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Inhibition of Hemoglobin Degrading Protease Falcipain-2 as a Mechanism for Anti-Malarial Activity of Triazole-Amino Acid Hybrids.
Singh, Vigyasa; Hada, Rahul Singh; Uddin, Amad; Aneja, Babita; Abid, Mohammad; Pandey, Kailash C; Singh, Shailja.
Afiliación
  • Singh V; Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
  • Hada RS; Department of Life Sciences, Shiv Nadar University, Gautam Buddha Nagar UP, 201314, India.
  • Uddin A; Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
  • Aneja B; Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
  • Abid M; Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, 7610001, Israel.
  • Pandey KC; Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
  • Singh S; Host-Parasite Interaction Biology Group, National Institute of Malaria Research, Indian Council of Medical Research, Sector-8, Dwarka, New Delhi 110077, India.
Curr Top Med Chem ; 20(5): 377-389, 2020.
Article en En | MEDLINE | ID: mdl-32000644
BACKGROUND: Novel drug development against malaria parasite over old conventional antimalarial drugs is essential due to rapid and indiscriminate use of drugs, which led to the emergence of resistant strains. METHODS: In this study, previously reported triazole-amino acid hybrids (13-18) are explored against Plasmodium falciparum as antimalarial agents. Among six compounds, 15 and 18 exhibited antimalarial activity against P. falciparum with insignificant hemolytic activity and cytotoxicity towards HepG2 mammalian cells. In molecular docking studies, both compounds bind into the active site of PfFP-2 and block its accessibility to the substrate that leads to the inhibition of target protein further supported by in vitro analysis. RESULTS: Antimalarial half-maximal inhibitory concentration (IC50) of 15 and 18 compounds were found to be 9.26 µM and 20.62 µM, respectively. Blood stage specific studies showed that compounds, 15 and 18 are effective at late trophozoite stage and block egress pathway of parasites. Decreased level of free monomeric heme was found in a dose dependent manner after the treatment with compounds 15 and 18, which was further evidenced by the reduction in percent of hemoglobin hydrolysis. Compounds 15 and 18 hindered hemoglobin degradation via intra- and extracellular cysteine protease falcipain-2 (PfFP-2) inhibitory activity both in in vitro and in vivo in P. falciparum. CONCLUSION: We report antimalarial potential of triazole-amino acid hybrids and their role in the inhibition of cysteine protease PfFP-2 as its mechanistic aspect.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Triazoles / Hemoglobinas / Cisteína Endopeptidasas / Aminoácidos / Antimaláricos Límite: Humans Idioma: En Revista: Curr Top Med Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: India Pais de publicación: Emiratos Árabes Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Triazoles / Hemoglobinas / Cisteína Endopeptidasas / Aminoácidos / Antimaláricos Límite: Humans Idioma: En Revista: Curr Top Med Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: India Pais de publicación: Emiratos Árabes Unidos