Synthesis and in vitro Evaluation of Potential Anti‐Leishmanial Targeted Drugs of Pyrimethamine

Advances in Prodrug Design

“…Based on this approach and with the purpose of obtaining drugs targeted to mannoside receptors found in macrophages, Carvalho and coworkers [36] designed potential anti-leishmanial drugs (Fig. 14).…”

“…With the same purpose, Chakravarty and colleagues, in 1983 [58], synthesized peptide prodrugs of doxorubicine, rationally designed based on plasmin selectivity. Source: Adapted from [36]. The prodrugs showed to be more selective than the parent drug in in vitro tests.…”

Síntese de pró-fármacos dendriméricos potencialmente antichagásicos e leishmanicidas derivados de hidroximetilnitrofural, 3-hidroxiflavona e quercetina

“…This represents a new and potential target to be considered. Pyrimethamine, an antimalarial drug, was found to be able to inhibit both enzymes (DHFR-TS and PTR-1) of the leishmanial folate pathway, although this effect in vivo appears only in relatively high concentrations [94]. Based on that finding and on Leishmania amastigotes living inside mammal's macrophages [95], where mannose receptors are found on the surface membrane [96], Carvalho and co-workers [94] have synthesized targeted drugs of pyrimethamine, carboxymethyldextran-thiomannopyranosidepyrimethamine (CMD-P), and succinyldextran-thiomannopyranoside-pyrimethamine (SD-P) ( Figure 10), in order to release the drug into those cells.…”

“…Pyrimethamine, an antimalarial drug, was found to be able to inhibit both enzymes (DHFR-TS and PTR-1) of the leishmanial folate pathway, although this effect in vivo appears only in relatively high concentrations [94]. Based on that finding and on Leishmania amastigotes living inside mammal's macrophages [95], where mannose receptors are found on the surface membrane [96], Carvalho and co-workers [94] have synthesized targeted drugs of pyrimethamine, carboxymethyldextran-thiomannopyranosidepyrimethamine (CMD-P), and succinyldextran-thiomannopyranoside-pyrimethamine (SD-P) ( Figure 10), in order to release the drug into those cells. The targeted drugs were tested against macrophages infected with L. (L.) amazonensis amastigotes in the presence or absence of CMD-P and SD-P at concentrations ranging from 100 to 200 µg/mL for 24 h. After treatment with a 200 µg/mL CMD-P dosis a 46,4% reduction of the infection rate was observed and similar results were verified with a lower dosis of CMD-P (100 µg/mL).…”

Leishmanicidas potenciais: estudo da síntese de fármacos dirigidos dendriméricos de primeira geração com hidroximetilnitrofural

“…A disponibilidade de programas computacionais de química e os bancos de dados em rede são ferramentas importantes para a descoberta e planejamento racional de novos fármacos (EKINS et al, 2007;NADENDLA, 2004;SANT'ANNA, 2009 (CARVALHO et al, 2003;LIPKOWITZ, BOYD, 1990;BARREIRO et al, 1997;CLARK, 1985;MA et al, 2011;NADENDLA, 2004;STENTA, PERARO, 2011;MA et al, 2011 (BUNDGAARD, 1985;SILVA et al, 2005;WERMUTH, 2008;ETTMAYER et al, 2004;TESTA, CALDWELL, 1996;TESTA, 2004;TESTA, KRÄMER, 2009;HUTTUNEN, RAUNIO, RAUTIO, 2011;RAUTIO et al, 2008;MÜLLER, 2009;TESTA, 2009b;VERMA et al, 2009). …”