- Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase
-
In the last two decades, trans-sialidase of Trypanosoma cruzi (TcTS) has been an important pharmacological target for developing new anti-Chagas agents. In a continuous effort to discover new potential TcTS inhibitors, 3-amino-3-arylpropionic acid derivatives (series A) and novel phthaloyl derivatives (series B, C and D) were synthesized and molecular docking, TcTS enzyme inhibition and determination of trypanocidal activity were carried out. From four series obtained, compound D-11 had the highest binding affinity value (?11.1 kcal/mol) compared to reference DANA (?7.8 kcal/mol), a natural ligand for TS enzyme. Furthermore, the 3D and 2D interactions analysis of compound D-11 showed a hydrogen bond, π-π stacking, π-anion, hydrophobic and Van der Waals forces with all important amino acid residues (Arg35, Arg245, Arg314, Tyr119, Trp312, Tyr342, Glu230 and Asp59) on the active site of TcTS. Additionally, D-11 showed the highest TcTS enzyme inhibition (86.9% ± 5) by high-performance ion exchange chromatography (HPAEC). Finally, D-11 showed better trypanocidal activity than the reference drugs nifurtimox and benznidazole with an equal % lysis (63 ± 4 and 65 ± 2 at 10 μg/mL) and LC50 value (52.70 ± 2.70 μM and 46.19 ± 2.36 μM) on NINOA and INC-5 strains, respectively. Therefore, D-11 is a small-molecule with potent TcTS inhibition and a strong trypanocidal effect that could help in the development of new anti-Chagas agents.
- Kashif, Muhammad,Chacón-Vargas, Karla Fabiola,López-Cedillo, Julio Cesar,Nogueda-Torres, Benjamín,Paz-González, Alma D.,Ramírez-Moreno, Esther,Agusti, Rosalia,Uhrig, Maria Laura,Reyes-Arellano, Alicia,Peralta-Cruz, Javier,Ashfaq, Muhammad,Rivera, Gildardo
-
p. 252 - 268
(2018/07/14)
-
- Resolution synthesis method of 3-amino-3-(4-hydroxyphenyl)propionic acid
-
The invention relates to a resolution synthesis method of 3-amino-3-(4-hydroxyphenyl)propionic acid, mainly aiming at solving the technical problems of an existing synthesis method of more steps and high cost. The resolution synthesis method comprises the following steps: enabling p-hydroxybenzaldehyde to react with ammonium acetate and malonic acid in an ethanol solution to generate a compound 1; enabling the compound 1 to react with triethylamine and di-tert-butyl dicarbonate in a mixed solution of water and acetone to generate a compound 2; enabling the compound 2 to react with R(+)-1-phenethylamine in a tetrahydrofuran solution; acidifying an intermediate product with hydrochloric acid to generate a compound 3; enabling the compound 3 to react with an ethanol solution of hydrochloric acid to obtain hydrochloride, and enabling the hydrochloride to react with a sodium hydroxide water solution to obtain a target compound 4; enabling the compound 2 to react with S-1-phenethylamine in the tetrahydrofuran solution, and acidifying an intermediate product with the hydrochloric acid to generate a compound 5; enabling the compound 5 to react with the ethanol solution of the hydrochloric acid to obtain hydrochloride and enabling the hydrochloride to react with a sodium hydroxide water solution to obtain a target compound 6. (R)- and (S)-3-amino-3-(4-hydroxyphenyl)propionic acid is widely applied in a polypeptide biopharmaceutical industry.
- -
-
Paragraph 0009; 0010; 0011
(2018/03/28)
-
- Synthesis and binding activity of endomorphin-1 analogues β-amino acids
-
Endomorphin-1 (Tyr-Pro-Trp-PheNH2) has been proposed as the most potent endogenous ligand of the μ-opioid receptors. In this paper, we describe the synthesis of some endomorphin-1 based tetrapeptides in which a residue of the sequence Tyr-Pro-Trp-PheNH2 is replaced by the corresponding β-isomer. These novel peptides showed different affinities for the opioid receptors labeled with [3H]-DAMGO in rat brain membranes, depending on the β-amino acid. In particular, the tetrapeptide containing β-Pro (Tyr-β-(R)-Pro-Trp-PheNH2) displayed a higher affinity than endogenous endomorphin-1, as revealed by their K(i) values (0.33 and 11.1 nM, respectively). (C) 2000 Elsevier Science Ltd.
- Cardillo, Giuliana,Gentilucci, Luca,Melchiorre, Paolo,Spampinato, Santi
-
p. 2755 - 2758
(2007/10/03)
-
