Pyrrolo[1,2-a]quinoxalinic Core-Derived Compounds Targeting the Mycobacterium tuberculosis P-type ATPase Plasma Membrane Ca2+ Transporter, CtpF, as Potential Antituberculous Drugs

Background The resistance of Mycobacterium tuberculosis (Mtb) on first- and second-line anti-tuberculosis (TB) drugs is an issue for TB control; therefore, developing new anti-TB drugs is a priority in TB research. In this sense, the Ca2+ P-type ATPase plasma membrane transporter CtpF is an interesting anti-TB drug target. Methods In this work, the activity of 4C-substituted pyrrolo[1,2-a]quinoxalinic compounds on Mtb viability and Ca2+ ATPase activity mediated by the plasma membrane transporter, CtpF, was assessed. The pyrrolo[1,2-a]quinoxalines compounds were initially in silico and analyzed as potential inhibitors of the CtpF transporter. Molecular docking analyses showed that 4-(3,4-methylenedioxyphenyl) pyrrolo[1,2-a]quinoxaline (4b) and 4-(2-chlorophenyl) pyrrolo[1,2-a]quinoxaline (4c) compounds are potential CtpF inhibitors. These compounds were synthesized by green chemistry using deep eutectic solvent under environmentally friendly processes. Results Even though both compounds, 4b and 4c, inhibit the plasma membrane Ca2+ ATPase activity mediated by the CtpF transporter (IC50 of 8.05 ± 0.04 µM and 9.15 ± 0.03 µM for 4b and 4c, respectively), only the 4b compound was active on Mtb cells (MIC = 25 µg/mL). Interestingly, compound 4b also showed low toxicity on VERO cells (19.65 ± 0.51%) and hemolytic activity (1.45 ± 0.20%) in human O Rh (+) erythrocytes. Conclusions 4-(3,4-methylenedioxyphenyl) pyrrolo[1,2-a]quinoxalinic core-derived compounds could be useful for developing alternative anti-TB compounds.