Pergamon Bioorganic & Medicinal Chemistry Letters 9 (1999) 1651-1656 BIOORGAN1C & MEDICINAL CHEMISTRY LETrERS NITROQUINOLONES WITH BROAD-SPECTRUM ANTIMYCOBACTERIAL ACTIVITY IN VITRO Marino Artico, #* Antonello Mai, # Gianluca Sbardella, # Silvio Massa, + Chiara Musiu, ;~ Stefania LostiaJ: Francesca Demontis, ~ and Paolo La Colla ;t* #Dipartimento di Studi Farmaceutici, Universitgt di Roma "La Sapienza", p.le Aldo Moro 5, 1-00185 Roma, Italy +Dipartimento Farmaco Chimico Tecnologico, Universit~ di Siena, Banchi di Sotto 55, 1-53100 Siena, Italy CDipartimento di Biologia Sperimentale, Sezione di Microbiologia, Universitgt di Cagliari, Cittadella Universitaria, SS 554 - 1-09042 Monserrato (Cagliari), Italy Received 8 March 1999; accepted 30 April 1999 Abstract. During search on quinolonecarboxylic acids we used a facile, convenient two- or three-step procedure to synthesize new quinolone analogs, bearing at the C-7 position alkylamino substituents, and at the C-6 position a fluorine or alternatively a nitro group. The new derivatives were tested against both Gram- positive and Gram-negative bacteria and against a number of different mycobacteria. In vitro assays showed l-tert-butyl-7-tert-butylamino-6-nitro-1,4-dihydro-4-quinolone-3-carboxylic acid to be a potent inhibitor of Streptococcus and Staphylococcus with potencies superior to those of ofloxacin and ciprofloxacin, used as reference drugs. Some 6-nitroquinolones were found to exert good inhibiting activities against Mycobacterium tuberculosis and various atypical mycobacteria, whereas the 6-fluoro counterparts showed poor or no activity against this bacterium. © 1999 Elsevier Science Ltd. All rights reserved. Nitroheterocycles have been carefully studied as potential agents for the therapy of infectious diseases caused by pathogenic bacteria, fungi and protozoa.l Search on nitrofurans, nitroimidazoles and nitropyrroles has led to the discovery of potent drugs such as nitrofurantoin, 2 metronidazole 3 and pyrrolnitrin. 4 In particular, the nitrofuran and nitroimidazole groups have shown a remarkable broad spectrum of antimicrobial effects, antibacterial activity included. 5 Nevertheless, there are few reports concerning the antimycobacterial activity of members of these classes. Some years ago, 2-ethyl-2,3-dihydro-6-nitroimidazo[2,1-b]oxazole (1) 6 has been claimed to possess potent in vitro and in vivo antimycobacterial activity, with a good therapeutic index. Unfortunately, this compound has been reported to be mutagenic in the Ames test and this finding has compromised further development. 0 0 0 ~[~ N ~ . ~ . / C H 3 HN v N" HN" v N" HN" N v i i I I I RII R R R R R 1 2 3 4 R = R 1 or R:x R 1 R,R 1 = cyclopropyl, tert-butyl Nitroquinolones have been scarcely studied as antibacterial agents because of the poor activity shown by some members, such as 3-nitroquinolones, 7 against Gram-positive and Gram-negative bacteria. However, * Corresponding authors: tel&fax +39 06 4462731/E-maih artico@uniromal.it and tel +39 070 670989, fax +39 070 670802/E-maih placolla@unica.it 0960-894X/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(99)00251-6