General Synthetic Approach to 2-Phenolic Adenine Derivatives

Abstract

A simple and general 'one-pot' procedure for the synthesis of 2,9-diarylpurines with one or multiple hydroxyl groups in the 2-aryl unit is described, from the reaction of 5-amino-4-amidinoimidazoles with phenolic aldehydes.Purines have attracted attention of the scientific community mainly due to their biological activity. 1 During the last decade, purine derivatives were identified as a promising new class of antitubercular agents. The research was focused on the synthesis of nucleoside analogues as siderophore biosynthesis inhibitors 2 and on non-nucleosides. 3 In the non-nucleoside series, purines having an aryl, a small alkyl, or a proton on N-9 were essentially inactive, whereas 9-benzyl-6-(2-furyl)purines, 3b,h,j 9-sulfonyl-6-mercaptopurines, or 6-alkylthiopurines 3e,k were highly potent. In addition, we recently described the first example of 2,9-diarylpurines ( Figure 1) active against Mycobacterium tuberculosis. 4 The results from biological evaluation showed that the potency of the compounds depends on the substituents in N-9, C-2, and C-6 of the purine core. The presence of a 4-tolyl group in N-9 and a 3-hydroxyphenyl or a 4-hydroxyphenyl substituent in C-2 combined with a secondary amine in C-6 proved to be important features for activity ( Figure 1) but a clear structure-activity correlation pattern could not be identified. 4 Figure 1 Hit compounds active on Mycobacterium tuberculosisA number of synthetic methods were developed to incorporate functional groups in the purine core, but costly reagents are usually required. 5a,b In our research group purine derivatives have been obtained by a simple and inexpensive synthetic approach that uses the versatile reactivity of a substituted imidazole. 4,5c-l The 6-amino-2,9-diarylpurines ( Figure 1) are a new promising scaffold active against Mycobacterium tuberculosis and the presence of hydroxyl groups in the aryl subunit in C-2 was considered an important feature for activity. The microorganism needs iron for the biochemical processes, and multiple hydroxyl groups in the phenolic subunit could enhance the complexation with the metal. This perception prompted us to develop a new synthetic approach that would allow the efficient synthesis of purines 6 (Table 1) having a phenolic subunit in C-2 with two and three hydroxyl substituents. The previous method only allowed the introduction of phenolic units with one hydroxyl group as the reaction with polyphenolic aldehydes, performed in basic medium, was very slow (8-54 d) and extensive degradation occurred. 4 Herein we describe a new and general synthetic approach for 6-amino-9-aryl-2-hydroxy or 2-(polyhydroxyphenyl)purines 6 using imidazole 1, phenolic aldehydes 2, and a cascade of acid and base catalysis. When compound 1a (Scheme 1) was combined with 3,4,5-trihydroxybenzaldehyde (2a) in ethanol at 0°C, using trifluoroacetic acid as catalyst, the starting materials were dissolved and a new white solid precipitated after five minutes. This compound was identified as the trifluoroacetate salt of starting materi...

Synthesis of Novel 2,9-Disubstituted-6-morpholino Purine Derivatives Assisted by Virtual Screening and Modelling of Class I PI3K Isoforms

“…Compounds of structure 22a – g , 23a – d,f,g , and 24a – d,f,g were previously described and synthesised according to reported procedures [ 43 , 45 , 46 , 47 ]. The new derivatives 23e,h , 24e,h,i , and 25e,h were synthesised using the same experimental reaction conditions ( Scheme 1 ).…”

“…The 5-amino-4-cyanoformimidoylimidazoles 22a – h used in this work were synthesised according to previously described procedures [ 43 ], compounds 23 were obtained following procedures reported in [ 44 , 45 , 46 ], and compounds 24 – 25 were synthesised according to procedures described in [ 47 ]. Solvents and other chemicals commercially available were used as shipped.…”