Design, synthesis and biological evaluation of some imidazo[1,2- <i>a</i> ]pyridine derivatives as anti-tubercular agents: an in silico – <i>in vitro</i> approach

In this study, we designed, synthesized and evaluated some novel imidazo[1,2-<i>a</i>]pyridine derivatives as potential anti-TB agents. Preliminary <i>in vitro</i> screening for anti-TB activity of the synthesized compounds was performed against H37Rv strain using the microplate Alamar Blue assay (MABA). Network pharmacology was used to identify the possible targets and pathways of these compounds against Mtb infection. Molecular docking and molecular dynamics simulations were also performed to investigate the binding modes and stability of these compounds with the selected targets. The results showed that some of the synthesized compounds (<b>6b, 6c, 6e, 6f, 6h, 6i, 6j, 6n</b> and <b>6o</b>) exhibited potent anti-TB activity, with minimum inhibitory concentrations (MICs) ranging from 1.6 to 6.25 μg/mL. The network pharmacology analysis revealed that among the 455 putative targets of imidazo[1,2-<i>a</i>]pyridine derivatives, 24 targets are the potential targets for treatment of Mtb infection. Among these 24 targets, 10 hub-targets were identified (TLR4, ICAM1, TLR9, STAT3, TNFRSF1A, ERBB2, CXCR3, ACE, IKBKG and NOS2) which were significantly involved in GO processes such as positive regulation of DNA-binding transcription factor activity, peptidyl-tyrosine phosphorylation, positive regulation of inflammatory response, mononuclear cell proliferation, regulation of hemopoiesis and cytokine production involved in inflammatory response and KEGG pathways such as pathways in Tuberculosis, NF-kappa B signalling, HIF-1 signalling PD-L1 expression, and PD-1 checkpoint pathway in cancer. Molecular docking and dynamics simulations confirmed the stable interactions of imidazo[1,2-a]pyridine derivatives with core target active sites, highlighting their potential as novel anti-TB drug candidates.