Irreversible enzyme inhibitors. XCIV. inhibition of dihydrofolic reductase with derivatives of 2,6‐diaminopurines

Abstract

In order to gain additional information on the hydrophobic bonding region of dihydrofolic reductase, some derivatives of 2, 6‐diaminopurine with aryl or aralkyl groups at the N6, C8 and N9‐positions were investigated as inhibitors. Since none of the six compounds gave an increment in binding over the parent 2, 6‐diaminopurine, hydrophobic bonding to dihydrofolic reductase could not be detected with this ring system. Furthermore, 2, 6‐diaminopurine bridged from its 8‐position with methylene groups to the amino group of p‐aminobenzoic acid also failed to show an increment in binding. The 8‐substituted 2, 6‐diaminopurines were synthesized by base‐catalyzed cyclodehydration of the appropriate 5‐acylamido‐2, 4, 6‐triaminopyrimidines; the latter compounds were readily prepared by selective acylation of tetraaminopyrimidine.

Conformationally Restricted Analogues of Trimethoprim: 2,6-Diamino-8-substituted Purines as Potential Dihydrofolate Reductase Inhibitors from Pneumocystis carinii and Toxoplasma gondii

“…Weinstock et al . have reported an improved synthesis of the original method utilized by Baker and Santi for the synthesis of this intermediate. Adoption of this method using 2,4,5,6-tetraaminopyrimidine ( 24 ) fused with glycolic acid for 4 h (Scheme 2) followed by workup and basification afforded 2,4,6-triamino-5-(glycoamido)pyrimidine, 25 .…”

“…42 For the synthesis of analogue 20, a similar reaction with phenylacetaldehyde which involved refluxing the reaction mixture overnight in acidic methoxyethanol resulted in a complex mixture of products on TLC. However when the reaction was performed in acidic 43 have reported an improved synthesis of the original method utilized by Baker and Santi 44 for the synthesis of this intermediate. Adoption of this method using 2,4,5,6-tetraaminopyrimidine (24) fused with glycolic acid for 4 h (Scheme 2) followed by workup and basification afforded 2,4,6-triamino-5-(glycoamido)pyrimidine, 25.…”