Polyamines and Related Nitrogen Compounds in the Chemotherapy of Neglected Diseases Caused by Kinetoplastids

Abstract

Neglected diseases due to the parasitic protozoa Leishmania and Trypanosoma (kinetoplastids) affect millions of people worldwide, and the lack of suitable treatments has promoted an ongoing drug discovery effort to identify novel nontoxic and cost-effective chemotherapies. Polyamines are ubiquitous small organic molecules that play key roles in kinetoplastid parasites metabolism, redox homeostasis and in the normal progression of cell cycles, which differ from those found in the mammalian host. These features make polyamines attractive in terms of antiparasitic drug development. The present work provides a comprehensive insight on the use of polyamine derivatives and related nitrogen compounds in the chemotherapy of kinetoplastid diseases. The amount of literature on this subject is considerable, and a classification considering drug targets and chemical structures were made. Polyamines, aminoalcohols and basic heterocycles designed to target the relevant parasitic enzyme trypanothione reductase are discussed in the first section, followed by compounds directed to less common targets, like parasite SOD and the aminopurine P2 transporter. Finally, the third section comprises nitrogen compounds structurally derived from antimalaric agents. References on the chemical synthesis of the selected compounds are reported together with their in vivo and/or in vitro IC50 values, and structureactivity relationships within each group are analyzed. Some favourable structural features were identified from the SAR analyses comprising protonable sites, hydrophobic groups and optimum distances between them. The importance of certain pharmacophoric groups or amino acid residues in the bioactivity of polyamine derived compounds is also discussed.

Cytotoxicity of Essential Oil Cordia verbenaceae against Leishmania brasiliensis and Trypanosoma cruzi

“…The kinetoplastid class is a diverse group of single-celled flagellate organisms, many of which are human parasites, that commonly present a reduction in or total elimination of biochemical pathways that can be augmented or provided by their hosts [ 2 , 3 ]. Diseases ignored by parasites such as Leishmania brasiliensis and Trypanosoma cruzi (kinetoplastids) affect thousands of people worldwide, and so there is an ongoing effort to identify new chemotherapies [ 4 , 5 ].…”

Polyamine Metabolism in Leishmania Parasites: A Promising Therapeutic Target

“…Even less is known about the function or regulation of polyamines in parasites, despite their significance in parasite biology. This is underscored by recent studies highlighting their importance as potential therapeutic targets in trypanosomatids, which include Leishmania spp., T. brucei , and Trypanosoma cruzi [ 30 , 32 , 33 , 52 , 53 , 54 ]. The polyamine pathway in T. brucei , the causative agent of African sleeping sickness, is the target of the drug D, L-α-difluoromethylornithine (DFMO, eflornithine, ornidyl), an inhibitor of ornithine decarboxylase (ODC), that has shown remarkable therapeutic efficacy in the treatment of African trypanosomiasis [ 32 , 34 , 35 , 36 , 37 ].…”

“…Two recent articles have reviewed classes of diamine and polyamine analogs and their efficacy against kinetoplastid parasites, including Leishmania spp. [ 53 , 187 ], and we will thus only briefly summarize these studies. A plethora of compounds have been synthesized that can be categorized broadly into diamine (putrescine analogs), triamine (spermidine analogs), tetramine (spermine analogs), longer polyamines, and cyclic derivatives.…”

<p>A Lysosome-Targetable Fluorescence Probe Based on L-Cysteine-Polyamine-Morpholine-Modified Quantum Dots for Imaging in Living Cells</p>

“…[36][37][38][39][40] In recent years, polyamine derivatives have attracted increasing attention due to their ability to enhance the selectivity and bioactivity of compounds. [41][42][43][44][45][46] Protein primary structure consists of amino acids linked by peptide bonds. Because amino acids are generally water-soluble and inexpensive, they have been used as capping agents for QDs.…”