In vivo studies performed with activated macrophages of guinea pigs have shown that gene inactivation of this enzyme provoked accelerated mycobacterial cell death after macrophage invasion. More recently, Zhou and co-workers proposed that PtpB promotes mycobacterial survival in vitro by inhibiting extracellular signal-regulated kinase 1/2 and p38 pathways and increasing the phosphorylation of Akt, resulting in reduced production of interleukin-6 and decreased apoptotic activity, respectively. Alber and coworkers have synthesized a strong, competitive and selective PtpB inhibitor, namely OMTS showing an IC50 of 0.44 ��M, and solved the three-dimensional structure of the PtpB-inhibitor complex by means of X-ray crystallography. Other groups also have successfully identified inhibitors of PtpB: indole derivatives with selectivity indexes up to 100, cyclic hexapeptides from cyanobacterium Tychonema sp. with IC50 around 8.0 ��M, an isoxazole with Ki value of 0.22 ��M, selective indolin-2- on-3-spirothiazolidinones with IC50 values of 35.5 to 1.2 ��M and, recently, benzofurans with sub-micromolar inhibitory activity. Based on these evidences, PtpB has emerged as an important target for anti-TB pharmacological intervention and new inhibitors are in high demand. The screening of natural compounds libraries is a consolidated strategy in drug discovery, which employs the criteria of biological prevalidation and relevance to nature. Natural products have long been recognized as an important source of therapeutically effective agents, also because they embody rigid, non-flat three dimensional AdipoRon hydrochloride structures which may positively influence the probability of clinical success of a drug. Indeed, natural products can offer unprecedented opportunities for finding novel hits or leads against a wide range of biological targets. In previous works, we were pioneers in testing libraries of chalcones to find PtpA and PtpB inhibitors, underlining that screening natural products libraries may fuel the discovery of bioactive molecules. Moreover, in silico screening is a widely appreciated and reliable tool for prioritizing small molecules for biological testing. Accordingly, in this work we screened in silico an in house AG 045572 library of natural compounds by means of a structure-based approach composed of molecular docking, rescoring and visual inspection to prioritize few natural compounds as possible PtpB inhibitors that were subsequently assayed in vitro.