RESUMO
Novel isoxazoline amide benzoxaboroles were designed and synthesized to optimize the ectoparasiticide activity of this chemistry series against ticks and fleas. The study identified an orally bioavailable molecule, (S)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (23), with a favorable pharmacodynamics profile in dogs (Cmax=7.42ng/mL; Tmax=26.0h; terminal half-life t1/2=127h). Compound 23, a development candidate, demonstrated 100% therapeutic effectiveness within 24h of treatment, with residual efficacy of 97% against American dog ticks (Dermacentor variabilis) on day 30 and 98% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 25mg/kg in dogs.
Assuntos
Amidas/farmacologia , Antiparasitários/farmacologia , Compostos de Boro/farmacologia , Ctenocephalides/efeitos dos fármacos , Dermacentor/efeitos dos fármacos , Ectoparasitoses/tratamento farmacológico , Isoxazóis/farmacologia , Administração Oral , Amidas/administração & dosagem , Amidas/química , Animais , Antiparasitários/administração & dosagem , Antiparasitários/química , Compostos de Boro/administração & dosagem , Compostos de Boro/química , Gatos , Cães , Relação Dose-Resposta a Droga , Ectoparasitoses/parasitologia , Isoxazóis/administração & dosagem , Isoxazóis/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-AtividadeRESUMO
The lack of efficient hydrogen storage material is one of the bottlenecks for the large-scale implementation of hydrogen energy. Here, a series of new hydrogen storage materials, i.e., anilinide-cyclohexylamide pairs, are proposed via the metallation of an aniline-cyclohexylamine pair. DFT calculations show that the enthalpy change of hydrogen desorption (ΔHd) can be significantly tuned from 60.0 kJ per mol-H2 for the pristine aniline-cyclohexylamine pair to 42.2 kJ per mol-H2 for sodium anilinide-cyclohexylamide and 38.7 kJ per mol-H2 for potassium anilinide-cyclohexylamide, where an interesting correlation between the electronegativity of the metal and the ΔHd was observed. Experimentally, the sodium anilinide-cyclohexylamide pair was successfully synthesised with a theoretical hydrogen capacity of 4.9 wt%, and the hydrogenation and dehydrogenation cycle can be achieved at a relatively low temperature of 150 °C in the presence of commercial catalysts, in clear contrast to the pristine aniline-cyclohexylamine pair which undergoes dehydrogenation at elevated temperatures.
RESUMO
A series of nonsecosteroidal vitamin D3 receptor (VDR) ligands with phenyl-pyrrolyl pentane skeleton were synthesized for cancer therapy. In contrast to 1α,25-dihydroxyvitamin D3 (Calcitriol), these VDR ligands exhibited anti-proliferative activity without inducing hypercalcemia. These compounds were evaluated for vitamin D3-agonistic ability and anti-proliferative activity in vitro. Among them, compounds 5k and 5i exhibited equivalent vitamin D3-agonistic activity compared with Calcitriol. Meanwhile, compound 5k displayed promising inhibiting profile against MCF-7, HepG-2 and Caco-2 with IC50 values of 0.00586 µM, 0.176 µM, and 1.01 µM (Calcitriol: 5.58 µM, 80.83 µM and 4.46 µM) respectively. Compound 5i inhibited proliferation of PC-3 with IC50 value of 0.00798 µM (Calcitriol: 17.25 µM). Additionally, neither of these compounds significantly elevated serum calcium in rats.