Novel amidines and analogues as promising agents against intracellular parasites: a systematic review

Abstract

SUMMARY Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.

Anti-parasitic effect of novel amidines against Trypanosoma cruzi: phenotypic and in silico absorption, distribution, metabolism, excretion and toxicity analysis

“…Experimental chemotherapy for CD presents serious challenges in part due to experimental difficulties related to reliable demonstration of a sterile cure, particularly during the chronic stage of infection when parasite burden is low and tissue distribution is not fully understood (Chatelain and Konar, 2015;Francisco et al 2015). Our group has studied the in vitro and in vivo activity of AA and analogues and the bulk of the data revealed very promising action of these cations against intracellular pathogens, including T. cruzi (Soeiro et al 2013). Presently, nine aromatic compounds were evaluated by phenotypic and in silico studies.…”

Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease

“…Cysteine protease inhibitors (morpholinecarbonyl-phenylalanine-homophenylalanine-vinyl sulphone phenyl and morpholineureaphenylalanine-homophenylalaninefluoromethyl ketone) induced severe alterations in the Golgi complex with chagasin accumulation in enlarged cisternae, suggesting a disturbance in the transport within the ER-Golgi system 34 . Multiple intracellular compartment damage has been reported with other active drugs against T. cruzi [35][36][37] . Mitochondrial swelling and the presence of concentric structures were frequently noticed in parasites treated with lysophospholipid analogues 38 and naphthoquinone derivatives 39 .…”

“…Trypomastigotes (3 Â 10 6 parasites/well) were incubated for 24 h at 37 C in the presence or absence of serial dilutions of HAD1 or HAD2 compounds (0.04-90 mM). After treatment, the resazurin 0.005% was added to the parasites for 4 h at 37 C and the fluorescence emission measurements were registered at 530 nm and 630 nm in a Molecular Devices Flexstation 3 MultiMode Microplate Reader (Molecular Devices, Sunnyvale, CA). The inhibitory concentration (IC 50 ), the drug concentration that reduces 50% of trypomastigotes viability, was determined by fitting the dose-response curve to inhibitory activity compared with the untreated control.…”

“…The efficacy of the compounds was also evaluated, in terms of eliminating the intracellular parasites, by incubating 24 h-infected mammalian cells primary cultures (macrophages and cardiomyocytes) for 72 h at 37 C with a serial dilution (3.3-90 mM) of HAD1 and HAD2 compounds, followed by fixation with Bouin solution fixative. The percentage of infection was determined by quantification of a minimum of 200 cells in randomly selected microscopic fields using a Zeiss Axioplan microscope (Zeiss, Rochester, NY).…”

“…Mitochondrial swelling and the presence of concentric structures were frequently noticed in parasites treated with lysophospholipid analogues 38 and naphthoquinone derivatives 39 . Remarkable changes were also induced in the kinetoplast-mitochondrial system, microtubule, and reservosomes organization after treatment of T. cruzi with DNA-intercalating drugs and sterol biosynthesis inhibitors, leading to kinetoplast collapse and cell death 36,37,40 .…”