Antimalarial potentially active against resistance: design and synthesis of dendrons and dendrimers directed to infected erythrocytes

Author(s)

Luccas Missfeldt Sanches

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2023-06-15

Examining board members

Elizabeth Igne Ferreira; Marina Candido Primi; Alcindo Aparecido Benito dos Santos

• Advisor: Elizabeth Igne Ferreira

Abstract

Malaria is a potentially fatal disease caused by protozoa of the genus Plasmodium which affects erythrocytes. In several regions of the world, parasites resistant to the most used drugs are reported, leading to an increase in disease mortality. Artemisinin combination therapies (ACTs) are strongly recommended by the World Health Organization (WHO) for malaria treatment, even in cases of resistance. Heparin and its derivatives can bind to Plasmodium falciparum infected erythrocytes, which make them viable directing groups for drug targeting, a strategy that can increase the quantity of active compounds in the disease affected region. In this context, dendrimers are viable drug carriers that are able to cross different barriers and they are an interesting platform for building structures directed to infected erythrocytes by heparin derivatives and able to carry ACTs. These structures could increase the therapeutic efficacy, selectivity and aid the control of Plasmodium drug resistance. The work presented in this thesis shows synthetic efforts to obtain these directed dendrimers, the evaluation of efficacy, toxicity, solubility, permeability and clearance of potentially active compounds covalently bound to linkers and a new synthetic route for building ACTs directed by heparin derivatives to infected erythrocytes. A computational work is also presented to evaluate if heparin derivatives could be used as directing groups for P. vivax infected erythrocytes. (AU)

• FAPESP's process: 18/10359-0 - Potentially active antimalarials against resistance: planning and synthesis of dendrons and dendrimers targeting infected erythrocytes
• Grantee: Luccas Missfeldt Sanches
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)