International Journal of Antimicrobial Agents 32 (2008) 40–45 Bactericidal activity of 2-nitroimidazole against the active replicating stage of Mycobacterium bovis BCG and Mycobacterium tuberculosis with intracellular efficacy in THP-1 macrophages Arshad Khan, Sampa Sarkar, Dhiman Sarkar ∗ Combi Chem-Bio Resource Center, National Chemical Laboratory, Dr Homi Bhabha Road, Pune 411008, India Received 13 October 2007; accepted 29 February 2008 Abstract This study evaluated the antituberculous potential of 2-nitroimidazole under in vitro conditions. Minimal bactericidal concentrations of the compound against actively replicating Mycobacterium bovis BCG and Mycobacterium tuberculosis H37Ra were found to be 0.226 g/mL and 0.556 g/mL in enriched and minimal medium, respectively. Minimal inhibitory concentrations were >100 times lower than reported antituberculous nitroimidazoles such as nitrofurantoin and furaltadone, indicating the greater potential of 2-nitroimidazole. No discernible effect of 2-nitroimidazole was seen on saprophytic Mycobacterium smegmatis and the representative bacterial strain Escherichia coli DH5, indicating the specificity of the molecule against tuberculous mycobacteria. The compound was also found to be effective against M. tuber- culosis in the intracellular environment of the human monocytic cell line THP-1, with a reduction in viability of bacilli by 2.5 log after 144 h of incubation at a concentration of 0.113 g/mL. A five-fold higher concentration (0.565 g/mL) of 2-nitroimidazole sterilised the macrophages of intracellular pathogens within 192h, without affecting the host. However, 2-nitroimidazole was unable to affect significantly the viability of dormant non-replicating bacilli of M. bovis BCG and M. tuberculosis in Wayne’s in vitro model. Overall, the results indicate that 2-nitroimidazole is a potent antituberculous agent active against the organism’s active replicating stage, with promising intracellular efficacy as well. © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Tuberculosis; Antimycobacterial agents; 2-Nitroimidazole; Nitroimidazoles; THP-1 macrophage 1. Introduction Tuberculosis (TB) is the leading cause of death of ca. 2 million of the world’s population every year [1,2]. In the last 40 years, no new drug has been developed for the treat- ment of TB [3]. The length and complexity of antibiotic therapy for TB and the emergence of multidrug-resistant strains make a compelling case for the development of new efficacious antituberculous drugs [4,5]. There is currently a great deal of interest in developing new drugs that are not only active against drug-resistant TB but that can also shorten the duration of therapy. New drug development for ∗ Corresponding author. Tel.: +91 20 2590 2400; fax: +91 20 2590 2624. E-mail address: dhimansarkar77@gmail.com (D. Sarkar). TB has been directed towards the use of the nitroimida- zole class of compounds because of their novel mechanism of action and lower chances of developing resistance [6]. Metronidazole, nitrofurantoin, furaltadone, nitrofurazone, nitroimidazopyran PA-824 and CGI-17341 are the active molecules identified in the recent past against TB, which all belong to the 5-nitroimidazole series [7–10]. A recent finding in Helicobacter pylori has clearly shown that 2- nitroimidazole-derived molecules are highly effective against strains resistant to even 5-nitroimidazole derivatives [11]. So far, attention has not been paid to evaluation of the effectiveness of 2-nitroimidazole series compounds for their antituberculous potential despite their known antibacterial activity [12]. Nitroimidazoles also remain a major attraction to medicinal chemists to work with because of their very low 0924-8579/$ – see front matter © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2008.02.022