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Tuberculosis is a disease that remains a significant threat to public health worldwide, and this is mainly due to the selection of strains increasingly resistant to Mycobacterium tuberculosis, its causative agent. One of the validated targets for the development of new antibiotics is DNA gyrase. This enzyme is a type II topoisomerase responsible for regulating DNA topology and, as it is essential in bacteria. Thus, to contribute to the search for new molecules with potential to act as competitive inhibitors at the active site of M. tuberculosis DNA gyrase B, the present work explored a dataset of 20,098 natural products that were filtered using the FAF-Drugs4 server to obtain a total of 5462 structures that were subsequently used in virtual screenings. The consensus score analysis between LeDock and Auto-Dock Vina software showed that ZINC000040309506 (pyrrolo[1,2-a]quinazoline derivative) exhibit the best binding energy with the enzyme. In addition, its subsequent optimization generated the derivative described as PQPNN, which show better binding energy in docking analysis, more stability in molecular dynamics simulations and improved pharmacokinetic and toxicological profiles, compared to the parent compound. Taken together, the pyrrolo[1,2-a]quinazoline derivative described for the first time in the present work shows promising potential to inhibit DNA gyrase B of M. tuberculosis.

Lauryl gallate loaded in superparamagnetic poly(methyl methacrylate) nanoparticles surface modified with folic acid were synthesized by miniemulsion polymerization in just one step. In vitro biocompatibility and cytotoxicity assays on L929 (murine fibroblast), human red blood, and HeLa (uterine colon cancer) cells were performed. The effect of folic acid at the nanoparticles surface was evaluated through cellular uptake assays in HeLa cells. Results showed that the presence of folic acid did not affect substantially the polymer particle size (~120 nm), the superparamagnetic behavior, the encapsulation efficiency of lauryl gallate (~87 %), the Zeta potential (~38 mV) of the polymeric nanoparticles or the release profile of lauryl gallate. The release profile of lauryl gallate from superparamagnetic poly(methyl methacrylate) nanoparticles presented an initial burst effect (0-1 h) followed by a slow and sustained release, indicating a biphasic release system. Lauryl gallate loaded in superparamagnetic poly(methyl methacrylate) nanoparticles with folic acid did not present cytotoxicity effects on L929 and human red blood cells. However, free lauryl gallate presented significant cytotoxic effects on L929 and human red blood cells at all tested concentrations. The presence of folic acid increased the cytotoxicity of lauryl gallate loaded in nanoparticles on HeLa cells due to a higher cellular uptake when HeLa cells were incubated at 37 °C. On the other hand, when the nanoparticles were incubated at low temperature (4 °C) cellular uptake was not observed, suggesting that the uptake occurred by folate receptor mediated energy-dependent endocytosis. Based on presented results our work suggests that this carrier system can be an excellent alternative in targeted drug delivery by folate receptor.

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The World Health Organization reported that tuberculosis remains on the list of the top ten threats to public health worldwide. Among the main causes is the limited effectiveness of treatments due to the emergence of resistant strains of Mycobacterium tuberculosis. One of the main drug targets studied to combat M. tuberculosis is DNA gyrase, the only enzyme responsible for regulating DNA topology in this specie and considered essential in all bacteria. In this context, the present work tested the ability of 2824 anthraquinones retrieved from the PubChem database to act as competitive inhibitors through interaction with the ATP-binding pocket of DNA gyrase B of M. tuberculosis. Virtual screening results based on molecular docking identified 7122772 (N-(2-hydroxyethyl)-9,10-dioxoanthracene-2-sulfonamide) as the best-scored ligand. From this anthraquinone, a new derivative was designed harbouring an aminotriazole moiety, which exhibited higher binding energy calculated by molecular docking scoring and free energy calculation from molecular dynamics simulations. In addition, in these last analyses, this ligand showed to be stable in complex with the enzyme and further predictions indicated a low probability of cytotoxic and off-target effects, as well as an acceptable pharmacokinetic profile. Taken together, the presented results show a new synthetically accessible anthraquinone with promising potential to inhibit the GyrB of M. tuberculosis.

The World Health Organization reported that tuberculosis remains on the list of the top ten threats to public health worldwide. Among the main causes is the limited effectiveness of treatments due to the emergence of a diverse spectrum of resistant strains of Mycobacterium tuberculosis, the causative agent of the disease. One of the main drug targets studied to combat M. tuberculosis is DNA gyrase, the only enzyme responsible for regulating DNA topology in this specie and considered essential in all bacteria. In this context, the present work tested the ability of 2,824 anthraquinones retrieved from the PubChem database to act as competitive inhibitors through interaction with ATP-binding pocket of DNA gyrase B of M. tuberculosis. Virtual screening results based on molecular docking identified 7122772 (N-(2-hydroxyethyl)-9,10-dioxoanthracene-2-sulfonamide) as the best-scored ligand. From this anthraquinone, a new derivative was designed harbouring an aminotriazole moiety, which exhibited higher binding energy calculated by molecular docking scoring and free energy calculation from molecular dynamics simulations. In addition, in these last analyses, this ligand showed to be stable in complex with the enzyme and further predictions indicated an acceptable pharmacokinetic profile. Taken together, the presented results show a new anthraquinone synthetically accessible and with promising potential to inhibit the GyrB of M. tuberculosis.