We previously reported a milestone in the optimization of NBD-11021, an HIV-1 gp120 antagonist, by developing a new and novel analogue, NBD-14189 (Ref1), which showed antiviral activity against HIV-1HXB2, with a half maximal inhibitory concentration of 89 nM. However, cytotoxicity remained high, and the absorption, distribution, metabolism, and excretion (ADME) data showed relatively poor aqueous solubility. To optimize these properties, we replaced the phenyl ring in the compound with a pyridine ring and synthesized a set of 48 novel compounds. One of the new analogues, NBD-14270 (8), showed a marked improvement in cytotoxicity, with 3-fold and 58-fold improvements in selectivity index value compared with that of Ref1 and NBD-11021, respectively. Furthermore, the in vitro ADME data clearly showed improvements in aqueous solubility and other properties compared with those for Ref1. The data for 8 indicated that the pyridine scaffold is a good bioisostere for phenyl, allowing the further optimization of this molecule.

中文翻译：

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通过合理的设计，合成和抗病毒评估，改进gp120进入拮抗剂作为抗HIV-1剂的临床前优化，具有改善的细胞毒性和ADME特性。

我们先前报道了开发新的新型类似物NBD-14189（Ref1），从而优化了HIV-1 gp120拮抗剂NBD-11021的里程碑，该类似物显示出对HIV-1HXB2的抗病毒活性，且最大抑制浓度为一半为89 nM。但是，细胞毒性仍然很高，吸收，分布，代谢和排泄（ADME）数据显示相对较差的水溶性。为了优化这些特性，我们用吡啶环取代了化合物中的苯环，并合成了48种新型化合物。一种新的类似物NBD-14270（8）表现出明显的细胞毒性改善，与Ref1和NBD-11021相比，选择性指数值分别提高了3倍和58倍。此外，体外ADME数据清楚地表明，与Ref1相比，水溶性和其他性能有所改善。8的数据表明吡啶骨架是苯基的良好生物等排体，从而允许对该分子的进一步优化。