Scheme 1: Diversity of structures synthesized by combining IMCR’s.

However, the issue of whether certain isocyanide multicomponent reactions can be combined is still unresolved, particularly due to the potential for varying the initial compounds involved.

Figure 1: Drugs possessing imidazo[1,2-a]pyridine unit.

Figure 2: Drugs possessing peptide unit.

Therefore, an urgent problem is to synthesize structurally complex compounds, molecular hybrids containing pharmacophoric and peptidomimetic fragments, to explore their biological activity.

Scheme 2: Diversity of GBB reaction products as precursors for Ugi reaction.

It is obvious that the exploration of the possibility to create hybrid molecules by combining GBB-3CR and Ugi is successful, so one of the promising areas is to increase the diversity of relevant compounds using substituted aminopyridines in GBB-3CR and the synthesis of new peptidomimetics.

Taking into account all these facts, we solved the task of developing a new approach for the synthesis of hybrid molecules containing substituted pharmacophoric heterocyclic and peptidomimetic fragments. An approach based on the preparation of an imidazo[1,2-a]pyridine-containing heterocyclic acid and its introduction as an acid component in the Ugi reaction was chosen. The route to the synthesis of the target molecules can be divided into two stages, with GBB-3CR in the first stage and the Ugi reaction in the second stage using the product of the first stage.

Scheme 3: Synthesis of new acids containing a substituted imidazo[1,2-a]pyridine fragment.

Scheme 4: Synthesis of new peptidomimetics containing a substituted imidazo[1,2-a]pyridine fragment.

Table 1: Library of peptidomimetics 7a–t containing a substituted imidazo[1,2-a]pyridine fragment.

aUgi 3-CR reaction – azomethine was inserted into the reaction.

Scheme 5: Synthesis and reactivity of new acids containing a substituted imidazo[1,2-a]pyridine fragment without CH2O linker fragment.

In addition, we also tested the one-pot method for the synthesis of similar structures . Aminopyridine, aldehyde and Sc(OTf)3 as catalyst were stirred in MeOH/DCM for 45 min at room temperature, then the isocyanide was added and the mixture was stirred for another 8 h. Without isolation, the corresponding aldehyde, amine and isocyanide were added to the resulting iminopyridine product and the mixture was then stirred at room temperature for 12 h. But again, the expected compounds could not be obtained.

Table 2: Screening conditions for synthesis of peptidomimetic 9а and 9b.

aDetermined by 1H NMR; bconditions that were checked for the synthesis of both compounds.

The obtained results show that for the synthesis of new compounds containing precisely substituted imidazo[1,2-a]pyridine and peptidomimetic fragments it is better to use acids with a linker between the carboxyl group and aryl ring. This molecular fragment increases the solubility of the whole molecule, which leads to an improvement in the reactivity of the acids, whereas the reactivity of acids 8a and 8b is rather low in Ugi reactions.

Table 3: Antibacterial activity results.