Synthesis and Evaluation of Nifurtimox–Adamantane Adducts with Trypanocidal Activity
The synthesis and pharmacological evaluation of C1-substituted adamantane hydrazones, their C2-substituted isomers, and C1-substituted adamantane furanoic carboxamides is described. These new adamantane derivatives exhibited an interesting pharmacological profile in terms of trypanocidal activity and selectivity. The most active adduct with the best selectivity in this study was found to be the phenylacetoxy hydrazone 1 b (2-[4-(tricyclo[3.3.1.13,7]dec-1-yl)phenyl]-N′-[(5-nitrofuran-2-yl)methylene]acetohydrazide; EC50=11±0.9 nm, SITb=770).
Foscolos, Angeliki-Sofia,Papanastasiou, Ioannis,Tsotinis, Andrew,Taylor, Martin C.,Kelly, John M.
supporting information
p. 1227 - 1231
(2019/07/09)
New hydrazones of 5-nitro-2-furaldehyde with adamantanealkanohydrazides: Synthesis and: In vitro trypanocidal activity
Nifurtimox, a hydrazone of 5-nitro-2-furaldehyde is used therapeutically against Trypanosoma brucei and Trypanosoma cruzi infections. Exploiting our previous observation that adamantane derivatives display trypanocidal activity, we designed and synthesised a range of hydrazones of 5-nitro-2-furaldehyde with adamantane alkanohydrazides. The most promising compounds had >20 times greater activity (IC50 ~ 100 nM) than nifurtimox, with selectivity indices of 20-80. SAR studies revealed that activity is associated with increased lipophilicity and influenced by conformational flexibility. Derivatives lacking a nitro group were practically inactive against both parasites. The approaches described demonstrate the feasibility of enhancing the potency of chemical entities with known trypanocidal activity.
Foscolos, Angeliki-Sofia,Papanastasiou, Ioannis,Foscolos, George B.,Tsotinis, Andrew,Kellici, Tahsin F.,Mavromoustakos, Thomas,Taylor, Martin C.,Kelly, John M.
supporting information
p. 1229 - 1236
(2016/07/06)
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