Synthesis, biological evaluation, and docking studies of pyrazole-linked benzothiazole hybrids as promising anti-TB agents.

• A series of new pyrazole-linked benzothiazole hybrids was synthesized and evaluated for their anti-TB activity. • Compounds 10j, 10k, 10l, 11c and 12 , respectively, displayed promising anti-TB activity in comparison to the reference compound isoniazid. • Their inhibition of the mycobacterium tuberculosis enoyl-acyl carrier protein reductase enzyme (InhA) was tested. • Compounds 10i, 10j and 12 , respectively, showed strong inhibition of InhA in comparison to the reference compound, triclosan, with IC 50 values of 6.4–7.9 μM. • A molecular docking study was carried out to investigate the predicted binding interactions of the synthesized inhA inhibitors in the binding pocket of the inhA enzyme. Tuberculosis (TB) is a global pandemic killing millions of people every year. Yet, resistant strains make curing TB quite challenging. Herein, a series of new pyrazole-linked benzothiazole hybrids was synthesized and evaluated for their anti-TB activity against three Mycobacterium tuberculosis strains (drug sensitive (DS), multidrug-resistant (MDR) and extensively drug-resistant (XDR)). The substituted 2,5-dimethylphenoxy -, 2,6-dichlorophenoxy -, 2,6-dimethoxyphenoxy -, 4-methylpiperazin-1-yl-,and pyrrolidin-1-ylpyrazole-benzothiazole conjugates (compounds 10j, 10k,10l, 11c and 12 respectively) displayed promising anti-TB activity in comparison to the reference compound isoniazid against the DS strain with (MIC: 1.74–3.68 μM/mL)To further study the mode of action of these anti-TB compounds, their inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase enzyme (InhA) was tested. The 3-acetamidophenoxy-, 2,6-dichlorophenoxy -,andpyrrolidin-1-ylpyrazole-benzothiazole conjugates(Compounds 10i, 10j and 12 respectively) showed strong inhibition of InhA in comparison to the reference compound, triclosan, with IC 50 values of 6.4–7.9 μM. Moreover, a molecular docking study was carried out to investigate the predicted binding interactions of the synthesized inhA inhibitors in the binding pocket of the inhA enzyme. The calculated docking energies of the developed novel pyrazole-linked benzothiazole hybrids were consistent with their tested anti-tubercular activity. [ABSTRACT FROM AUTHOR]