Design, synthesis, and in silico studies of pyrazine-based derivatives as potential antitubercular agents.

• In the present work, we designed new pyrazine derivatives via a rational approach by incorporating three pharmacophores. • Ten different pyrazine derivatives were synthesized in five synthetic steps and evaluated for their in vitro inhibitory potency against the mycobacterium tuberculosis H37Rv. • Among the title compounds, 8e and 8h demonstrated significant antitubercular activity with MIC values of 1.59 and 1.79 μg/ml respectively. • The activity profiles of the pyrazine derivatives were validated via performing molecular docking studies. • In silico prediction of physicochemical, ADME and drug-like properties revealed that most of the tested compounds were within those considered adequate for a drug candidate. Tuberculosis (TB) remains a major public health concern in spite of the existence of effective anti-TB medications. We present the design and synthesis of new compounds with pyrazine and pyridine/pyrimidine moieties. The Microplate Alamar Blue Assay (MABA) was used to test the activity of the synthesized compounds against the Mycobacterium tuberculosis (Mtb) H37Rv strain. Among the synthesized compounds, 8e and 8h showed considerable antitubercular activity. The most effective compounds were then effectively docked onto the active site of the Mtb enoyl reductase receptor. These compounds have demonstrated favorable binding interactions with amino acids present in the receptor. Furthermore, in silico prediction of physicochemical and pharmacokinetic properties revealed that the synthesized compounds can be used to generate novel anti-TB agents with increased activity and safety profiles. [ABSTRACT FROM AUTHOR]