Synthesis of gatifloxacin derivatives and their biological activities against Mycobacterium leprae and Mycobacterium tuberculosis Catherine Gomez a , Prishila Ponien a , Nawal Serradji a , Aazdine Lamouri a , Alix Pantel b,c , Estelle Capton b , Vincent Jarlier b,c,d , Guillaume Anquetin a,⇑ , Alexandra Aubry b,c,d,⇑ a Université Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR CNRS 7086, 15 rue J-A de Baïf, 75205 Paris Cedex 13, France b UPMC Université Paris 06, ER5 (EA 1541), laboratoire de Bactériologie-Hygiène, F-75005 Paris, France c AP-HP, Hôpital Pitié-Salpêtrière, laboratoire de Bactériologie-Hygiène, F-75013 Paris, France d Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, F-75013 Paris, France article info Article history: Received 12 October 2012 Revised 29 November 2012 Accepted 3 December 2012 Available online 20 December 2012 Keywords: Quinolones Mycobacterium leprae Mycobacterium tuberculosis DNA gyrase SAR Gatifloxacin abstract Novel 3 0 -piperazinyl derivatives of the 8-hydrogeno and 8-methoxy-6-fluoro-1-cyclopropyl-4- quinolone-3-carboxylic acid scaffolds were designed, synthesized and characterized by 1 H, 13 C and 19 F NMR, and HRMS. The activity of these derivatives against pathogenic mycobacteria (M. leprae and M. tuberculosis), wild-type (WT) strains or strains harboring mutations implicated in quinolone resistance, were determined by measuring drug concentrations inhibiting cell growth (MIC) and/or DNA supercoiling by DNA gyrase (IC 50 ), or inducing 25% DNA cleavage by DNA gyrase (CC 25 ). Compound 4 (with a methoxy in R 8 and a secondary carbamate in R 3 0 ) and compound 5 (with a hydrogen in R 8 and an ethyl ester in R 3 0 ) displayed biological activities close to those of ofloxacin but inferior to those of gatifloxacin and moxiflox- acin against M. tuberculosis and M. leprae WT DNA gyrases, whereas all of the compounds were less active in inhibiting M. tuberculosis growth and M. leprae mutant DNA gyrases. Since R 3 0 substitutions have been poorly investigated previously, our results may help to design new quinolone derivatives in the future. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Controlling leprosy and tuberculosis (TB), two communicable diseases caused by Mycobacterium leprae and Mycobacterium tuber- culosis, respectively, is often challenging due to the emergence of multidrug-resistant strains. 1 The World Health Assembly decided, in 1991, to ‘eliminate leprosy as a public health problem’ by the year 2000. After an important decrease in the number of new cases of leprosy detected each year worldwide, from 763,000 in 2000 to 299,000 in 2005, the decrease was gradual since 2005, with 228,000 new cases at the end of 2010. 1 In conjunction with this still high number of new cases, leprosy resistant to dapsone and rifampin therapy emerged. Similarly, TB affecting millions of peo- ple worldwide remains a public health challenge, partly due to the emergence of multidrug-resistant tuberculosis (MDR-TB), that is, TB resistant to both isoniazid and rifampin, which currently rep- resents a serious obstacle to TB control. As a consequence of the threat of drug-resistant TB and leprosy, the WHO Stop TB Strategy 2 and the Final Push strategy to eliminate leprosy 3 emphasize the need to increase surveillance, control, and treatment efforts. The development of new antimycobacterial drugs should have two objectives: shorten treatment to improve compliance and maintain activity against drug-resistant strains. Quinolones are good candi- dates for the development of more powerful agents against leprosy and tuberculosis. 4 They play a critical role in the treatment of MDR-TB and drug-resistant leprosy. Moxifloxacin and gatifloxacin (Fig. 1) are the most active quinolones against M. tuberculosis and M. leprae, and are under evaluation to shorten the treatment of TB and leprosy caused by susceptible mycobacteria. 4 Unfortu- nately, MDR-TB strains resistant also to quinolones have emerged, leading to virtually untreatable 0 eXtensively Drug Resistant 0 (XDR) tuberculosis. Cases of leprosy resistant to dapsone, rifampin and quinolones have been reported also. 5 In the future, quinolone resis- tance will likely increase in TB and leprosy due to (i) poor MDR-TB management, (ii) increasing use of quinolones in susceptible TB, and (iii) wide use of quinolones for empirical treatment of a larger range of non-mycobacterial infections such as urinary and respira- tory tract infections, diarrhea and typhoid fever, which are com- mon infections in the areas of high prevalence of tuberculosis and leprosy. 6,7 Quinolones act by forming a reversible ternary complex with their bacterial targets (DNA gyrase and topoisomerase IV) and DNA, blocking bacterial growth and chromosome fragmentation, 0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2012.12.011 ⇑ Corresponding authors. Tel.: +33 1 57 27 72 57; fax: +33 1 57 27 72 63 (G.A.). Present address: Laboratoire de Bactériologie, Faculté de Médecine Pierre et Marie Curie, 91 Boulevard de l’hôpital, 75634 Paris Cedex 13, France. Tel.: +33 1 40 77 97 46; fax: +33 1 45 82 75 77 (A.A.). E-mail addresses: guillaume.anquetin@univ-paris-diderot.fr (G. Anquetin), alexandra.aubry@upmc.fr (A. Aubry). Bioorganic & Medicinal Chemistry 21 (2013) 948–956 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc