Publication date: Jun 13, 2025

Tuberculosis (TB) remains a major global health threat, with Mycobacterium tuberculosis (Mtb) causing high morbidity and mortality. The rise of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) necessitates novel therapeutics with improved efficacy and safety. Among heterocyclic frameworks, pyrazine and oxadiazole derivatives have shown promising antimycobacterial activity. Pyrazinamide is a key pyrazine-based drug, whereas 1,3,4-oxadiazoles exhibit strong enzyme inhibition. In this study, a series of pyrazine-1,3,4-oxadiazole derivatives were synthesized and characterized using infrared (IR), mass spectrometry, nuclear magnetic resonance (NMR), and elemental analysis. Their antitubercular activity was evaluated against the Mtb HRv strain using the microplate alamar blue assay (MABA). The compounds exhibited minimum inhibitory concentration (MIC) values ranging from 3. 13 to 12. 5 ug/mL (9. 39-55. 75 uM). Notably, compounds 2e, 2f, and 2n exhibited the highest potency, attributed to halogen substitutions that enhanced lipophilicity and target interactions. Molecular docking studies reinforced these results, with compound 2f demonstrating a strong binding affinity (-9. 0 kcal/mol) for the DprE1 enzyme, surpassing standard anti-TB drugs, isoniazid (-5. 3 kcal/mol) and rifampicin (-7. 9 kcal/mol). In addition, molecular dynamics (MD) simulation results revealed that compound 2f exhibits superior structural stability, compactness, and consistent binding interactions with DprE1. These findings highlight the potential of pyrazine-oxadiazole hybrids as promising scaffolds for developing novel antitubercular agents.

Semantics

Original Article