Design, synthesis and biological evaluation of small molecules with potential antibacterial and antiviral activity

Abstract

In recent years, the ongoing explosion of antibiotic-resistance and viral infections has posed a major threat to global public health and called for the development of new therapeutics. Here, a set of novel compounds are designed, synthesized, and tested for antibacterial and antiviral activities. The synthetic small molecules included in the dissertation are nature-inspired indole derivatives. The indole nucleus is an essential element of several natural and synthetic products with significant biological properties. Recent research has highlighted the effect of indole-based compounds as potential antimicrobial and anticancer candidates. The first part of the dissertation is focused on a set of novel indole derivatives and describes their design, synthesis, and biological evaluation for potential antibiotic activity. Few compounds showed a significant reduction in the growth of standard and drug-resistant strains of gram-positive bacteria. Novel compounds GK517.3 and GK506.2Im inhibited bacterial growth of gram-positive bacteria, S. aureus and E. faecalis at 51.73 and 50.62 mg/mL, respectively and kills 99.9% of bacteria at 103.5 and 101.2 mg/mL, respectively. GK517.3 inhibited the growth of MRSA at 16.17 mg/mL and showed the bactericidal property at 32.35 mg/mL. The encouraging results of the novel indole derivatives pave a way for developing new therapeutic strategies using this unique scaffold to treat antibiotic resistance. The second part of the dissertation includes a novel one-pot synthesis method to furnish b-carboline dimer molecules. For the first time, antiviral activity of b-carboline dimers (GZ440/6) was evaluated against COVID-19 using cell-based assays. The data suggest that the GZ440/6 can inhibit the COVID-19 virus without any cytotoxicity and might include inhibition of virus attachment and/or entry into the cell.