3 research outputs found
The Dependence of the Superconducting Transition Temperature of Organic Molecular Crystals on Intrinsically Non-Magnetic Disorder: a Signature of either Unconventional Superconductivity or Novel Local Magnetic Moment Formation
We give a theoretical analysis of published experimental studies of the
effects of impurities and disorder on the superconducting transition
temperature, T_c, of the organic molecular crystals kappa-ET_2X and beta-ET_2X
(where ET is bis(ethylenedithio)tetrathiafulvalene and X is an anion eg I_3).
The Abrikosov-Gorkov (AG) formula describes the suppression of T_c both by
magnetic impurities in singlet superconductors, including s-wave
superconductors and by non-magnetic impurities in a non-s-wave superconductor.
We show that various sources of disorder lead to the suppression of T_c as
described by the AG formula. This is confirmed by the excellent fit to the
data, the fact that these materials are in the clean limit and the excellent
agreement between the value of the interlayer hopping integral, t_perp,
calculated from this fit and the value of t_perp found from angular-dependant
magnetoresistance and quantum oscillation experiments. If the disorder is, as
seems most likely, non-magnetic then the pairing state cannot be s-wave. We
show that the cooling rate dependence of the magnetisation is inconsistent with
paramagnetic impurities. Triplet pairing is ruled out by several experiments.
If the disorder is non-magnetic then this implies that l>=2, in which case
Occam's razor suggests that d-wave pairing is realised. Given the proximity of
these materials to an antiferromagnetic Mott transition, it is possible that
the disorder leads to the formation of local magnetic moments via some novel
mechanism. Thus we conclude that either kappa-ET_2X and beta-ET_2X are d-wave
superconductors or else they display a novel mechanism for the formation of
localised moments. We suggest systematic experiments to differentiate between
these scenarios.Comment: 18 pages, 5 figure
Antikinetoplastid SAR study in 3-nitroimidazopyridine series: identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties
To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program
Antikinetoplastid SAR study in 3-nitroimidazopyridine series: identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties
To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program