(2S,3R)-tert-Butyl N-[4-(N-benzyl-4-fluoro­benzene­sulfonamido)-3-hy­droxy-1-phenyl­butan-2-yl]carbamate

In the title mol­ecule, C28H33FN2O5S, the mean plane about the tertiary amine group (sum of the angles subtended at the sp 2-hybridized N atom = 359.7°) forms a dihedral angle of 16.66 (6)° with the phenyl ring adjacent to the carbamate group. The sulfonamide benzene ring and the hy­droxy group lie to either side of the C2NS plane, whereas the benzyl­phenyl (connected to the N atom) and carbamate substituents lie to the other side. Supra­molecular layers propagating in the ac plane are found in the crystal, linked by hy­droxy–sulfonamide O—H⋯O and carbamate–carbamate N—H⋯O hydrogen bonds along with C—H⋯O and C—H⋯π inter­actions

Oral effectiveness of PMIC4, a novel hydroxyethylpiperazine analogue, in Leishmania amazonensis

Made available in DSpace on 2015-05-04T16:34:36Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) claudia_levyetal_IOC_2014.pdf: 620953 bytes, checksum: e1bae1d82f29d4be01678c3fa2ec7a2c (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Síntese de Fármacos. Rio de Janeiro, RJ, Brasil.Universidade Federal de Pelotas. Centro de Ciências Químicas, Farmacêuticas e de Alimentos. Laboratório de Química Aplicada à Bioativos. Pelotas, RS, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Síntese de Fármacos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Síntese de Fármacos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.Pentavalent antimonials have saved the lives of thousands of Leishmania-infected patients more than seventy years but, unfortunately, they are highly toxic and require parenteral delivery. Therefore, the search for safer and orally delivered alternative is a need. This paper describes the antileishmanial properties of PMIC4, a novel hydroxyethylpiperazine analogue. PMIC4 showed potent activity against intracellular amastigotes of Leishmania amazonensis, with IC50 of 1.8 lM and selectivity index higher than 100-fold, calculated in relation to the toxicity on the host cell. Following laboratory animal welfare policies, we analyzed the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties and calculated the Lipinski’s rule of five of PMIC4 before proceeding to in vivo tests. PMIC4 satisfied Lipinski’s rule of five and presented high probability of human intestinal absorption, suggesting a good chance of druglikeness and oral bioavailability. For in vivo studies, PMIC4 was administered via intralesional injection (3.4 mg/kg/day, three times a week) or orally (34.0 mg/kg/day, five times a week) to L. amazonensisinfected BALB/c mice throughout the 98 day experiments. At the end of the treatment period, serum markers of toxicity were measured. When administered orally, PMIC4 controlled the lesions in L. amazonensis- infected BALB/c mice without altering serological markers of toxicity. These results demonstrate that PMIC4 is a promising molecular scaffold, orally effective against experimental leishmaniasis