New pyrazolo[1,5- <i>a</i> ]pyrimidine-fused chromeno[2,3- <i>b</i> ]pyridine hybrids linked to 4,6-diarylnicotinonitrile units: Synthesis, antibacterial screening and SAR study

The goal of this study is to investigate the antibacterial activity of pyrazolo[1,5-a]pyrimidine-fused chromeno[2,3-b]pyridine hybrids 1a-1n linked to 4,6-diarylnicotinonitrile units. The desired hybrids are prepared, in 77-88% yields, by reacting the appropriate 4,6-diarylnicotinonitrile-based salicylaldehydes 2a-2j with 3-cyanopyrazolo[1,5-a]pyrimidine-linked acetonitriles 3a,b. The reaction was mediated in refluxing ethanolic sodium ethoxide solution for 6–8 h. The new pentacyclic hybrids displayed a diverse antibacterial activity. A structure-activity relationship study was adopted to explore the influence of the electronic nature of the aryl units attached to the nicotinonitrile-C4 and C6 on the obtained activity. The hybrids linked to 4-(4-methoxyphenyl)-6-(p-tolyl)nicotinonitrile 1i and 1 m, or 4,6-bis(4-methoxyphenyl)nicotinonitrile 1j and 1n, demonstrated comparable in vitro MIC/MBC values to ciprofloxacin. The MIC and MBC values varied from 4.5-3.0 and 4.9–5.9 µM, respectively.