboul-Fadl 1,*, Hatem A. Abdel-Aziz 1, Mohammed K. Abdel-Hamid 2, Tilal Elsaman 1, Jane Thanassi 3 and Michael J. Pucci 3 1 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia 2 Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt 3 Antimicrobial Drug Discovery, Achillion Pharmaceuticals 300 George Street New Haven, CT 06511, USA ? th Presented at the 47 International Conference on Medicinal Chemistry (RICT 2011), Lyon-France, 6-8 July 2011. * Author to whom correspondence should be addressed; E-Mail: fadl@.sa; Tel.: +966-1-467-7341; Fax: +966-1-467-6220. Received: 27 July 2011; in revised form: 23 August 2011 / Accepted: 7 September 2011 / Published: 13 September 2011 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