Synthesis, In Silico Study and Antibacterial Evaluation of New Cyanopyridine Based Scaffold

Synthesis, antibacterial evaluation, and in silico study of new series of cyanopyridines, and fused cyanopyridines are described. One-pot reaction of N-(2-ethylphenyl)-2-cyanoacetamide (1) with arylmethylketones and various aldehydes afforded 4, 6-diaryl-2-oxopyridine-3-carbonitriles, 4-9. Cyclocondensation of 1 using various aldehydes and diethyl malonate/malononitrile afforded 3-esters, 10-12 and pyridine-3, 5-dicarbonitrile derivatives, 13-15. Then, compounds 13, 14 were employed for the synthesis of various fused compounds, namely pyrazolo[3,4-d]pyridines, 16-18 and pyrido[2,3-d]pyrimidines, 21-26. These target compounds were tested in vitro for their antibacterial activity (minimum inhibitory concentration [MIC]) against Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus (MRSA) using amoxicillin and trimethoprim/sulfamethoxazole (TMP/SMX) as reference standards. Compounds 4, 8, and 10-12 exhibited remarkable antibacterial profile compared to the standard drugs. Besides, in silico absorption, distribution, metabolism, and excretion (ADME) prediction studies indicated that most of the potent compounds are orally bioavailable with no permeation to the blood-brain barrier (BBB).