Evaluation of Structurally Diverse Benzoazepines Clubbed with Coumarins as Mycobacterium tuberculosis Agents

Abstract

Tuberculosis caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. In continuation with our anti-tuberculosis research programme, in this work, we have prepared molecularly diverse coumarins clubbed with benzothiazepines as well as its aza-analogues-benzodiazepines by molecular hybridization. The resulting compounds were screened for their M. tuberculosis activity against H 37 Rv strains using microplate alamar blue assay. Among the designed diversity, the compounds 5k, 5n and 5o were found significantly active in primary anti-tuberculosis assay at minimum inhibitory concentration <6.25 lM. Moreover, the IC 50 values of 5k and 5o in level-2 screening were observed as >10 lg/mL and 3.63 lg/mL, respectively. Design and synthesis of more focused library and its three-dimensional quantitative structure activity relationship analysis are underway.Key words: benzodiazepines, benzothiazepines, coumarins, H 37 Rv, microplate alamar blue assay, MtbReceived 11 January 2012, revised 13 May 2012 and accepted for publication 5 June 2012 Tuberculosis (TB) is one of the most devastating and second infectious diseases causes of mortality followed by acquired immune deficiency syndrome (AIDS). According to world health organization (WHO) statistics, 33% world's population has been exposed to TB bacterium a . In the last year, it was anticipated that there may be around 9.8 million new cases a . A number of anti-TB drugs are ineffective against TB because of the development of resistant strains (1). The limited effectiveness of current chemotherapy stems largely from the lengthy and complicated nature of first-line anti-TB drugs (2,3). The most problematic issue with the current TB regimen is insufficient adherence to the treatment course, attributable to its length, complexity and adverse effects, led to difficult-and expensiveto-treat multidrug-resistant tuberculosis (MDR-TB) (4). The world's two most populous countries, India and China, account for more than 50% of the world's MDR-TB cases (5). Treatment for MDR-TB typically requires 18-24 months of combination therapy with second-line drugs those are less efficacious, more toxic and expensive than the first-line drugs (6). In few regions, almost 20% of MDR-TB cases were classified as extensively drug-resistant tuberculosis (XDR-TB) (7). The treatment options for XDR-TB are very limited as XDR-TB bacilli are resistant not only to isoniazid and rifampicin, but also to fluoroquinolones and aminoglycosides (8). More recently, another definition of XDR-TB as MDR-TB resistant to any fluoroquinolone and at least one of the second-line drugs (capreomycin, kanamycin and amikacin) used in TB treatment (9). There are serious adverse effects with most MDR-TB and XDR-TB drugs, such as nephrotoxicity and ototoxicity with aminoglycosides, hepatotoxicity with ethionamide and dysglycaemia with gatifloxacin (10). In few cases, XDR-TB has been shown aggressive form of TB, causing very high mortality (10).The improvement in TB chemotherapy can be ...

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