title: Design, synthesis and anti-leishmanial activity of novel symmetrical bispyridinium cyclophanes.
abstract: Nine novel symmetrical bispyridinium cyclophanes have been synthesized. They are rigid derivatives with an upper spacer which joins the two exocyclic amino groups, and a lower spacer joining the two positively charged nitrogen atoms. At least one of the two spacers is an aliphatic linker, such as an alkane or oxyalkane fragment. The activity of these compounds has been evaluated against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania major. All the cyclophanes are more active against L. major, with EC50 in intracellular amastigotes of between 1 and 17 μM, they exhibit very low toxicity against mammalian cells THP-1 and in some cases they present a higher selectivity index than the reference anti-leishmanial drugs amphotericin B and miltefosine. Compound 9 [2,8-Diaza-1,9(4,1)-dipyridinacyclotetradecaphan-1(1),9(1)-bis(ilium) dibromide] is the most active one among cyclophane derivatives against intracellular amastigotes of L. donovani (EC50 7.6 ± 0.2 μM) while L. major amastigotes are 6-fold more susceptible to the compound (EC50 1.26 ± 0.3 μM). Compound 9 produces depolarization of the mitochondrial membrane and a decrease in the ATP levels that leads to death of the parasites. The anti-leishmanial activity of this macrocyclic salts is independent of the Leishmania enzymes ethanolamine kinase and choline/ethanolamine kinase.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, c/ Campus de Cartuja s/n, 18071 Granada, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Gómez-Pérez
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Manzano
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: García-Hernández
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, c/ Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: jmcampos@ugr.es.
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Campos
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000981:Antiprotozoal Agents; D047028:Macrocyclic Compounds; D011726:Pyridinium Compounds
keywords: Bispyridinium; Cyclophanes; Leishmania; Microwave; Mitochondrial membrane potential; THP-1 cells