Rab geranylgeranyl transferase (RGGT) is an interesting therapeutic target, as it ensures proper functioning of Rab GTPases, a class of enzymes responsible for the regulation of vesicle trafficking. Relying on our previous studies, we synthesized a set of new α‐phosphonocarboxylic acids as potential RGGT inhibitors, with emphasis on the elaboration of imidazole‐containing analogues. We identified two compounds with activity similar to that of previously reported RGGT inhibitors, showing structural similarity to imidazo[1,2‐a]pyridine‐containing analogues in terms of their substitution pattern. Interestingly, analogues of the N‐series, derived from another phosphonocarboxylate RGGT inhibitor, 2‐fluoro‐3‐(1H‐imidazol‐1‐yl)‐2‐phosphonopropanoic acid, turned out to be inactive in our model, indicating that an additional substituent localized at positions C2 or C4 of the imidazole ring, may adversely affect the potency against the targeted enzyme.

中文翻译：

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咪唑类α-膦酸酯作为Rab Geranylgeranyl Transferase（RGGT）抑制剂的合成及生物学评估

Rab geranylgeranyl transferase（RGGT）是一个有趣的治疗靶标，因为它可以确保Rab GTPases（一类负责调节小泡运输的酶）的正常功能。在我们之前的研究的基础上，我们合成了一组新的α-膦酰基羧酸作为潜在的RGGT抑制剂，重点研究了含咪唑类似物的制备方法。我们鉴定了两种具有与先前报道的RGGT抑制剂相似活性的化合物，就其取代方式而言，它们与含咪唑并[1,2 - a ]吡啶的类似物在结构上相似。有趣的是，N系列的类似物衍生自另一种膦酰基羧酸盐RGGT抑制剂2-氟-3-（1 H-咪唑-1-基）-2-膦酰基丙酸在我们的模型中被证明是无活性的，这表明位于咪唑环C2或C4位的其他取代基可能会对目标酶的效能产生不利影响。