Antibacterial activity of synthetic pyrido[2,3- d ]pyrimidines armed with nitrile groups: POM analysis and identification of pharmacophore sites of nitriles as important pro-drugs

• Published in: New journal of chemistry 2018, Vol.42 (19), p.15610-15617
• Main Authors: Dongre, Rajendra Sukhdeorao, Meshram, Jyostna S., Selokar, Rupali Sudhakarrao, Almalki, Faisal A., Hadda, Taibi Ben
• Format: Article
• Language: English
• Subjects: Aldehydes; Antibacterial materials; Aromatic compounds; Bacteria; Biological activity; Catalysis; Catalysts; Ethanol; Gram-positive bacteria; Hepatitis B; HIV; Human immunodeficiency virus; Isomers; Malononitrile; Nitriles; Organic chemistry; Pharmacology; Pyrimidines; Reaction time; Side effects; Streptomycin; Triethylamine; Uracil
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/C8NJ02081G

A clean and simple one-pot multi-component methodology was developed for the preparation of 7-amino-2,4-dioxo-5-aryl-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-6-carbonitriles via the reaction of 6-amino uracil, aromatic aldehydes and malononitrile using triethylamine (TEA) base as a catalyst in aqueous ethanol medium at NTP. The reaction protocol has assorted advantages viz. ; mild reaction conditions, short reaction time, environmentally friendly procedure, low cost chemicals, and easy isolation of derivatives with excellent yields of bioactive products (85–95%). All the synthesised pyrido[2,3- d ]pyrimidines bearing nitrile groups ( 4a–4h ) showed comparatively good in vitro antibacterial activities against Staphylococcus and Bacillus cereus (Gram-positive bacteria) and P. merabitis and S. maresens (Gram-negative bacteria). Nevertheless, compound 4h exhibited the highest antibacterial activity and had an excellent % inhibition as compared to standard streptomycin. Overall, compound 4h had enhanced antibacterial activity compared to its positional isomers compound 4f and compound 4g . This increase in bioactivity going from 4f (R = 4-nitro) to 4h (R = 2-nitro) is attributed to the hydrolysis of the CN to an amide which restores the vital intramolecular interaction between the ortho -nitro-phenyl and amide linkages (ONO δ− ⋯H δ+ N) and offers a crucial template for antibacterial NH, O-pharmacophore sites. The synthesized compound 4h was tested to verify that it had fewer side effects than the standard/streptomycin. But, its possible inclusion in selective fungal/viral media viz. HIV or Hepatitis B/C is a subject of further research. This multi-component synthetic protocol uses cheap ingredients like Et 3 N catalyst and ethanol as the green solvent.