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Bioorg Med Chem. 2015 May 1;23(9):2221-40. doi: 10.1016/j.bmc.2015.02.062. Epub 2015 Mar 18.

Identification of novel class of falcipain-2 inhibitors as potential antimalarial agents.

Author information

1
Center for Molecular Design and Preformulations, and Toronto General Research Institute, University Health Network, #5-356, Toronto Medical Discoveries Tower/MaRS Center, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
2
International Centre for Genetic Engineering & Biotechnology, Aruna Asif Ali Marg, New Delhi 100 067, India.
3
Center for Molecular Design and Preformulations, and Toronto General Research Institute, University Health Network, #5-356, Toronto Medical Discoveries Tower/MaRS Center, 101 College Street, Toronto, Ontario M5G 1L7, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
4
Center for Molecular Design and Preformulations, and Toronto General Research Institute, University Health Network, #5-356, Toronto Medical Discoveries Tower/MaRS Center, 101 College Street, Toronto, Ontario M5G 1L7, Canada; Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan 333031, India.
5
Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan 333031, India.
6
International Centre for Genetic Engineering & Biotechnology, Aruna Asif Ali Marg, New Delhi 100 067, India. Electronic address: pawanm@icgeb.res.in.
7
International Centre for Genetic Engineering & Biotechnology, Aruna Asif Ali Marg, New Delhi 100 067, India. Electronic address: amohd@icgeb.res.in.
8
Center for Molecular Design and Preformulations, and Toronto General Research Institute, University Health Network, #5-356, Toronto Medical Discoveries Tower/MaRS Center, 101 College Street, Toronto, Ontario M5G 1L7, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada. Electronic address: lkotra@uhnres.utoronto.ca.

Abstract

Falcipain-2 is a papain family cysteine protease and an emerging antimalarial drug target. A pseudo-tripeptide scaffold I was designed using in silico screening tools and the three dimensional structures of falcipain-2, falcipain-3, and papain. This scaffold was investigated at four positions, T1, T2, T3, and T3', with various targeted substitutions to understand the structure-activity relationships. Inhibitor synthesis was accomplished by first obtaining the appropriate dipeptide precursors with common structural components. The pyrrolidine moiety introduced interesting rotamers in a number of synthesized molecules, which was confirmed using high-temperature (1)H NMR spectroscopy. Among the synthesized compounds, 61, 62, and 66 inhibited falcipain-2 activity with inhibition constants (Ki) of 1.8 ± 1.1, 0.2 ± 0.1 and 7.0 ± 2.3 μM, respectively. A group of molecules with a pyrrolidine moiety at the T2 position (68, 70, 71, 72, and 73) also potently inhibited falcipain-2 activity (Ki=0.4 ± 0.1, 2.5 ± 0.5, 3.3 ± 1.1, 7.5 ± 1.9, and 4.6 ± 0.7 μM, respectively). Overall, compound 74 exhibited potent anti-parasitic activity (IC₅₀=0.9 ± 0.1 μM), corresponding with its inhibitory activity against falcipain-2, with a Ki of 1.1 ± 0.1 μM. Compounds 62 and 67 inhibited the growth of the drug resistant parasite Dd2 with better efficacy, and compound 74 exhibited a 7- to 12-fold higher potency against Dd2 and MCamp isolates, than the laboratory strain (3D7). These data suggest that this novel series of compounds should be further investigated as potential antimalarial agents.

KEYWORDS:

Anti-parasitic agents; Antimalarial agents; Cysteine proteases; Docking; Falcipain-2 inhibitors; Malaria; Structure–activity relationship

PMID:
25840796
DOI:
10.1016/j.bmc.2015.02.062
[Indexed for MEDLINE]

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