Author(s):
Long, Solida ; Duarte, Denise ; Carvalho, Carla ; Oliveira, Rafael ; Santarém, Nuno ; Palmeira, Andreia ; Resende, Diana I. S. P. ; Silva, Artur M. S. ; Moreira, Rui ; Kijjoa, Anake ; Cordeiro Da Silva, Anabela ; Nogueira, Fátima ; Sousa, Emília ; Pinto, Madalena M. M.
Date: 2022
Persistent ID: http://hdl.handle.net/10362/134564
Origin: Repositório Institucional da UNL
Subject(s): Pyrazino[2,1- b]quinazoline-3,6-dione; antimalarial; P. falciparum; Leishmania; Trypanosoma brucei; Biochemistry, Genetics and Molecular Biology(all); Parasitology; Infectious Diseases; Pharmacology, Toxicology and Pharmaceutics(all); SDG 1 - No Poverty; SDG 3 - Good Health and Well-being; SDG 9 - Industry, Innovation, and Infrastructure; SDG 11 - Sustainable Cities and Communities; SDG 12 - Responsible Consumption and Production; SDG 13 - Climate Action; SDG 15 - Life on Land; SDG 17 - Partnerships for the Goals
Description
Funding Information: This research was supported by national funds through FCT-Foundation for Science and Technology within the scope of UIDB/04423/2020, UIDP/04423/2020, IUD/04413/2020 and under the project PTDC/SAU-PUB/287336/2017 (reference POCI-01-0145-FEDER-028736), cofinanced 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. This work is a result of the project ATLANTIDA (reference NORTE-01-0145-FEDER-000040), supported by the Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement and through the European Regional Development Fund (ERDF). The work was also funded by FEDER-Fundo Europeu de Desenvolvimento Regional through COMPETE 2020-Programa Operacional para a Competitividade e Internacionalização (POCI), Portugal 2020, and by Portugese fundings through (FCT-Fundação para a Ciência e a Technologia/Ministério da Ciência, Technologia e Inovação, under the project “Instituto de Investigação e Inovação em Ciências da Saúde” “(POCI-01-0145-FEDER-007274)”. N.S. and C.C. are supported by Fundação e Ciência (MEC) cofunded by FEDER through the COMPETE 2020 Operational Programme for Competitiveness and Internationlisation (POCI) referent POCI-010-0145-FEDER-031013. S.L is thankful to Erasmus Mundus Action 2 (LOTUS+ LP15DF0205) for a full PhD scholarship and HEIP-RUPP-SGA-11 project. The authors thank Sara Cravo for technical support. Publisher Copyright: © The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00589.
Malaria, leishmaniasis, and sleeping sickness are potentially fatal diseases that represent a real health risk for more than 3,5 billion people. New antiparasitic compounds are urgent leading to a constant search for novel scaffolds. Herein, pyrazino[2,1-b]quinazoline-3,6-diones containing indole alkaloids were explored for their antiparasitic potential against Plasmodium falciparum, Trypanosoma brucei, and Leishmania infantum. The synthetic libraries furnished promising hit compounds that are species specific (7, 12) or with broad antiparasitic activity (8). Structure-activity relationships were more evident for Plasmodium with anti-isomers (1S,4R) possessing excellent antimalarial activity, while the presence of a substituent on the anthranilic acid moiety had a negative effect on the activity. Hit compounds against malaria did not inhibit β-hematin, and in silico studies predicted these molecules as possible inhibitors for prolyl-tRNA synthetase both from Plasmodium and Leishmania. These results disclosed a potential new chemotype for further optimization toward novel and affordable antiparasitic drugs.
