While the hydrophobicity of the binding pocket could contribute to the high LCZ696 chemical structure binding affinity value of −7.7 kcal/mol. Figure 7 Ligand 8 electrostatic interaction with the active site of wild type receptor shows a favourable plateau of electrostatic interaction which could account for its binding affinity value of −7. 7 kcal / mol. Earlier in vitro and in vivo studies have shown an increased activity of moxifloxacin-conjugated dansylated carboxymethylglucan

(M-DCMG) than free moxifloxacin against persisting M. tuberculosis within macrophages [36]. But this conjugation is not supportive for conjugation with PA-824 since Carboxymethylglucan has been shown to have antioxidant activities [37] which could counteract the essential ROS generation by PA-824 for bactericidal activity. Interestingly,

it is also pointed that the efficacy of M-DCMG in improving the activity of Moxifloxacin [36] was that its ability to localize with the persisting tissues of C57BL/6 mice infected with M. tuberculosis. Since PA-824 is known to localize to persisting tissues [19], its conjugation with moxifloxacin could provide a better therapeutic advantage against SCH772984 molecular weight the persistors. Wang et al.,[38] noted that fuoroquinolones such as moxifloxacin, appear to show enhanced action in the presence of ROS. This this website support the enhanced structure-activity relationship against M. tuberculosis by ligand 8, which is a combinatorial structure of moxifloxacin with an ROS/RNS generator – PA-824. The support for the ester linkage for the structure activity of the combinatorial drug design is provided by the work by Georgopapadakou and Bertasso, [39], who showed that cephalosporin 3′-quinolone ester (Ro 23–9424) is effective in cases when neither of its individual components, cephalosporin

and quinolone, are active. In the same way when there is resistance for moxifloxacin and PA-824 as individual drugs, the ester combination of both (ligand 8) could have a synergistic activity against M. tuberculosis which could help in combination therapy. Further, since ligand 8 showed binding at the hydrophobic pocket (red colour) of the Ddn receptor (Figure 6), it can be considered that the ligand has more of hydrophobic interactions. This feature could maintain the stability of the ester bond in the presence of plasma Liothyronine Sodium and esterases as described by Simões et al., [40]. A combination treatment of rifampin, moxifloxacin, amikacin and PA-824 has shown potent killing of MTB in vitro in 14 days [41]. Recently, another study of phase II clinical trials in South Africa, the combination therapy PaMZ, which consists of the novel TB drug candidate PA-824, moxifloxacin and pyrazinamide killed more than 99 per cent of people’s TB bacteria within just 14 days and is potentially suitable for treating both drug sensitive and multidrug resistant tuberculosis [42].