New benzimidazole derivatives as antiplasmodial agents and plasmepsin inhibitors: Synthesis and analysis of structure-activity relationships

Zafar Saied Saify, M. Kamran Azim, Waseem Ahmad, Mehrun Nisa, Daniel E. Goldberg, Shaheen A. Hussain, Shamim Akhtar, Arfa Akram, Arshad Arayne, Anna Oksman, Ishtiaq A. Khan

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

The newly synthesized benzimidazole compounds were suggested to be inhibitors of Plasmodium falciparum plasmepsin II and human cathepsin D by virtual screening of an internal library of synthetic compounds. This was confirmed by enzyme inhibition studies that gave IC 50 values in the low micromolar range (2-48 μM). Ligand docking studies with plasmepsin II predicted binding of benzimidazole compounds at the center of the extended substrate-binding cleft. According to the plausible mode of binding, the pyridine ring of benzimidazole compounds interacted with S1′ subsite residues whereas the acetophenone moiety was in contact with S1-S3 subsites of plasmepsin II active center. The benzimidazole derivatives were evaluated for capacity to inhibit the growth of intraerythrocytic P. falciparum in culture. Four benzimidazole compounds inhibited parasite growth at ≤3 μM. The most active compound 10, 1-(4-phenylphenyl)-2[2-(pyridinyl-2-yl)-1,3-benzdiazol-1-yl] ethanone showed an IC 50 of 160 nM. The substitution of a phenyl group and a chlorine atom at the para position of the acetophenone moiety were shown to be crucial for antiplasmodial activity.

Original languageEnglish
Pages (from-to)1282-1286
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number2
DOIs
StatePublished - Jan 15 2012

Keywords

  • Antimalarial
  • Aspartic protease
  • Cathepsin D
  • FlexX docking
  • Flow cytometry

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