Synthesis and Biological Evaluation of Imidazole‐Bearing α‐Phosphonocarboxylates as Inhibitors of Rab Geranylgeranyl Transferase (RGGT)

Abstract

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.

Functionalization of the imidazo[1,2-a]pyridine ring in α-phosphonoacrylates and α-phosphonopropionates via microwave-assisted Mizoroki–Heck reaction

“…We have previously synthesized a number of phosphonocarboxylates (PC) to study their structure-activity relationship with RGGT, using compounds 1 and 2 as advanced intermediates in the synthesis of RGGT inhibitors ( Figure 1) [10,11]. We have found that the presence of a substituent at C6 position of the imidazo[1,2-a]pyridine is favorable for retaining the activity of PC toward RGGT.…”

Targeting Small GTPases and Their Prenylation in Diabetes Mellitus

“…Among the currently known phosphonocarboxylates, the most active ones contain imidazo[1,2- a ] 282 , 283 , 281 or the imidazole ring. 284 , 285 …”

“…Among the currently known phosphonocar- boxylates, the most active ones contain imidazo[1,2-a] 282,283,281 or the imidazole ring. 284,285 Another strategy is based on the direct targeting of Rab GTPases. Only few such attempts have been reported in the literature.…”

Synthesis of the 6-Substituted Imidazo[1,2-a]Pyridine-3-yl-2- Phosphonopropionic Acids as Potential Inhibitors of Rab Geranylgeranyl Transferase

“…The synthesis of compounds representing the first group followed our previously reported strategy (Kazmierczak et al, 2017), which starts from appropriate commercially available 5substituted-2-aminopyridines 3a-d, which are transferred into imidazo [1,2-a]pyridine aldehydes 4a-d (Kusy et al, 2019), the latter being subject to Knoevenagel condensation with trialkyl phospohonocarboxylate in the presence of TiCl 4 and TEA (Scheme 1, details in Supplementary Materials) (Kazmierczak et al, 2017;Joachimiak et al, 2018). Thus, the obtained compounds 5a-c, m were subjected to the reaction with NaBH 4 and NiCl 2 hydrate in MeOH, giving products 6a-c, m with yields 48-87%.…”