An Overview on the Therapeutics of Neglected Infectious Diseases-Leishmaniasis and Chagas Diseases

Abstract

Neglected tropical diseases (NTDs) as termed by WHO include twenty different infectious diseases that are caused by bacteria, viruses, and parasites. Among these NTDs, Chagas disease and leishmaniasis are reported to cause high mortality in humans and are further associated with the limitations of existing drugs like severe toxicity and drug resistance. The above hitches have rendered researchers to focus on developing alternatives and novel therapeutics for the treatment of these diseases. In the past decade, several target-based drugs have emerged, which focus on specific biochemical pathways of the causative parasites. For leishmaniasis, the targets such as nucleoside analogs, inhibitors targeting nucleoside phosphate kinases of the parasite's purine salvage pathway, 20S proteasome of Leishmania, mitochondria, and the associated proteins are reviewed along with the chemical structures of potential drug candidates. Similarly, in case of therapeutics for Chagas disease, several target-based drug candidates targeting sterol biosynthetic pathway (C14-ademethylase), L-cysteine protease, heme peroxidation, mitochondria, farnesyl pyrophosphate, etc., which are vital and unique to the causative parasite are discussed. Moreover, the use of nano-based formulations towards the therapeutics of the above diseases is also discussed.

Keywords: chagas; drugs; infectious disease; leishmaniasis; therapeutics.

GRAPHICAL ABSTRACT

FIGURE 1

Chemical structure of standard antileishmanial drugs.

FIGURE 2

Immucillines, the nucleoside analogs as hit candidates against leishmaniasis.

FIGURE 3

Chemical evolution of proteasome targeting triazolopyrimidine scaffold inhibitors that act by inhibiting the activity of chymotrypsin protease.

FIGURE 4

Compounds that inhibit β5 subunits of proteasome.

FIGURE 5

Benzazepane-based hit compounds that act as inhibitors by targeting Leishmania inositol phosphorylceramide synthases.

FIGURE 6

Chemical structure of anti-leishmaniasis hit compounds.

FIGURE 7

Chemical structure of antichagasic nitro heterocyclic compounds.

FIGURE 8

Potent anti-Chagas azole-derived compounds that target sterol biosynthetic pathway.

FIGURE 9

Potent anti-Chagas nonazole-derived drugs that target sterol biosynthetic pathway.

FIGURE 10

Anti-Chagas drugs that inhibit cathepsin L-cysteine protease.

FIGURE 11

Potent anti-Chagas drugs that variously deregulate mitochondrial functions.

FIGURE 12

Potent anti-Chagas isoxazole-derived drugs that target trypanothione reductase.

FIGURE 13

Quinoline derivative that inhibits heme peroxidation by forming heme-quinoline complex as potent antichagasic lead candidate.