In this work a number of derivatives
of an anti-tubercular agent PA-824 were studied using computational tools. This
study extends earlier reports regarding the in vitro and in vivo efficacies of
the nitroimidazopyran PA-824 against Mycobacterium tuberculosis. PA-824 was
tested in vitro against a broad panel of multidrug-resistant clinical isolates
and was found to be highly active against all isolates (MIC < 1 ?g/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 ?g/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, Rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than Rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, Rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis. (3) For this work Chemical Drawing and Visualization of the structures under investigation were carried out by using the drawing tool Marvin Sketch. The present study with a view to develop the Quantitative Structure- Activity Relationship (QSAR) for the derivatives of PA-824.For this, regression analysis is carried out using physiochemical properties from Chemsketch and power MV and biological activities such as antituberculosic activity, Antimycobacterial and antibacterial activity, which is obtained from the online tool PASS. Pharmacodynamics and pharmacokinetic behaviour of the developed molecules was studied over insilico tools like "OSIRIS Property explorer" and "Molinspiration". In order to carry out the docking simulations, experiments were conducted to find out the molecule which will lock the protein to the most effective manner using the software Autodock. The structure of the target protein 420-dependent glucose-6-phosphate dehydrogenase was obtained from Protein Data Bank (PDB id: 3C8N). Toxicity was predicted using LAZAR toxicity prediction.