Multicomponent Synthesis of 2,3-Dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,6-diones: A Novel Heterocyclic Scaffold with Antibacterial Activity

Abstract

A multicomponent reaction of 3-aminopyrazol-5-ones with substituted salicylic aldehydes and acetylacetic ester leading to the formation of novel 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,6-diones was discovered. The elucidation of the reaction scope revealed that 5-aminopyrazoles, 3-amino-1,2,4-triazoles and 6-aminouracil could be used as the heterocyclic amine component. Selected heterocyclic products were found to possess notable antibacterial activities.

Multicomponent reactions (MCRs) are a powerful synthetic tool. In this approach, three or more reactants are combined together in a single reaction flask to generate a product incorporating most of the atoms contained in the starting materials. MCRs have been widely exploited in combinatorial and medicinal chemistry and they are particularly useful for the preparation of polycondensed heterocyclic systems.¹

In this connection, hetero-fused benzopyranopyridines are a poorly studied class of polycondensed heterocycles (Figure 1a). Only four types of scaffolds (A, C, D, E) have been reported in the literature out of the six possible molecular frameworks (A–F) and the synthetic approaches used by researchers to access these structures have invariably involved multistep sequences.^2–13 Importantly, compounds based on these heterocyclic systems have been reported to possess anti-inflammatory,² antibacterial^2,10 and antifungal¹⁰ activities (Figure 1b). As part of our efforts aimed at the discovery of MCRs to synthesize compounds with anticancer and antibacterial activities,^14–25 we discovered a new approach to access the type C molecular framework. Herein, we describe this synthetic finding as well as the preliminary biological evaluation of compounds synthesized using this new method.

Figure 1.

(a) Six possible types of hetero-fused benzopyranopyridines (b) and representative compounds with biological activities

Specifically, we found that combining 3-aminopyrazol-5-ones 1a–c with substituted salicylic aldehydes 2a–h and acetylacetic ester (3) leads to the formation of 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridin-1,6-diones 4a–o (Scheme 1). Generally good yields of these polyheterocyclic compounds are obtained when mixtures of the three starting components and one drop of piperidine are refluxed in acetic acid for 3 h. This three-component process works well any tested combination of substituted salicylic aldehydes 2 and 3-aminopyrazol-5-ones 1. The desired products precipitate upon cooling of the reaction mixtures and a simple filtration provides analytically pure material (> 95%).²⁶

Scheme 1.

MCR synthesis of 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridin-1,6-diones 4a–o

We propose that the mechanistic route for this transformation involves an in situ formation of 3-acetylcoumarins 5 and their subsequent condensation with aminopyrazolones 1 (Scheme 2). Indeed, we demonstrated that this process can be conducted stepwise by condensing salicylic aldehyde (2a) with acetylacetic ester (3) and isolating 3-acetylcoumarin (5a) in a quantitative yield (Scheme 2a). 5a was further reacted with 3-amino-1H-pyrazol-5(4H)-one (1a) under the same reaction conditions and gave a comparable yield of polyheterocycle 4a (Scheme 2b).

Scheme 2.

3-Acetylcoumarins as intermediates in the discovered MCR

To investigate the scope of this process with respect to the acetylacetic ester component, we attempted to replace it with ethyl benzoylacetate. However, the reaction was unsuccessful in this case, possibly due to the change in electronic and steric environment of the ketone carbonyl. On the other hand, the replacement of the aminoheterocyclic component was much more forgiving. Thus, we explored the corresponding reactions of 5-amino-1-phenyl-3-methylpyrazole (6), 3-amino-1,2,4-triazole (7) and 6-aminouracil (8, Scheme 3). The desired polyheterocycles 9, 10 and 11 were obtained in acceptable yields, indicating the potential of this MCR to be used as a general method to access polyheterocyclic scaffolds C (see Figure 1).²⁷

Scheme 3.

MCR synthesis of polyheterocycles 9, 10 and 11

The initial evaluation of the synthesized polyheterocycles for antimicrobial activities revealed significant antibacterial properties associated with several analogues specifically against Gram-(+) strains. Thus, compounds 4i and 4o inhibited the growth of S. epidermidis with the MIC values of 6.3 µM and 25 µM, respectively. Furthermore, heterocycle 4i was also effective against methicillin-resistant S. aureus (MRSA), inhibiting the growth of this clinically important nosocomial pathogen with an MIC value of 25 µM. Further exploration of the MCR scope and antimicrobial activities associated with these novel heterocyclic structures are underway and will be reported in due course.