Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88700, Reynosa, Mexico.
Departamento de Parasitología, Escuela Nacional de Ciencias Biológicas, 07320, Ciudad de México, Mexico.
Eur J Med Chem. 2018 Aug 5;156:252-268. doi: 10.1016/j.ejmech.2018.07.005. Epub 2018 Jul 7.
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 LC 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.
在过去的二十年中，克氏锥虫 trans-sialidase（TcTS）一直是开发新型抗恰加斯病药物的重要药理靶点。为了不断发现新的潜在 TcTS 抑制剂，我们合成了 3-氨基-3-芳基丙酸衍生物（系列 A）和新型邻苯二甲酰衍生物（系列 B、C 和 D），并进行了分子对接、TcTS 酶抑制和杀锥虫活性测定。在所获得的四个系列中，与天然 TS 酶配体 DANA（-7.8 kcal/mol）相比，化合物 D-11 具有最高的结合亲和力值（-11.1 kcal/mol）。此外，化合物 D-11 的 3D 和 2D 相互作用分析显示，它与 TcTS 活性部位的所有重要氨基酸残基（Arg35、Arg245、Arg314、Tyr119、Trp312、Tyr342、Glu230 和 Asp59）形成氢键、π-π 堆积、π-阴离子、疏水和范德华力。此外，D-11 通过高效离子交换色谱（HPAEC）显示出最高的 TcTS 酶抑制率（86.9%±5）。最后，与对照药物硝呋替莫和苯并咪唑相比，D-11 表现出更好的杀锥虫活性，在 NINOA 和 INC-5 株上的等裂解率（分别为 63%±4%和 65%±2%）和 LC 值（分别为 52.70±2.70 μM 和 46.19±2.36 μM）。因此，D-11 是一种具有强效 TcTS 抑制作用和强大杀锥虫作用的小分子，有望用于开发新型抗恰加斯病药物。
