Molecular Pharmacology, Vol 11, 751-758, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

The Molecular Components of Nitrofurantoin Critical to Its Inhibitory Effect upon Platelet Aggregation

¹ Departments of Medicine and Pharmacology and Clinical Pharmacology Unit, Northwestern University School of Medicine, Chicago, Illinois 60611

Nine analogues of nitrofurantoin were studied in order to determine the molecular components critical to its inhibitory effect upon primary ADP-induced platelet aggregation. The structural alterations represented by these analogues indicate that the inhibitory effect of nitrofurantoin is due to the simultaneous presence of the nitro group on the furan ring and the specific arrangement of the diketo groups on the imidazole ring. Molecular orbital calculations predicted the key role of the electron-deficient nitrofurantoin moiety in the inhibitory effect. A specific ADP-nitrofurantoin complex was demonstrated in solution by nuclear magnetic resonance spectroscopy, but the dissociation constant for the complex (approximately 10^-1 M) cannot account for the competitive inhibitory effect of nitrofurantoin on platelet aggregation (K_i 10^-5 M). The over-all data suggest that the nitrofuran and diketoimidazole portions of nitrofurantoin contribute to its inhibitory effect through different mechanisms. These studies also suggest a set of molecular requirements for the synthesis of new inhibitors which could be clinically useful.

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ACKNOWLEDGMENT The authors would like to express their gratitude to Dr. Arthur Atkinson, Jr., for valuable discussions.