title: Synthesis, Screening and in silico Simulations of Anti-Parasitic Propamidine/Benzimidazole Derivatives.
abstract: BACKGROUND
  We designed hybrid molecules between propamidine and benzimidazole in order to retain the antiprotozoal action, but decreasing the toxic effect of the molecule.
  
  
  OBJECTIVE
  Design and prepare 12 hybrids for testing their antiparasitic effect over three protozoa: Giardia intestinalis, Trichomonas vaginalis and Leishmania mexicana, as well as conduct several in silico simulations such as toxicological profile, molecular docking and molecular dynamics in order to understand their potential mode of action.
  
  
  METHODS
  Hybrids 1-3, 6-9 and 12 were obtained using a chemical pathway previously reported. Compounds 4, 5, 10 and 11 were prepared using a one-pot reduction-cyclization reaction. The in vitro antiparasitic and cytotoxic activities of these compounds were conducted. It was calculated several properties such as toxicity, PK behavior, as well as docking studies and molecular dynamics of the most active compound performed in a DNA sequence dodecamer in comparison with propamidine.
  
  
  RESULTS
  Compound 2 was 183, 127 and 202 times more active against G. intestinalis than metronidazole, pentamidine and propamidine. It was eleven times more active than pentamidine against L. mexicana. This compound showed low in vitro mammalian cytotoxicity. Molecular simulations showed a stable complex 2-DNA that occurred in the minor groove, analogous to propamidine-DNA complex.
  
  
  CONCLUSIONS
  Compound 2, exhibited the higher bioactivity, especially towards G. intestinalis and L. mexicana. This study demonstrated that the replacement of benzimidazole scaffold instead of toxic amidine group in propamidine, results in an enhancement of antiprotozoal bioactivity. The preliminary molecular dynamics simulation suggests that the ligand-DNA complex is stable.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Mendez-Cuesta
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Herrera-Rueda
authors.forename: Sergio
authors.initials: S
authors.lastname: Hidalgo-Figueroa
authors.forename: Hugo
authors.initials: H
authors.lastname: Tlahuext
authors.forename: Rosa
authors.initials: R
authors.lastname: Moo-Puc
authors.forename: Juan B
authors.initials: JB
authors.lastname: Chale-Dzul
authors.forename: Manuel
authors.initials: M
authors.lastname: Chan-Bacab
authors.forename: Benjamín O
authors.initials: BO
authors.lastname: Ortega-Morales
authors.forename: Emanuel
authors.initials: E
authors.lastname: Hernandez-Nunez
authors.forename: Oscar
authors.initials: O
authors.lastname: Mendez-Lucio
authors.forename: Jose L
authors.initials: JL
authors.lastname: Medina-Franco
authors.affiliation: Laboratorio de Quimica Farmaceutica, Facultad de Farmacia, Universidad Autonoma del Estado de Morelos, 62209, Cuernavaca, Morelos, Mexico.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarrete-Vazquez
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001550:Benzamidines / Q000737:chemistry*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D060326:Chemistry Techniques, Synthetic; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000977:Antiparasitic Agents; D001550:Benzamidines; D001562:Benzimidazoles; D004247:DNA; C005555:propamidine
keywords: Benzimidazole; Giardia; Leishmania; Trichomonas; antiprotozoal activity; propamidine