设计和发现双靶点抑制剂的化合物是一项具有挑战性的任务，旨在合成比单靶点药物更安全、更有效的新药，特别是用于治疗多因素性疾病如癌症。对多个靶点的同时调控可能是一种优化患者遵从性和耐受性的替代合成方法，从而最小化由于少数靶点调控引起的基于靶点的药物耐药风险。为此，我们首次构想了设计和合成双配体 σR/HDACi，以评估其作为解决这种复杂疾病创新候选药物的可能性。在筛选了多个肿瘤细胞系进行的所有合成化合物中，化合物6 (Kiσ1R = 38 ± 3.7; Kiσ2R = 2917 ± 769 and HDACs IC50 = 0.59 µM) 是最有前途的抗增殖剂候选药物，在HCT116细胞系中的IC50为0.9 µM，对正常细胞没有明显毒性。分子对接研究进一步证实了其在σ1R和全谱 HDACs上的亲和力，支持可能存在于两个靶点之间的平衡亲和力和活性。版权所有 © 2023 作者。由 Elsevier Inc. 发布，保留所有权利。

Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simultaneous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands σR/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (Kiσ1R = 38 ± 3.7; Kiσ2R = 2917 ± 769 and HDACs IC50 = 0.59 µM) is the most promising candidate as an antiproliferative agent with an IC50 of 0.9 µM on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over σ1R and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.