Design and Development of New Pyrazine-Based Molecules as Potent Antitubercular Agents

Abstract

Tuberculosis (TB) remains a significant global health concern, with millions of new cases and deaths reported each year. The emergence of drug-resistant strains, such as multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), has underscored the need for more effective antitubercular treatments. Pyrazine, a versatile compound capable of forming hydrogen bonds and dipole-dipole interactions, has garnered attention for its potential in developing new drugs due to its wide range of pharmacological applications. To capitalize on this, we aimed to create novel molecules by incorporating various potent heterocyclic motifs into the pyrazine structure. We successfully designed five new series of pyrazine-based compounds through molecular hybridization, structural modification, and bioisosterism. These series include derivatives incorporating 1,3,4-oxadiazole/[1,2,4] triazolo[3,4-b][1,3,4]thiadiazine (T1-T18), 1,2,4-triazole (T19-T36), pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold (T37-T52), 4-quinazolinone (T53-T68), and 2-aminophenyl and 2-oxoacetyl incorporated pyrazine-2-carbohydrazide derivatives (T69-T88). These compounds were synthesized using multistep synthetic protocols and characterized using 1H-NMR, 13C-NMR, and HRMS techniques. Furthermore, we evaluated the synthesized compounds for their in vitro antitubercular activity against the mycobacterium tuberculosis H37Rv strain, as well as their antibacterial activity against S. aureus, S. mutans, E. coli, and S. Typhi, and antifungal activity against A. niger. Additionally, we assessed the cytotoxicity of active molecules on non-cancerous cells using an MTT assay. To gain insights into their mechanism of action, we conducted in silico ADMET, DFT calculations, and molecular docking studies.