Computational Design, Synthesis, and Biological Assessment of Some Pyrrolo[3,4-c]Pyrroles Targeting Mycobacterium Tuberculosis

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), continues to be a major global health burden, particularly with the alarming rise of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains that compromise the efficacy of conventional therapies. Hence, we designed a new set of spirooxindole- and spiroindenoquinoxaline-derived pyrrolo[3,4-c] pyrroles that have been synthesized through atom economic one-pot multicomponent reactions of isatin/indenoquinoxaline and phenylalanine to form an azomethine ylide with maleimide derivatives as dipolarophiles through 1,3-dipolar cycloaddition reaction. The reaction proceeds through the in situ generation of azomethine ylides. The newly synthesized compounds were structurally characterized using FT-IR, ¹H, and ¹3C NMR spectroscopy, and their stereochemistry was unambiguously confirmed through single-crystal X-ray diffraction analysis. Molecular docking and dynamics simulations of selected compounds (4b and 5a) revealed favorable binding interactions with the Mtb enzyme decaprenylphosphoryl-β-D-ribofuranose oxidoreductase, suggesting their potential role in inhibiting cell wall biosynthesis. In vitro anti-tubercular activity was evaluated using the MABA assay against the H37Rv strain, with isoniazid, rifampicin, and ethambutol as positive controls. Among the synthesized analogs (4a–4d, 5a–5d), compounds 4d and 5d, bearing a 4-chloro substituent, showed the most potent activity (12.5 µg/mL), while others exhibited notable inhibitory effects, indicating strong therapeutic potential.