Antimicrobial resistance has become a major threat to public health worldwide making the discover of new antimicrobial agents, with innovative chemistry and modes of action, a global priority. Indole alkaloids related to fumiquinazolines have shown several biological activities, including antimicrobial potential. Therefore, our project aims to synthesize new alkaloids related to the fumiquinazolines and to evaluate their antibacterial activities.

Herein, we present the synthesis of two naturally occurring compounds and of new fumiquinazoline related alkaloids through a multi-step synthetic pathway. Structure elucidation of the compounds was made by NMR and HRMS. To assess their antibacterial potential, the minimum inhibitory concentration (MIC) of each compound against a panel of four clinically relevant bacterial species (which includes both reference and multi-resistant strains) was determined. Additionally, a preliminary synergism study was made. The most promising alkaloid showed activity against methicillin resistant Staphylococcus aureus (MRSA) comparable to the natural product neofiscalin A (MIC= 8 µg/mL) as well as activity against vancomycin resistant Enterococcus faecalis (VRE) (MIC= 32 µg/mL).

Acknowledgments: This research was supported by national funds through FCT- Foundation for Science and Technology within the scope of UIDB/04423/2020, UIDP/04423/2020 (Group of Natural Products and Medicinal Chemistry CIIMAR), and under the project PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER-028736), co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF and by FCT through national funds, as well as CHIRALBIOACTIVE-PI-3RL-IINFACTS-2019 and R&D&I ATLANTIDA (reference NORTE-01-0145-FEDER-000040), supported by NORTE2020, through ERDF. MCA acknowledges the BYT+ scholarship to CIIMAR.