Fast-Acting Small Molecules Targeting Malarial Aspartyl Proteases, Plasmepsins, Inhibit Malaria Infection at Multiple Life Stages
Authors: Vinoth Rajendran
Vandana
Nikesh Gupta
Agam P Singh
Poonam
Angela O Achieng
Akansha Pant
Mansi Pandit
Jiang He
Jyoti Singh
Latha Narayanan
Armiyaw S Nasamu
Brajendra K Singh
Prahlad C Ghosh
Afshana Quadiri
Brijesh Rathi
Amit K Singh
Ramesh Chandra
Prakasha Kempaiah
Kailash C Pandey
Snigdha Singh
Daniel E Goldberg
Ben M Dunn
Journal: ACS infectious diseases (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: hydroxyethylamine; marked killing inhibitor; multistage malaria inhibitor; phthalimide; plasmepsins.
Affiliations: Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry , Hansraj College University Enclave, University of Delhi , Delhi 110007 , India., Department of Chemistry , University of Delhi , Delhi 110007 , India., Department of Biochemistry , University of Delhi South Campus , New Delhi 110021 , India., Institute for Medical Engineering and Science, Koch Institute for Integrative Cancer Research , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States., Center for Global Health, Department of Internal Medicine , University of New Mexico Health Sciences Center , Albuquerque , New Mexico 87131 , United States., Host−Parasite Interaction Biology Group, National Institute of Malaria Research, Lab. No. 219, Sector-8 Dwarka, New Delhi 110077, India, Host-Parasite Interaction Biology Group , National Institute of Malaria Research , Lab. No. 219, Sector-8 Dwarka, New Delhi 110077 , India., Departments of Medicine and Molecular Microbiology , Washington University School of Medicine , St Louis , Missouri 63110 , United States., Bioinformatics Infrastructure Facility , Sri Venkateswara College, University of Delhi South Campus , New Delhi 110021 , India., Infectious Diseases Laboratory , National Institute of Immunology , Aruna Asaf Ali Marg , New Delhi 110067 , India., Special Centre for Nanosciences , Jawaharlal Nehru University , New Delhi 110067 , India., Department of Chemistry, Miranda House, University of Delhi North Campus, Delhi 110007, India, Department of Medicine , Loyola University Stritch School of Medicine , 2160 South First Avenue , Chicago , Illinois 60153 , United States., Department of Biochemistry & Molecular Biology , University of Florida College of Medicine , P.O. Box 100245, Gainesville , Florida 32610 , United States., Department of Biochemistry , National Institute for Research in Environmental Health, ICMR , Bhopal 462001 , India., Department of Chemistry , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.

Abstract:  The eradication of malaria remains challenging due to the complex life cycle of Plasmodium and the rapid emergence of drug-resistant forms of Plasmodium falciparum and Plasmodium vivax. New, effective, and inexpensive antimalarials against multiple life stages of the parasite are urgently needed to combat the spread of malaria. Here, we synthesized a set of novel hydroxyethylamines and investigated their activities in vitro and in vivo. All of the compounds tested had an inhibitory effect on the blood stage of P. falciparum at submicromolar concentrations, with the best showing 50% inhibitory concentrations (IC50) of around 500 nM against drug-resistant P. falciparum parasites. These compounds showed inhibitory actions against plasmepsins, a family of malarial aspartyl proteases, and exhibited a marked killing effect on blood stage Plasmodium. In chloroquine-resistant Plasmodium berghei and P. berghei ANKA infected mouse models, treating mice with both compounds led to a significant decrease in blood parasite load. Importantly, two of the compounds displayed an inhibitory effect on the gametocyte stages (III-V) of P. falciparum in culture and the liver-stage infection of P. berghei both in in vitro and in vivo. Altogether, our findings suggest that fast-acting hydroxyethylamine-phthalimide analogs targeting multiple life stages of the parasite could be a valuable chemical lead for the development of novel antimalarial drugs. 

Retracted: No

PubPeer comments:
 Figure 3E appears to include a repeated image, although the dimensions of one have been cropped differently and altered relative to the other. Marked in orange. *** ![file] , 
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 #2 Dr. Kempaiah, thank you for your reply. Are you submitting this correction to the journal? Also, a couple of follow up questions: 1. Did your investigation determine why the dimensions of the image were altered? This was not only the selection of same image twice, one appears edited. 2. Do you have an explanation for why the color of your replacement image differs from the other 8 images in the figure? , 
 Thanks for seeking clarification Two photos of the same blood smear from treated culture were taken for each drug. In this case, we had two photos for compound 5 at 0h, one of which was unintentionally assigned to compound 2 at 6h and was taken at a slightly different angle. This is why it seems like the dimensions of the image were edited, while in actual sense this is not the case. Please understand that these images are snapshots and not exact representation of overall drug effect on total parasite growth. for the second question: This may be attributed to differences in editing of the image pixel. , 
 #4 Is there a correction on this? I did not immediately find one at the journal site. ,