Investigation of novel hybrid analogues for their antitubercular pharmacological potential

Abstract Background Tuberculosis (TB) remains a major global health issue, with about 95% of deaths occurring in developing countries and India and China accounting for 38% of these cases. The challenge of multidrug-resistant TB (MDR-TB) arises from ineffective treatments. This study focuses on the design of heterocyclic analogues targeting the DprE1 enzyme, which plays a critical role in cell-wall synthesis in Mycobacterium tuberculosis. By inhibiting DprE1 enzyme production, these compounds hinder bacterial growth. Method In silico study involved network pharmacology, molecular docking, molecular dynamics, and drug likeness analysis. Network pharmacology was employed to predict the targets of the inhibitors and GO gene enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation conducted to explore the interacting pathways. DprE1 enzyme (PDB ID: 4KW5) was selected as the target protein. Ligand preparation, receptor grid generation, molecular docking, and molecular dynamics simulations were conducted. ADME properties and structure-based drug likeness were predicted. Heterocyclic analogues were synthesized and characterized using TLC, melting point, FTIR, NMR, and mass spectroscopy. The antitubercular activity was evaluated through disc diffusion and colorimetric resazurin microtiter plate assay. Results Protein–protein interaction (PPI) network analysis identified significant tuberculosis-related proteins, with KEGG pathway analysis indicating therapeutic potential. Docking scores for the heterocyclic analogues ranged from −10.26 to 15.48 kcal/mol against DprE1, confirming effective binding. Characterization data confirmed their structures, with IR spectra showing amide linkages, NMR spectra revealing imidazolidine ring signals, and mass spectrometry confirming molecular weights. In vitro studies showed antitubercular activity against Mycobacterium smegmatis, with inhibition zones between 11 and 17 mm. Benzothiazole–imidazolidine analogues, especially PK-2, PK-3, and PK-4, displayed strong interactions with DprE1 and promising in vitro activity, suggesting their potential against MDR-TB. Conclusion This study explores benzothiazole–imidazolidine analogues as potential antituberculosis agents targeting the DprE1 enzyme, aiming to counteract multidrug-resistant TB (MDR-TB). Four synthesized analogues (PK-1 to PK-4) were analysed for pharmacokinetic interactions, revealing effects on pathways including protein kinase, NF-kappa B, and PI3K-Akt signalling. Molecular docking and dynamics studies demonstrated high binding energies and stable interactions with DprE1, notably in PK-2, PK-3, and PK-4, which exhibited stronger inhibition zones. Characterization by TLC, IR, NMR, and mass spectroscopy confirmed the analogues structures, indicating potential for future testing against resistant TB strains and applications in other therapeutic areas. Highlights Benzothiazole heterocyclic analogues were synthesized and evaluated against tuberculosis. Network pharmacology identified DprE1 and other TB-related protein targets. Molecular docking confirmed strong binding of analogue 2 with the DprE1 enzyme. Disc diffusion assay validated antitubercular activity against Mycobacterium smegmatis . Analogue 2 emerged as the most active compound, highlighting its potential as a new lead.