Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis

Hong, David, Gibbons, Peter, Leung, Suet C, Amewu, Richard, Stocks, Paul A, Stachulski, Andrew, Horta, Pedro, Cristiano, Maria L. S., Shone, Alison, Moss, Darren, Ardrey, Alison, Sharma, Raman, Warman, Ashley, Bedingfield, Paul, Fisher, Nicholas, Aljayyoussi, Ghaith, Mead, Sally, Caws, Maxine ORCID: https://orcid.org/0000-0002-9109-350X, Berry, Neil, Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, O’Neill, Paul M and Nixon, Gemma L (2017) 'Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis'. Journal of Medicinal Chemistry, Vol 60, Issue 9, pp. 3703-3726.

Text Quinolone J Med Chem - TB - final - revised.docx - Accepted Version Available under License Creative Commons Attribution. Download (2MB)

Abstract

In 2014, tuberculosis (TB) globally infected 9.6 million people, resulting in an estimated 1.5 million deaths.(1) With the emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB, the need for new drug treatments targeting the disease has never been greater.(2) Current first line drugs for TB were developed in 1952–1966 (Figure 1). Shortcomings of these drugs include: (i) long treatment regimens (6–9 months), leading to patient noncompliance, (ii) adverse drug–drug interactions with anti HIV drugs (HIV/AIDS is a common coinfection), and (iii) limited or no activity against MDR and XDR Mycobacterium tuberculosis (Mtb).(3) Bedaquiline(4, 5) and delamanid(6, 7) are the only recently FDA approved drugs for the treatment of TB, and their approval is currently only for MDR in cases where established treatments have failed (Figure 1).(8) To find an effective treatment for MDR and XDR, it is believed that a drug with a novel mode of action is required in order to circumvent resistance.

Item Type:	Article
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 250 Anti-infective agents (General) QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 268 Antitubercular agents. Antitubercular antibiotics QW Microbiology and Immunology > Bacteria > QW 125 Actinibacteria, Actinomycetales. WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General)
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1021/acs.jmedchem.6b01718
Depositing User:	Stacy Murtagh
Date Deposited:	19 May 2017 10:03
Last Modified:	26 Jan 2021 09:22
URI:	https://archive.lstmed.ac.uk/id/eprint/7109

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