Laboratoire de Chimie Organique Hétérocyclique, Centre de Recherche des Sciences des Médicaments, Pôle de Compétences Pharmacochimie, URAC 21, Faculté des Sciences, Mohammed V University Rabat, Rabat, Morocco.
Department of Theoretical and Applied Chemistry, South Ural State University, Chelyabinsk, Russia.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):151-167. doi: 10.1080/14756366.2021.1995380.
An efficient pathway was disclosed for the synthesis of 3-chloro-6-nitro-1-indazole derivatives by 1,3-dipolar cycloaddition on dipolarophile compounds and . 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 as a promising growth inhibitor of . 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- 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- complex. The studied compounds are promising leads for structural optimisation to enhance the antileishmanial activity.
揭示了一条通过 1,3-偶极环加成反应在双烯和亲偶极体化合物上合成 3-氯-6-硝基-1-吲唑衍生物的有效途径。面对两种区域异构体分离的问题，点击化学方法使我们能够从 82%到 90%的产率获得具有良好产率的三唑-1,4 区域异构体。此外，采用 MTT 测定法测定了化合物的抗利什曼原虫生物活性，报告化合物 是利什曼原虫硫醇还原酶的有前途的生长抑制剂。分子对接表明与 Leishmania trypanothione reductase 酶具有高度稳定的结合，并产生了疏水和亲水相互作用的网络。对 TryR-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。研究的复合物在结构偏差约为 1-3 Å 的情况下保持良好的平衡。MM/GBSA 结合自由能说明了 TryR-复合物的高稳定性。研究的化合物是结构优化的有希望的先导化合物，以增强抗利什曼原虫活性。
