Synthesis and antibacterial activity of some novel pyrazolopyridine derivatives

Abstract

Eight pyrazolo [3,4-b]pyridine derivatives have been synthesized by Friedländer condensation of 5-aminopyrazole-4-carbaldehyde with active methylene compounds in basic medium. These compounds have been screened for their antibacterial activity against two Gram-negative and two Gram-positive bacterium. Pyrazolopyridines having the carboxamide group at the 5-position showed moderate to good activity against P. aeruginosa, E. coli, S. pneumoniae, and B. cereus.The evolution of antibacterial resistance in bacterial strains against the currently available antibacterial agents is an increasing concern in recent years. For instance, Gram-positive bacterial pathogen such as Staphylococcus aureus is resistant to Methicillin, and Streptococcus pneumoniae and Enterococci are resistant to Penicillin and Vancomycin, respectively [1]. On the other hand, Gram-negative bacteria such as H. influenza and M. catarrahalis are resistant to β-lactams, quinolones, and macrolides [2]. In order to overcome the threat of widespread multidrug resistance in Gram-positive as well as Gram-negative bacterial strains, there is an ongoing demand for new antibacterials.Pyrazolo [3,4-b]pyridines as aza-analogs of indazoles [3] have long served as attractive targets in organic synthesis due to their excellent antibacterial activity [4]. Moreover, pyrazolo[3,4-b]pyridines also exhibit other promising biological activities, including anxiolytic (e.g., Tracazolate) [5], dopamine D3-receptor antagonist and partial agonist [6], dopamine D4 antagonist [7], adenosine A1-receptor antagonist [8,9], antiherpetic [10], antiinflammatory [11], and antiallergic [12] properties. The methods so far reported for the synthesis of pyrazolopyridines include: i) the annelation of the pyrazole ring onto the suitably substituted pyridine ring [13][14][15][16][17][18][19], and ii) the annelation of the pyridine ring onto the appropriately substituted pyrazole ring [13,[20][21][22][23][24][25][26][27][28][29][30]. As part of our ongoing program [31] for the development of new antibacterials, we are particularly interested in the synthesis of pyrazolo [3,4-b]pyridines by the latter method. Like others, our strategy involves the Friedländer condensation of 5-aminopyrazoles with active methylene compounds as the key step. In this paper we report the full details of our efforts on the synthesis of some novel pyrazolo[3,4-b]pyridine derivatives and their antimicrobial profile against two Gram-positive and two Gram-negative bacterium species.

Facile Synthesis of New 6‐Alkylamino‐1H‐pyrazolo[3,4‐b]pyridine‐5‐carbonitrile Derivatives

“…Our synthesis started from 5‐chloro‐1,3‐diphenyl‐1 H ‐pyrazole‐4‐carbaldehyde 1 which was converted to 2‐((5‐chloro‐1,3‐diphenyl‐1 H ‐pyrazol‐4‐yl)methylene) malononitrile 3 when heated with malononitrile 2 in ethanol containing a few drops of glacial acetic acid at reflux temperature. The compound 3 was then allowed to interact with primary alkyl amines in the presence of DBU as catalyst in ethanol under reflux.…”

Chemoselective Synthesis of 5‐Alkylamino‐1H‐pyrazole‐4‐carbaldehydes by Cesium‐ and Copper‐Mediated Amination

“…Employing 5‐chloropyrazole‐4‐carbaldehyde ( 1b ) in the presence of two equivalents of cyclohexylamine ( 2a ), one equivalent of cesium carbonate, DMF as solvent, and microwave heating at 250 °C afforded 3‐methyl‐1‐phenyl‐1 H ‐pyrazolo[3,4‐ b ]quinoline ( 5 ) in 80 % yield (Scheme ). Although compound 5 has previously been reported in the literature,14 these new reaction conditions can have a synthetic advantage, since it is possible to obtain tetrahydropyrazolo[3,4‐ b ]quinolines and their analogues in one step, which is vastly preferable over other reported multistep methods 15…”

An easy direct arylation of 5-pyrazolones

“…5-Pyrazolones are attracting considerable research interest because of their unique chemical properties and their structures that facilitate their application as biological and pharmaceutical intermediates and products [1–3]. Over the years, many of the biological activities of pyrazolones such as their antipyretic, analgesic [4–5], anti-inflammatory [6–7], antitumor [8–9], antiviral, antibacterial [10], and herbicidal [11] properties have been discovered and investigated.…”