Ultrasound-assisted ionic liquid-mediated green method for synthesis of 1,3-diphenylpyrazole-based spirooxindolopyrrolizidines, their anti-tubercular activity, molecular docking study and ADME predictions

Abstract

The aim of the study is to develop the synthesis of a novel series of potent anti-tubercular (anti-TB) activity of 1,3-diphenylpyrazole-based spirooxindolopyrrolizidine derivatives via an efficient green approach achieved by using an ionic liquid ([Bmim]BF₄) under ultrasonication. The title compounds 4a–4ad with a general molecular formula C_aH_bX_(0–2)N_cO_d (X = F/Cl/Br) were produced with high yields in shorter reaction time and well characterized by using spectral techniques; and finally single crystal X-ray diffraction method (4b). The newly synthesized compounds were evaluated for their in vitro anti-TB activity against Mycobacterium tuberculosis H37Rv strain. Among all, six compounds 4e (C₃₆H₂₉N₅O₄), 4g (C₃₄H₂₈N₄O₃), 4q (C₃₆H₂₈F₂N₄O₂), 4r (C₃₆H₂₈ClFN₄O₂), 4y (C₃₆H₂₉BrN₄O₂) and 4z (C₃₆H₂₈BrFN₄O₂) exhibited significant anti-TB activity with MIC value 6.25 μg mL⁻¹, when compared to the standard drug ethambutol (MIC:1.56 μg mL⁻¹). In silico molecular docking studies were performed against M. tuberculosis enoyl–acyl carrier protein reductase inhibitor. The compounds 4o, 4p, 4y and 4aa were exhibited least binding energies −12.58, −12.61, −12.58 and −12.57 kcal mol⁻¹, respectively. These results reveal that the produced compounds might be used for the future generation of novel anti-TB drugs.