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Synthetic strategies towards bioactive nature-inspired indole-containing alkaloids
Solida Long 1 , Diana I. S. P. Resende 1, 2 , Patrícia Pereira-Terra 2, 3 , Joana Freitas-Silva 2, 3 , Artur M. S. Silva 4 , Maria Elizabeth Tiritan 1, 2, 5 , Anake Kijjoa 2, 3 , Eugénia Pinto 2, 6 , Paulo Costa 2, 3 , Madalena Pinto 1, 2 , Emília Sousa * 1, 2
1  Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
2  Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Lexões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal
3  ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
4  Organic Chemistry, Natural Products and Food stuffs (QOPNA), Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
5  CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde (IINFACTS), Rua Central de Gandra, 1317, 4585-116 Gandra PRD, Portugal
6  Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Portugal

10.3390/ECMC2019-06291
Abstract:

Currently drug resistance is rising to dangerously high levels worldwide and threatening our ability to treat even common infectious diseases. Secondary metabolites, especially alkaloids containing an indole group and structurally related to fumiquinazolines, are of crucial importance in the area of drug discovery, having representatives such as fiscalin B that was reported as substance P antagonist and neofiscalin A, a potent antibacterial agent active in both reference and multidrug-resistant isolates. [1] Herein, the synthesis of quinazolinone alkaloid derivatives containing an indole moiety is reported, using two different methodologies – a highly efficient three-component one-pot microwave-assisted and a multi-step Mazurkiewicz-Ganesan approach. With this approach, 38 derivatives were obtained in low to moderate yields and were further tested for their antitumor [2,3], neuroprotection [2], antibacterial, and antifungal activities. While 16 compounds exhibited weak to moderate tumor cell growth inhibitory activity, other four compounds showed potential for in vitro neuroprotection in Parkinson disease. It was also observed for some derivatives a good antibacterial activity against clinical Staphylococcus aureus resistant to methicillin (MRSA). Structure-activity relationship was established and four hit compounds containing the quinazolinone scaffold emerged as potential drug candidates.

Acknowledgements: We thank the UID/Multi/04423/2019 through national funds provided by FCT-Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the program PT2020. This research was developed under Project No. 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, and Solida Long thanks Erasmus-Lotus+ program (LOTUS+, LP15DF0205).

References:

[1] Resende, D. I. S. P.; Boonpothong, P.; Sousa, E.; Kijjoa, A.; Pinto, M. M. M., Chemistry of the fumiquinazolines and structurally related alkaloids. Natural Product Reports 2019, 36, 7-34.

[2] Long, S.; Resende, D. I. S. P.; Kijjoa, A.; Silva, A. M. S.; Fernandes, R.; Xavier, C. P. R.; Vasconcelos, M. H.; Sousa, E.; Pinto, M. M. M., Synthesis of New Proteomimetic Quinazolinone Alkaloids and Evaluation of Their Neuroprotective and Antitumor Effects. Molecules 2019, 24 (3), 534.

[3] Long, S.; Resende, D.; Kijjoa, A.; Silva, A.; Pina, A.; Fernández-Marcelo, T.; Vasconcelos, M.; Sousa, E.; Pinto, M., Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products. Mar. Drugs 2018, 16 (8), 261.

Keywords: antitumor; neuroprotection; quinazolinones; fiscalin B; fumiquinazoline; synthesis; enantioselectivity
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