Synthesis, Antileishmanial Activity and In Silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes
Background: Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Among the four main clinical forms of the disease, visceral leishmaniasis is the most se-vere, fatal in 95% of cases. The undesired side-effects from first-li
Alexandre-Moreira, Magna S.,Aquino, Pedro G. V.,Bourguignon, Jean-Jacques,Bri-Card, Jacques,Freitas, Johnnatan D.,Meneghetti, Mario R.,Nascimento, Igor J. S.,Queiroz, Aline C.,Rodrigues, Klinger A. F.,Rodrigues, Raiza R. L.,Santos, Mariana S.,Schmitt, Martine,de Aquino, Thiago M.,Araújo, Morgana V.,Fran?a, Paulo H. B.,Rodrigues, érica E. E. S.,Santos-Júnior, Paulo F. S.,da Silva-Júnior, Edeildo F.,de Araújo-Júnior, Jo?o X.
Neuropeptide FF receptors (NPFF1R and NPFF2R) and their endogenous ligand Neuropeptide FF have been shown previously to display anti-opioid properties and to play a critical role in the adverse effects associated with chronic administrations of opiates including the development of opioid-induced hyperalgesia and analgesic tolerance. In this work, we sought to identify novel NPFF receptors ligands by focusing our interest on a series of heterocycles as rigidified non-peptide NPFF receptor ligands, starting from already described aminoguanidine hydrazones (AGH's). Binding experiments and functional assays highlighted AGH 1n and its rigidified analog 2-amino-dihydropyrimidine 22e for in vivo experiments. As earlier shown with the prototypical dipeptide antagonist RF9, both 1n and 22e reduced significantly the long lasting fentanyl-induced hyperalgesia in rodents. Altogether these data indicate that AGH rigidification maintains nanomolar affinities for both NPFF receptors, while improving antagonist character towards NPFF1R.
This disclosure describes platinum chelates of 2-hydrazino-1-aza (or 1,3-diaza,1-oxa-3-aza or 1-thia-3-aza)-1-cyclo-alkenes which possess activity as antitumor agents.
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(2008/06/13)
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