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Eur J Pharm Sci. 2015 May 25;72:81-92. doi: 10.1016/j.ejps.2015.02.017. Epub 2015 Mar 11.

Identification of potential Mycobacterium tuberculosis topoisomerase I inhibitors: a study against active, dormant and resistant tuberculosis.

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Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.


Mycobacterium tuberculosis (Mtb) topoisomerase I (Topo I), involved in the relaxation of negatively supercoiled DNA, plays an important role in the viability of pathogen Mtb. Being one of the most significant enzymes; it also takes part in crucial biological pathways such as transcription and replication of the pathogen. The present study aims at the development of Mtb Topo I 3D protein structure which in turn was employed for the virtual screening of compound libraries in a process of identification of a hit molecule. The identified hit, hydroxycamptothecin, was active at 6.25 μM which was further derivatized synthetically into fifteen novel analogues. Among these, four compounds (3b, 3g, 3h and 3l) emerged to be active displaying IC50 values ranging from 2.9 to 9.3 μM against Mtb Topo I and were non-cytotoxic at 25 μM. These four compounds also proved their efficacy when tested against active, dormant and resistant forms of Mtb. The most potent inhibitor 3b was screened for in vivo anti-mycobacterial activity using zebrafish model and was found to be more effective when compared to first line anti-tubercular drugs, isoniazid and rifampicin. The binding affinity of this compound towards Mtb Topo I was analyzed by differential scanning fluorimetry which resulted in a positive shift in melting temperature when compared to the native protein thereby proving its stabilization effect over protein.


Mycobacterium tuberculosis; Topoisomerase I; Tuberculosis

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