Discovery and Pharmacological Studies of 4-Hydroxyphenyl-Derived Phosphonium Salts Active in a Mouse Model of Visceral Leishmaniasis

  • J Med Chem. 2019 Dec 12;62(23):10664-10675. doi: 10.1021/acs.jmedchem.9b00998.
José Ignacio Manzano  1 ,  Eduardo J Cueto-Díaz  2 ,  Ana Isabel Olías-Molero  3 ,  Ana Perea  1 ,  Tomás Herraiz  4 ,  Juan J Torrado  5 ,  José María Alunda  3 ,  Francisco Gamarro  1 ,  Christophe Dardonville  2
Affiliations
  • 1. Instituto de Parasitología y Biomedicina "López Neyra", IPBLN-CSIC , Parque Tecnológico de Ciencias de la Salud , 18016 Granada , Spain.
  • 2. Instituto de Química Médica, IQM-CSIC , Juan de la Cierva 3 , E-28006 Madrid , Spain.
  • 3. Departamento de Sanidad Animal, Facultad de Veterinaria , Universidad Complutense de Madrid , Avda. Puerta de Hierro s/n , 28040 Madrid , Spain.
  • 4. Instituto de Ciencia y Tecnología de Alimentos y Nutrición, ICTAN-CSIC , Juan de la Cierva 3 , E-28006 Madrid , Spain.
  • 5. Departamento de Farmacia Galénica y Tecnología Alimentaria, Facultad de Farmacia , Universidad Complutense de Madrid , Plaza de Ramón y Cajal s/n , 28040 Madrid , Spain.
PMID: 31702921 DOI: 10.1021/acs.jmedchem.9b00998
Abstract

We report the discovery of new 4-hydroxyphenyl phosphonium salt derivatives active in the submicromolar range (EC50 from 0.04 to 0.28 μM, SI > 10) against the protozoan Parasite Leishmania donovani. The pharmacokinetics and in vivo oral efficacy of compound 1 [(16-(2,4-dihydroxyphenyl)-16-oxohexadecyl)triphenylphosphonium bromide] in a mouse model of visceral leishmaniasis were established. Compound 1 reduced the Parasite load in spleen (98.9%) and liver (95.3%) of infected mice after an oral dosage of four daily doses of 1.5 mg/kg. Mode of action studies showed that compound 1 diffuses across the plasma membrane, as designed, and targets the mitochondrion of Leishmania parasites. Disruption of the energetic metabolism, with a decrease of intracellular ATP levels as well as mitochondrial depolarization together with a significant Reactive Oxygen Species production, contributes to the leishmanicidal effect of 1. Importantly, this compound was equally effective against antimonials and miltefosine-resistant clinical isolates of Leishmania infantum, indicating its potential as antileishmanial lead.