Urease Enzyme Inhibitory of Heavy Metals and Organic Solvents in Ammonia Making for Synthesis of Nifedipine Antihypertensive Drug

Simultaneous development of technology is composed with environmental hazardous with heavy-metals and organic solvents and thus toxic catalysts/organic solvents must be replaced with biocatalysts and water. Urease is a hydrolase enzyme and urease-urea can be considered a safe source of toxic ammonia in synthesis of nifedipine. Nifedipine is an antihypertensive drug synthesized by four–component reaction of 2 mmol methyl acetoacetate, 2–nitro-benzaldehyde, and ammonia using catalysts and organic solvents. The object of this research is replacement of toxic ammonia with urease-urea and organic solvents with water and study of heavy-metals and organic-solvent inhibition of urease on the synthesis of nifedipine.
In this experimental work, by controlling of yield and time of nifedipine synthesis via reaction of methyl acetoacetate, 2–nitro-benzaldehyde, and urease/urea in water, optimum urease/urea concentration, temperature, and pH for maximum yield were determined. Then, the effect of heavy-metal/organic solvent inhibitors on the production of ammonia and urease-catalyzed synthesis of nifedipine have been investigated.
Based on the yield of nifedipine, the activity of urease for ammonia production depends on parameters such as urease/urea amount, temperature, pH, and kind or concentration of inhibitors. The results accorded urease specificity for maximum dissociation of urea in experiment with 10 mg/mL urease, pH=7, and 70 C° in water, while heavy-metal ion/organic solvent inhibitory of urease showed trends of Hg2>Ag>Cu2>Pb2>Cd2 and acetonitrile>chloroform>dichloromethane to reduce in ammonia concentration and nifedipine.
Urease-urea makes a biocompatible source of ammonia for synthesis of anti–hypertension drug of nifedipine, while inhibitors such as heavy metal cations especially Hg2, organic solvents, and sulfuric acid decrease the reaction rate. Biocompatibility, use of water and no organic solvent/catalyst, high yield and selectivity are advantages of this green method in comparison to previous reported methods.