Antichagásicos potenciais: síntese de pró-fármacos recíprocos de megazol e primaquina

Author(s)

Michelle Carneiro Polli

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2003-02-28

Examining board members

Elizabeth Igne Ferreira; Chung Man Chin; Leoberto Costa Tavares

• Advisor: Elizabeth Igne Ferreira

Abstract

Chagas\'s disease is one of the most severe parasitoses of Latin America. According to WHO, over 16 million people are infected and about 50.000 deaths occur in endemic countries annually. Only two drugs are available: benznidazol and nifurtimox. Both are active only in the acute phase of the disease. So, the Jack of effective drugs against the disease leads to an urgent search for new antichagasic agents. Megazol is a nitro-heterocyclic compound with high potential antichagasic activity. Primaquine, clinically used in malaria, also showed tripanomicidal activity. Prodrug design is a molecular modification approach that aims to improve drug properties. Based on those facts, and due to the low sinergism between primaquine and megazol found in in vitro assays with T. cruzi, the final purpose of this work was to synthesize mutual prodrugs of those drugs. Based on the knowledge of cruzipain specificity, protease found only in T. cruzi, peptide - Lys-Arg -- and aminoacids - Lys, Arg -- were planned to be used as spacer groups. Initially, these two drugs were linked through a succinic unspecific spacer group for comparison. ln the case of specific mutual prodrugs, only the synthetic intermediates - succinylmegazol, succinylmegazol methyl ester, succinilprimaquine, Lys(Cl-Z)-primaquine, Arg(Tos)-primaquine and Lys(Cl-Z)-Arg(Tos)-primaquine, which synthesis was optimized - were obtained. These intermediates will be further transformed in specific drug delivery system. Probably, the prodrug with peptide spacer group will have better activity and higher selectivity than the succinic derivative, as expected. The biological assay carried out with megazol-succinyl-primaquine mutual prodrug showed a high value of IC50, probably due to incomplete drug release. (AU)