Abstract

An efficient pathway was disclosed for the synthesis of 3-chloro-6-nitro-1H-indazole derivatives by 1,3-dipolar cycloaddition on dipolarophile compounds 2 and 3. Faced the problem of separation of two regioisomers, a click chemistry method has allowed us to obtain regioisomers of triazole-1,4 with good yields from 82 to 90% were employed. Also, the antileishmanial biological potency of the compounds was achieved using an MTT assay that reported compound 13 as a promising growth inhibitor of Leishmania major. Molecular docking demonstrated highly stable binding with the Leishmania trypanothione reductase enzyme and produced a network of hydrophobic and hydrophilic interactions. Molecular dynamics simulations were performed for TryR-13 complex to understand its structural and intermolecular affinity stability in a biological environment. The studied complex remained in good equilibrium with a structure deviation of ∼1–3 Å. MM/GBSA binding free energies illustrated the high stability of TryR-13 complex. The studied compounds are promising leads for structural optimisation to enhance the antileishmanial activity.

摘要

公开了一种通过在亲偶极化合物2和3上进行 1,3-偶极环加成合成 3-chloro-6-nitro-1 H-吲唑衍生物的有效途径。面对分离两种区域异构体的问题，点击化学方法使我们能够以 82% 至 90% 的良好收率获得三唑 1,4 的区域异构体。此外，化合物的抗利什曼原虫生物效力是使用 MTT 测定实现的，该测定报告化合物13是一种有希望的利什曼原虫生长抑制剂. 分子对接显示出与利什曼原虫锥虫硫酮还原酶高度稳定的结合，并产生了疏水和亲水相互作用的网络。对 TryR- 13复合物进行了分子动力学模拟，以了解其在生物环境中的结构和分子间亲和力稳定性。所研究的复合物保持良好的平衡，结构偏差为~1-3 Å。MM/GBSA 结合自由能说明了 TryR- 13复合物的高稳定性。所研究的化合物是结构优化以增强抗虫活性的有希望的线索。