Background

Antibacterial resistance has increased dramatically, becoming an emergency in healthcare. Despite enormous efforts, the number of therapeutically useful compounds that aim for circumventing the resistance is continuously decreasing and no truly novel class of compounds has been introduced to a successful therapy. In order to stop the clinical consequences of the development and spread of antimicrobial resistance both the preservation of current antimicrobials through their appropriate use, as well as the discovery and development of new agents are mandatory. Likewise, malaria represents a major threat to the public health worldwide. Along with widespread resistance to historical antimalarials, is emergent the need to identify new chemical diversity, ideally with novel antimalarial modes of action.

Technology Overview

The present disclosure relates to pyrazino [1,2-b]quinazoline-3,6-diones, in particular it relates to pyrazino [1,2-b]quinazoline-3,6-diones compounds having antibacterial activity and/or antimalarial activity. The invention encompasses the synthesis and the use of synthetic pyrazino [1,2-b]quinazoline-3,6-diones derivatives, inspired by complex marine compounds with antimicrobial properties. Synthesis by one-pot condensation reactions using cheap building blocks is highly selective and environmentally friendly. Best lead compounds are potent antimicrobials against methicillin-resistant Staphylococcus aureus (MIC 4-8 µg/mL) and Plasmodium falciparum 3D7 (IC50 0.02-2 µg/mL). Molecular docking studies support the inhibition of gene expression of Plasmodium and Leishmania sp. via prolyl-tRNA synthetase. Compounds had no hemolytic nor cytotoxic effects at MIC/IC50 concentrations. Halogenation, stereocenters and aliphatic side chains are correlated with antimicrobial activity.

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Further Details:

Long S, Duarte D, Carvalho C, Oliveira R, Santarém N, Palmeira A, Resende DISP, Silva AMS, Moreira R, Kijjoa A, Cordeiro da Silva A, Nogueira F, Sousa E, Pinto MMM. Indole-Containing Pyrazino[2,1-_b_]quinazoline-3,6-diones Active against Plasmodium and Trypanosomatids. ACS Med Chem Lett. 2022 Jan 11;13(2):225-235. doi: 10.1021/acsmedchemlett.1c00589.
Long S, Resende DISP, Kijjoa A, Silva AMS, Fernandes R, Xavier CPR, Vasconcelos MH, Sousa E, Pinto MMM. Synthesis of New Proteomimetic Quinazolinone Alkaloids and Evaluation of Their Neuroprotective and Antitumor Effects. Molecules. 2019 Feb 1;24(3):534. doi: 10.3390/molecules24030534.
Resende DISP, Boonpothong P, Sousa E, Kijjoa A, Pinto MMM. Chemistry of the fumiquinazolines and structurally related alkaloids. Nat Prod Rep. 2019 Jan 1;36(1):7-34. doi: 10.1039/c8np00043c.

Stage of Development

Technology Readiness Level (TRL): 3 - Experimental proof of concept.

Benefits

One-step synthesis from cheap building blocks;
Potent antimicrobial activity against multi-resistant bacterial pathogens and antimalarial activity;
Non-hemolytic and non-cytotoxic at MIC concentration.

Applications

Medicines or drugs in pharmaceutical compositions;
Cosmetics with wound healing and scaring prevention properties;
Disinfection agents.

Opportunity

Available for licensing, research and product development agreements.
Collaboration for further validation in large scale setups.

Anti-Infective Pyrazino [1,2-B]Quinazoline-3,6-Diones Derivatives and their Production

Patents

IP Status

Seeking