Synthesis of 6,8-diaminopurines via acid-induced cascade cyclization of 5-aminoimidazole precursors and preliminary anticancer evaluation.

Inspired by the pharmacological interest generated by 6-substituted purine roscovitine for cancer treatment, 5-aminoimidazole-4-carboxamidine precursors containing a cyanamide unit were prepared by condensation of 5-amino-N-cyanoimidazole-4-carbimidoyl cyanides with a wide range of primary amines. When these amidine precursors were combined with acids, a fast cascade cyclization occurred at room temperature, affording new 6,8-diaminopurines with the N-3 and N-6 substituents changed relatively to the original positions they occupied in the amidine and imidazole moieties of precursors. The efficacy and wide scope of this method was well demonstrated by an easy and affordable synthesis of 22 6,8-diaminopurines decorated with a wide diversity of substituents at the N-3 and N-6 positions of the purine ring. Preliminary in silico and in vitro assessments of these 22 compounds were carried out and the results showed that 13 of these tested compounds not only exhibited IC50 values between 1.4 and 7.5 µM against the colorectal cancer cell line HCT116 but also showed better binding energies than known inhibitors in docking studies with different cancer-related target proteins. In addition, good harmonization observed between in silico and in vitro results strengthens and validates this preliminary evaluation, suggesting that these novel entities are good candidates for further studies as new anticancer agents.

2,4,5-Triaminopyrimidines as blue fluorescent probes for cell viability monitoring: synthesis, photophysical properties, and microscopy applications.

Monitoring cell viability is critical in cell biology, pathology, and drug discovery. Most cell viability assays are cell-destructive, time-consuming, expensive, and/or hazardous. Herein, we present a series of newly synthesized 2,4,5-triaminopyrimidine derivatives able to discriminate between live and dead cells. To our knowledge, these compounds are the first fluorescent nucleobase analogues (FNAs) with cell viability monitoring potential. These new fluorescent molecules are synthesized using highly efficient and cost-effective methods and feature unprecedented photophysical properties (longer absorption and emission wavelengths, environment-sensitive emission, and unprecedented brightness within FNAs). Using a live-dead Saccharomyces cerevisiae cell and theoretical assays, the fluorescent 2,4,5-triaminopyrimidine derivatives were found to specifically accumulate inside dead cells by interacting with dsDNA grooves, thus paving the way for the emergence of novel and safe fluorescent cell viability markers emitting in the blue region. As the majority of commercially available viability dyes emit in the green to red region of the visible spectrum, these novel markers might be useful to meet the needs of blue markers for co-staining combinations.

Synthesis and antimicrobial activity of novel 5-aminoimidazole-4-carboxamidrazones.

A mild and simple method was developed to prepare a series of fifteen 5-aminoimidazole 4-carboxamidrazones, starting from the easily accessible 5-amino-4-cyanoformimidoyl imidazoles. The antimicrobial activity of these novel amidrazones was screened against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Pseudomonas aeruginosa) bacteria and Candida sp. (Candida albicans, Candida krusei, Candida parapsilosis). Only a subset of compounds displayed fair-moderate activity against S. aureus and E. coli but all exhibited activity against Candida sp. The three most potent antifungal compounds were further tested against Cryptococcus neoformans, Aspergillus fumigatus and three dermatophytes (Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum gypseum). These three hit compounds strongly inhibited C. krusei and C. neoformans growth, although their activity on filamentous fungi was very weak when compared to the activity on yeasts.

Red-shifted and pH-responsive imidazole-based azo dyes with potent antimicrobial activity.

A novel route is described to obtain 2-aminoimidazole azo dyes with a unique substituent pattern in the heteroaryl unit that provides halochromic properties, exhibiting vibrant colours that change from magenta to deep blue. Potent antimicrobial properties against infectious yeasts were demonstrated. No cytotoxicity was detected for concentrations lower than 16 µg mL-1.

Efficient synthesis of 4,4'-bi-1H-imidazol-2-ones from 5-amino-alpha-imino-1H-imidazole-4-acetonitriles and isocyanates.

Reactions of 5-amino-alpha-imino-1H-imidazole-4-acetonitriles 1 with alkyl and aryl isocyanates led to efficient syntheses of 5'-amino-5-imino-4,4'-bi-1H-imidazol-2-ones 3 formed by intramolecular cyclization of the corresponding 5-amino-alpha-(N-alkyl/arylcarbamoyl)imino-1H-imidazole-4-acetonitriles 2. The cyclization occurs only slowly in solution but is considerably accelerated by the addition of a catalytic amount of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). The reaction of the N-arylamidine 6b, the synthetic precursor of the imidazole 1b, with benzyl isocyanate also led to the formation of 4,4'-bi-1H-imidazol-2-one 3b in quantitative yield. The imidazole intermediate 2b has been isolated and found to be identical with the compound obtained by reaction of the imidazole 1b and benzyl isocyanate. The N-arylamidine 6c (R = 4-NCC(6)H(4)) reacted with benzyl isocyanate in a similar way, but the electrophilicity of the amidine carbon atom resulted in rapid hydrolysis of the intermediate 7c leading ultimately to the isolation of the urea 9. The N-alkylamidines 6a and 6d behaved differently in their reaction with benzyl isocyanate, and the major product isolated in these reactions is again the urea 9.