Microwave-Assisted Synthesis, Structure, and Preliminary Biological Evaluation of Novel 6-Methoxy-5,6-dihydro-5-azapurines

Abstract

We herein disclose the microwave-assisted synthesis of previously unreported 6-methoxy-5,6-dihydro-5-azapurines, whose purine-like scaffold is promising for drug discovery. The method is simple, fast, and relies on easily accessible reagents such as trimethyl orthoformate, acetic acid, and aminotriazole-derived N,N'-disubstituted formamidines. The preliminary biological evaluation revealed that selected representatives of synthesized 6-methoxy-5,6-dihydro-5-azapurines dose-dependently reduce the viability of HepG2 and A549 cancer cells having little to no influence on five tested purinergic receptors.

Figure 1

Exemplary structures of biologically active purines, 5-azapurines, and structurally related dihydrotriazines.

Scheme 1. Synthesis of 5-Azapurines and 5,6-Dihydro-5-azapurines

Scheme 2. Synthesis of the Key Intermediates N,N′-Disubstituted Formamidines 20a–q

Scheme 3. Synthesis of 6-Methoxy-5,6-dihydro-5-azapurines 21

Scheme 4. Annular Tautomerism of 1,2,4-Triazol-5-amines (Tautomers A–C) and Two Cyclization Products 21 and 22 Potentially Arising from Tautomeric Forms A and C

Figure 2

(A) X-ray crystal structure of 21c displaying the thermal ellipsoids at the 30% probability level. (B) X-ray crystal structure of 21j displaying the thermal ellipsoids at the 30% probability level. Only one molecule of two found in the asymmetric unit of compound 21j is shown.

Figure 3

Sigmoidal curves obtained in the resazurin assay showing IC₅₀ values for synthesized compounds 21f and 21i in HepG2 and A549 cancer cells. Each data point represents an average of three independent experiments with SD.