Green synthesis and antibacterial evaluation of spiro fused tryptanthrin-thiopyrano[2,3-b]indole hybrids targeting drug-resistant S. aureus

[Display omitted] •Green synthesis of tryptanthrin-thiopyrano[2,3-b] indole hybrid molecules is described using solvent-free and electroorganic methods.•The nitro derivative of the compound exhibited low MIC 0.25 µg/mL (comparable to Levofloxacin) against S. aureus ATCC 29213.•The active compound exhibited equi-potent activity against clinically relevant multidrug-resistant MRSA and VRSA strains and its antimicrobial activity is not affected by existing drug-resistance mechanisms.•The active compound was found to synergize with Linezolid against S. aureus ATCC 29213 which indicated the potential to be utilized in combination with linezolid against drug-resistant S. aureus.•Time-kill kinetics showed the power of synergistic drug combinations against S. aureus ATCC 29213 and the combination exhibited a long PAE of ∼4 h. Green and facile synthesis of 24 tryptanthrin-thiopyrano[2,3-b]indole hybrid molecules is described (i) by a thermal one-pot multi-component strategy, (ii) using ammonium acetate in solvent-free conditions at 100 °C and (iii) by electrochemical method at room temperature. The in vitro antibacterial activities of compounds were evaluated against bacterial pathogen panel including clinically relevant highly drug-resistant MRSA/VRSA isolates, which led to the identification of nitro-substituted hybrid molecule 4c as being the most potent molecule against S. aureus ATCC 29213 with a high selectivity index. Upon further analysis, 4c exhibited concentration dependent bactericidal activity with a long PAE (post-antibiotic effect) and synergized with linezolid against S. aureus. From the in vitro metabolic stability assay (using rat liver microsomes) it was found that 4c has half-life of >120 min. The co-crystallographic studies indicated that amino group in compound 4c is the potential binding site. From all the studies, it was clear that compound 4c exhibits all the hallmarks for positioning it as a novel anti-staphylococcal therapeutic option.