title: Antileishmanial, DNA Interaction, and Docking Studies of Some Ferrocene-Based Heteroleptic Pentavalent Antimonials.
abstract: A series of ferrocenyl pentavalent antimonials (1-8) were synthesized and characterized by elemental analysis, FT-IR, and multinuclear ((1) H and (13) C) NMR spectroscopy. These antimonials were evaluated for their antileishmanial potential against Leishmania tropica KWH23, and by biocompatibility and membrane permeability assays. Moreover, mechanistic studies were carried out, mediated by DNA targeting followed by computational docking of ferrocenyl antimonials against the leishmanial trypanothione reductase enzyme. It was observed that the antimonials 1-8 were 390-fold more efficacious (IC50 ) as compared with the standard antimonial drug used. Cytotoxicity results showed that these antimonials are highly active even at low concentrations and are biocompatible with human macrophages. Antimonials 1-8 exhibited extensive intercalation with DNA and, furthermore, docking interactions highlighted the potential interactive binding of the anitimonials within the trypanothione reductase active site, with van der Waals interactions contributing significantly to the process. Hence, it is suggested that the reported antimonials demonstrate high efficacy, less toxicity, and target multiple sites of the Leishmania parasite.
authors.affiliation: Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Muhammad Khawar
authors.initials: MK
authors.lastname: Rauf
authors.affiliation: National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Ummara
authors.initials: U
authors.lastname: Shaheen
authors.affiliation: Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Faiza
authors.initials: F
authors.lastname: Asghar
authors.affiliation: Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Amin
authors.initials: A
authors.lastname: Badshah
authors.affiliation: National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Akhtar
authors.initials: A
authors.lastname: Nadhman
authors.affiliation: National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Sikander
authors.initials: S
authors.lastname: Azam
authors.affiliation: Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Muhammad Irshad
authors.initials: MI
authors.lastname: Ali
authors.affiliation: Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Gul
authors.initials: G
authors.lastname: Shahnaz
authors.affiliation: National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Masoom
authors.initials: M
authors.lastname: Yasinzai
mesh_terms: D000965:Antimony / Q000737:chemistry*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002463:Cell Membrane Permeability; D016054:DNA, Protozoan / Q000737:chemistry*; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007895:Leishmania tropica / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D000075163:Metallocenes; D062105:Molecular Docking Simulation; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D016054:DNA, Protozoan; D005296:Ferrous Compounds; D000075163:Metallocenes; D009942:Organometallic Compounds; D000965:Antimony; C004998:ferrocene
keywords: Binding constant; Ferrocenyl pentavalent antimonials; Molecular docking; Permeability; Pharmacophores