Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, 13385, Marseille Cedex 05, France.
Université de Limoges, UMR Inserm 1094, Neuroépidémiologie Tropicale, Faculté de Pharmacie, 2 Rue Du Dr Marcland, 87025, Limoges, France.
Eur J Med Chem. 2020 Nov 15;206:112668. doi: 10.1016/j.ejmech.2020.112668. Epub 2020 Aug 4.
To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.
为了研究抗锥虫 3-硝基咪唑并[1,2-a]吡啶药效团，通过合成 26 个原始衍生物并对利什曼原虫和布氏锥虫进行体外评估，进行了构效关系研究。这项 SAR 研究表明，抗锥虫药效团的限制比抗利什曼原虫药效团少，突出了咪唑并吡啶环的 2、6 和 8 位作为关键调节点。与该系列中的先前命中分子相比，合成的化合物均未提高抗利什曼原虫活性。然而，该系列中最好的抗锥虫化合物 8（EC = 17 nM，SI = 2650 和 E° = -0.6 V）不仅比所有参考药物和该系列中的先前命中分子更活跃，而且还表现出更好的水溶解度和更好的体外药代动力学特性：良好的微粒体稳定性（T > 40 分钟），中等白蛋白结合率（77％）和根据 PAMPA 测定法，中等血脑屏障通透性。此外，微核和彗星试验均表明硝基芳族分子 8 在体外没有遗传毒性。事实证明，8 的生物激活是由 T. b. brucei 型 1 硝基还原酶进行的，与 fexinidazole 相同。最后，一项小鼠药代动力学研究表明，8 在 100 mg/kg（NOAEL）的单次和重复口服给药后均具有良好的全身暴露，并且血浆半衰期（T = 7.7 h）令人满意。因此，8 分子似乎是启动命中到先导药物发现计划的良好候选者。
