Multistage antiplasmodial activity of hydroxyethylamine compounds, in vitro and in vivo evaluations

Neha Sharma; Yash Gupta; Meenakshi Bansal; Snigdha Singh; Prateek Pathak; Mohd Shahbaaz; Raman Mathur; Jyoti Singh; Mohammad Kashif; Maria Grishina; Vladimir Potemkin; Vinoth Rajendran; Poonam; Prakasha Kempaiah; Agam Prasad Singh; Brijesh Rathi

doi:10.1039/D0RA03997G

Multistage antiplasmodial activity of hydroxyethylamine compounds, in vitro and in vivo evaluations†

Neha Sharma,^a Yash Gupta,^b Meenakshi Bansal,

^a Snigdha Singh,^a Prateek Pathak,

^c Mohd Shahbaaz,^cd Raman Mathur,^b Jyoti Singh,^e Mohammad Kashif,^e Maria Grishina,^c Vladimir Potemkin,

^c Vinoth Rajendran,^f Poonam,

^cg Prakasha Kempaiah,^b Agam Prasad Singh

*^e and Brijesh Rathi

*^ac

Author affiliations

* Corresponding authors

^a Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College University Enclave, University of Delhi, Delhi 110007, India
E-mail: brijeshrathi@hrc.du.ac.in

^b Department of Medicine, Stritch School of Medicine, Loyola University Chicago, 2160 South 1st Avenue, Maywood, IL 60153, USA

^c South Ural State University, Laboratory of Computational Modelling of Drugs, Russia

^d South African National Bioinformatics Institute, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa

^e Infectious Diseases Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
E-mail: singhap@nii.ac.in

^f Department of Microbiology, School of Life Sciences, Pondicherry University, Puducherry 605014, India

^g Department of Chemistry, Miranda House, University of Delhi, Delhi 110007, India

Abstract

Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains of Plasmodium species. New therapeutics acting against the pathogenic asexual and sexual stages, including liver-stage malarial infection, have now attained more attention in achieving malaria eradication efforts. In this paper, two previously identified potent antiplasmodial hydroxyethylamine (HEA) compounds were investigated for their activity against the malaria parasite's multiple life stages. The compounds exhibited notable activity against the artemisinin-resistant strain of P. falciparum blood-stage culture with 50% inhibitory concentrations (IC₅₀) in the low micromolar range. The compounds' cytotoxicity on HEK293, HepG2 and Huh-7 cells exhibited selective killing activity with IC₅₀ values > 170 μM. The in vivo efficacy was studied in mice infected with P. berghei NK65, which showed a significant reduction in the blood parasite load. Notably, the compounds were active against liver-stage infection, mainly compound 1 with an IC₅₀ value of 1.89 μM. Mice infected with P. berghei sporozoites treated with compound 1 at 50 mg kg⁻¹ dose had markedly reduced liver stage infection. Moreover, both compounds prevented ookinete maturation and affected the developmental progression of gametocytes. Further, systematic in silico studies suggested both the compounds have a high affinity towards plasmepsin II with favorable pharmacological properties. Overall, the findings demonstrated that HEA and piperidine possessing compounds have immense potential in treating malarial infection by acting as multistage inhibitors.

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Multistage antiplasmodial activity of hydroxyethylamine compounds, in vitro and in vivo evaluations†

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Multistage antiplasmodial activity of hydroxyethylamine compounds, in vitro and in vivo evaluations

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