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Identification of novel class of falcipain-2 inhibitors as potential antimalarial agents.
Chakka, Sai Kumar; Kalamuddin, Mohammad; Sundararaman, Srividhya; Wei, Lianhu; Mundra, Sourabh; Mahesh, Radhakrishnan; Malhotra, Pawan; Mohmmed, Asif; Kotra, Lakshmi P.
Afiliación
  • Chakka SK; 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.
  • Kalamuddin M; International Centre for Genetic Engineering & Biotechnology, Aruna Asif Ali Marg, New Delhi 100 067, India.
  • Sundararaman S; International Centre for Genetic Engineering & Biotechnology, Aruna Asif Ali Marg, New Delhi 100 067, India.
  • Wei L; 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, Univ
  • Mundra S; 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
  • Mahesh R; Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan 333031, India.
  • Malhotra P; International Centre for Genetic Engineering & Biotechnology, Aruna Asif Ali Marg, New Delhi 100 067, India. Electronic address: pawanm@icgeb.res.in.
  • Mohmmed A; International Centre for Genetic Engineering & Biotechnology, Aruna Asif Ali Marg, New Delhi 100 067, India. Electronic address: amohd@icgeb.res.in.
  • Kotra LP; 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, Univ
Bioorg Med Chem ; 23(9): 2221-40, 2015 May 01.
Article en En | MEDLINE | ID: mdl-25840796
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Cisteína Endopeptidasas / Inhibidores de Cisteína Proteinasa / Antimaláricos Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Cisteína Endopeptidasas / Inhibidores de Cisteína Proteinasa / Antimaláricos Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido