González-Bacerio J, Méndez GY, Rivera DG, Alonso del Rivero-Antigua M, Gazarini DM, Chávez PMÁ, Carmona AK

Language: English
References: 31
Page: 1511-1516
PDF size: 656.97 Kb.

ABSTRACT

Infections by bacteria resistant to conventional antibiotics are a worldwide health problem. Likewise, the parasite causal agent of malaria, main tropical parasitic disease, has developed resistance to the traditional drugs. In this sense, aminopeptidases PepN, from the bacterium Escherichia coli, and PfA-M1, from the Plasmodium falciparum parasite, are new targets in these sicknesses. The objective of this work was the identification of synthetic inhibitors of ePepN and PfA-M1, with potentialities as anti-bacterial and anti-malarial agents. Using two multicomponent Ugi-reactions, two libraries of 33 bestatin- and actinonin-based peptidomimetics were synthesized and evaluated against PfA-M1. In addition, 22 tetrazole-peptidomimetics were synthesized and evaluated against ePepN. Three tetrazoles (YTE003, YTE007, YTE008) were identified as potent and selective ePepN inhibitors, regarding porcine M1 aminopeptidase (pAPN). YTE003 shows in vitro anti-bacterial activity, which supports its potential as leader compound in the field of anti-bacterial agents. Toward PfA-M1, compound KBE009 was identified as a potent inhibitor, with in vitro anti-malarial activity, that does not inhibit pAPN at concentrations of therapeutic relevance, and it is not cytotoxic up to 200 μmol/L against the human HUVEC cell line. It was found that KBE009 inhibits aminopeptidase activity in the whole and isolated parasite in the same order of magnitude as its in vitro anti-malarial activity. These properties lead into considering the peptidomimetic a promising molecule as a lead compound against malaria.

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