Active Natural Product Scaffolds against Trypanosomatid Parasites: A Review

Abstract

Neglected tropical diseases caused by trypanosomatid parasites are a continuing and escalating problem, which devastate the less economically developed cultures in countries in which they are endemic by impairing both human and animal health. Current drugs for these diseases are regarded as out-of-date, expensive, with unacceptable side-effects and mounting parasite resistance, meaning there is an urgent need for new therapeutics. Natural products have long been a source of potent, structurally diverse bioactive molecules. Herein are reviewed natural products with reported trypanocidal activity, which have been clustered based on core structural similarities, to aid the future discovery of new trypanocidal core motifs with potential routes to synthetically accessible natural product cores suggested.in both the New and Old Worlds, and these include L. amazonensis, L. major, L. infantum and L. donovani. The disease is transmitted via the bite of the female phlebotomine sand fly vector, with an estimated 300,000 new infections each year and over 1 billion people living in areas at risk, primarily throughout the tropics and subtropics. 10

Total synthesis of the actinoallolides and a designed photoaffinity probe for target identification

“…The isolated C 14 stereocentre in 10 could then be installed by an Ireland-Claisen rearrangement from the diester 11. The 'all syn' stereotetrad in 12 can then be formed by a titaniummediated aldol reaction/in situ reduction between methacrolein and ethyl ketone 13, itself synthesised in three steps from (R)-Roche ester (14). The decision to attach the terminal ethyl group at such a late stage was made in order to form the C 21 ketone as late as possible to facilitate late-stage diversification.…”

“…12 However, the ongoing development of effective pharmaceutical agents against the causative agents of these diseases has been challenging due to two major factors. 13,14 First, the eukaryotic nature of protozoan parasites means that trypanosomes are biologically more closely related than bacteria to human cells. This renders the development of selective anti-trypanosomal drugs more challenging.…”

Synthesis and evaluation of novel 2,4-disubstituted arylthiazoles against T. brucei

“…New drugs are urgently required, as those that are currently available are characterized by sideeffects and treatment failures. 4,5 Various initiatives [6][7][8] have led to the discovery of promiscuous trypanocidal derivatives from phenotypic highthroughput screening of a number of compound libraries. These have been further refined and optimized to enhance drug-like properties.…”

“…Compounds 4a, c bear the same thiazole ring substituents as derivatives 2 and 3. Additionally, the adamantane core was replaced in the camphor skeleton in adducts 4b, 4. The latter molecules are sulfonamides in alignment with the scaffolds of compounds III.…”

NewLeishmania donovaninucleoside hydrolase inhibitors from Brazilian flora

“…The use of plants for the discovery of new bioactive compounds, and the search for antileishmanial molecules from natural sources has been widely reported in the literature. [9][10][11][12][13] A large percentage of these compounds were identied using in vitro assays against promastigotes or intracellular amastigotes of several species of Leishmania. However, to our knowledge there are no prior reports in which naturally occurring compounds were tested against the target LdNH.…”