Novel Pyrido[2',1':2,3]imidazo[4,5- c ]quinoline Derivative Selectively Poisons Leishmania donovani Bisubunit Topoisomerase 1 to Inhibit the Antimony-Resistant Leishmania Infection in Vivo .

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Washington Dc : American Chemical Society
      Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
    • Subject Terms:
      Leishmania donovani* ; Leishmaniasis, Visceral*/drug therapy ; Leishmaniasis, Visceral*/parasitology ; Poisons*/therapeutic use ; Antiprotozoal Agents*/pharmacology ; Antiprotozoal Agents*/therapeutic use ; Leishmaniasis*/drug therapy ; Quinolines*/pharmacology ; Quinolines*/therapeutic use; Animals ; Mice ; Humans ; Antimony/pharmacology ; Antimony/therapeutic use ; DNA/chemistry ; Mice, Inbred BALB C
    • Abstract:
      The unique bisubunit structure of Leishmania donovani topoisomerase 1B (LdTop1) is a potential drug target in the parasites unlike the monomeric Top1 from its human host counterpart. Here, we report the design, synthesis, and validation of a chimeric pyrido[2',1':2,3]imidazo[4,5- c ]quinoline derivative ( C17 ) as a novel antileishmanial agent that poisons topoisomerase 1-DNA covalent complexes (LdTop1cc) inside the parasites and inhibits Top1 religation activity both in the drug sensitive and antimony-resistant L. donovani clinical isolates. Importantly, the human Top1 is not sensitive to C17 . Further, C17 overcomes the chemical instability of camptothecin (CPT) by generating persistent LdTop1cc-induced DNA breaks inside the parasites even after 12 h of drug removal. Intraperitoneal administration of C17 results in marked reduction of the Leishmania amastigotes from the infected spleen and liver of BALB/c mice. C17 confers a host protective immune-response up-regulating the Th1 cytokines facilitating parasite clearance which can be exploited for treating drug-resistant leishmaniasis.
    • Accession Number:
      9IT35J3UV3 (Antimony)
      0 (Poisons)
      0 (Antiprotozoal Agents)
      9007-49-2 (DNA)
      0 (Quinolines)
    • Publication Date:
      Date Created: 20230224 Date Completed: 20230310 Latest Revision: 20230313
    • Publication Date:
      20240829
    • Accession Number:
      10.1021/acs.jmedchem.2c01932
    • Accession Number:
      36823782