Original article Identification and development of 2,5-disubstituted oxadiazole as potential candidate for treatment of XDR and MDR tuberculosis Ravi L. Bakal a, * , Surendra G. Gattani b a Department of Medicinal Chemistry, Wadhwani College of Pharmacy, Dhamangaon Road, Yavatmal, Maharashtra 445001, India b H.R.Patel Institute of Pharmaceutical Education and Research, Near Karvand Naka, Shirpur Dist., Dhule, Maharashtra 425405, India article info Article history: Received 28 September 2011 Received in revised form 24 October 2011 Accepted 28 October 2011 Available online 6 November 2011 Keywords: MDR-TB Mycobacterium tuberculosis Oxadiazole Clinical isolates abstract Tuberculosis, the infection on the verge of eradication once, is now a great threat to mankind. Emergence of MDR and XDR-TB synergised with HIV and other immune-compressive diseases have increased the life threatening capacities of the disease. A small molecule has been identified here, which showed potent anti-tubercular activity. The identified hit compound has also been proved active against nearly 25 clinical isolates comparable with isoniazid. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Mycobacterium tuberculosis (MTB, M. tuberculosis), the etiolog- ical agent of tuberculosis (TB), is the leading cause of mortality due to bacterial pathogens, claiming about 2 million lives annually. The field of anti-tuberculosis drug discovery culminated in the 1960s with the incorporation of rifampicin and pyrazinamide in the tuberculosis drug regimen. The use of these two antimicrobials, in combination with isoniazid, ethambutol and/or streptomycin, represents a landmark in the treatment of human tuberculosis and resulted in the implementation of short-course chemotherapy (SCC), reducing the time of treatment from 18 to 6 months [1e3]. Short-course chemotherapy contributed towards controlling tuberculosis burden for the next 20 years. Nevertheless, tubercu- losis cases started to rise again in the 1990s under the pressure of the HIV pandemic and the emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) tuberculosis strains. MDR strains are resistant to at least isoniazid (INH) and rifampicin (RIF), whereas XDR strains are MDR isolates that are additionally resis- tant to fluoroquinolones and to one of the three injectable drugs capreomycin, amikacin and kanamycin. The emergence and dissemination of MDR and XDR isolates, estimated to account for more than 400,000 new cases per year, impart new challenges in tuberculosis control [4]. Indeed, current treatment of drug resistant tuberculosis requires 18e36 months and is associated with an unacceptable rate of treatment failure and relapse. Consequently, developing new compounds active against MDR and XDR tuber- culosis constitutes a main objective in anti-tuberculosis drug discovery. In addition, new antimycobacterial agents should ideally contribute to shorten tuberculosis treatment to 2 months or less [5,6]. Few promising drug candidates fulfilling these criteria have been discovered in recent years [7e9]. Mainly, TMC207, which has been shown to be highly active in proof-of-concept trials, and shows the potential to shorten the duration of therapy [10,11]. Recently, there are several reports citing oxadiazole as potential antibacterial and anti-tubercular agent [12e15]. Inspired by the citations, we decided to design around the heterocycles and eval- uate the antimycobacterial activity of the same. Nonetheless, given the number of tuberculosis cases and the rate of emergence of drug resistance, more compounds are clearly needed to combat and have a significant impact on the control and spread of tuberculosis. Thus in continuation with the search of new drug candidate we herein discuss this report about development of a lead to hit molecule. 2. Results and discussion 2.1. Chemistry In our attempt to synthesise cost effective drug, oxadiazole was identified as better target, easy and cheaper to synthesis. The * Corresponding author. Tel.: þ91 9421831717; fax: þ91 7232 238747. E-mail address: nddd2011@gmail.com (R.L. Bakal). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.10.054 European Journal of Medicinal Chemistry 47 (2012) 278e282