Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually, including 875 million children in developing economies. These diseases are also responsible for over 500,000 deaths per year and are characterized by long-term disability and severe pain. The impact of the combined NTDs closely rivals that of malaria and tuberculosis. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Natural products have been a valuable source of drug regimens that form the cornerstone of modern pharmaceutical care. In this review, we highlight the potential that remains untapped in natural products as drug leads for NTDs. We cover natural products from plant, marine, and microbial sources including natural-product-inspired semi-synthetic derivatives which have been evaluated against the various causative agents of NTDs. Our coverage is limited to four major NTDs which include human African trypanosomiasis (sleeping sickness), leishmaniasis, schistosomiasis and lymphatic filariasis.
Plasmepsins represent novel antimalarial drug targets. However, plasmepsin-based antimalarial drug discovery efforts in the past 2 decades have generally suffered some drawbacks including lack of translatability of target inhibition to potent parasite inhibition in vitro and in vivo as well as poor selectivity over the related human aspartic proteases. Most studies reported in this period have over-relied on the use of hemoglobinase plasmepsins I−IV (particularly I and II) as targets for the new inhibitors even though these are known to be nonessential at the asexual stage of parasite development. Therefore, future antimalarial drug discovery efforts seeking to identify plasmepsin inhibitors should focus on incorporating nonhemoglobinase plasmepsins such as V, IX, and X in their screening in order to maximize chances of success. Additionally, there is need to go beyond just target enzymatic activity profiling to establishing cellular activity, physicochemical as well as drug metabolism and pharmacokinetics properties and finally in vivo proof-of-concept while ensuring selectivity over related human host proteases.
Recent studies on 3,6-diphenylated imidazopyridazines have demonstrated impressive in vitro activity and in vivo efficacy in mouse models of malaria infection. Herein, we report the synthesis and antiplasmodium evaluation of a new series of amidated analogues and demonstrate that these compounds potently inhibit Plasmodium phosphatidylinositol-4-kinase (PI4K) type IIIβ while moderately inhibiting cyclic guanidine monophosphate (cGMP)-dependent protein kinase (PKG) activity in vitro. Using in silico docking, we predict key binding interactions for these analogues within the adenosine triphosphate (ATP)-binding site of PI4K and PKG, paving the way for structure-based optimization of imidazopyridazines targeting both Plasmodium PI4K and PKG. While several derivatives showed low nanomolar antiplasmodium activity (IC 50 < 100 nM), some compounds, including piperazine analogue 28, resulted in strong dual PI4K and PKG inhibition. The compounds also demonstrated transmission-blocking potential, evident from their potent inhibition of earlyand late-stage gametocytes. Finally, the current compounds generally showed improved aqueous solubility and reduced hERG (human ether-a-go-go-related gene) channel inhibition.
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