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?

New Journal of Chemistry Pub Date: 2018-08-16 DOI: 10.1039/C8NJ02081G

Abstract

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[triple bond, length as m-dash]N to an amide which restores the vital intramolecular interaction between the ortho-nitro-phenyl and amide linkages (ONOδ??Hδ+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 Et3N catalyst and ethanol as the green solvent.

Graphical abstract: 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
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