Synthesis-guided design and discovery of alkylated indoles with antibacterial activity against MRSA

Abstract

Substantially high morbidity and mortality rates are associated with antimicrobial resistance (AMR), which poses an alarming challenge to global healthcare. The causative, drug-resistant superbugs (headed by Staphylococcus aureus) adopt multiple strategies to escape the biocidal action of antibacterial drugs. This results in depleting the number of effective treatment alternatives and eventually leading to one of the nosocomial pathogens, Methicillin-resistant S. aureus (MRSA) related infections. Collectively, these concerns highlight a pressing urgency to replenish the drug discovery pipeline. In this context, we established an effective synthetic and screening platform to design and synthesize a series of C-3 alkylated indole derivatives. The biological assessment of the synthesized analogs identified potential hit molecules 9k and 11b with decent antimicrobial activity against the MRSA pathogen. Leveraging these initial hits, we re-designed and synthesized 2nd generation series of their analogues, through a strategic structural modification approach to further optimize their biological potential. Their antibacterial evaluation led to the identification of two aniline/amine-based potent hit molecules, 14f and 14l, with MIC values of 5.89 µM and 6.02 µM, respectively, against the MRSA pathogen. These hits presented a high safety profile with effective killing kinetics and anti-biofilm properties. The potent hits 14f and 14l exhibited membrane-targeting nature as confirmed through cell integrity and membrane permeability studies, and were also found to elicit secondary cellular responses such as oxidative stress generation and ATP depletion, leading to cell death. Thus, the present study lays the groundwork for the development of novel indole-based antibacterial scaffolds against MRSA.