1,2,3-Triazolo-Bridged Click Coupling of Pinane-Based Azidodiol Enantiomers with Pyrimidine- and Purine-Based Building Blocks: Synthesis, Antiproliferative, and Antimicrobial Evaluation

Key intermediate azidodiols were synthesized according to literature from commercially available (+)- and (-)-α-pinene in a four-step sequence, including epoxidation with <i>m</i>CPBA, allylic rearrangement, a second epoxidation and, finally, a regioselective azidolysis of the resulting epoxide by sodium azide, yielding the enantiomerically pure azidodiols. The pyrimidine-based alkyne building blocks were prepared from dichloropyrimidines following our method reported previously, while the purine-containing alkyne analogues were synthesized in a procedure of two or three steps. Click reactions were carried out in the presence of Cu(OAc)₂ and sodium ascorbate. The obtained pinane-coupled 2,4-diaminopyrimidines were screened for antiproliferative activity by MTT assay on HeLa, MD231, SiHa, MCF-7, and A2780 human cancer cell lines compared with fibroblast cells (NIH/3T3), on Gram-positive and Gram-negative pathogenic bacteria, and two yeasts, and the SAR was explained in detail. The prepared compounds showed moderate antiproliferative activity. While the starting azidodiols <b>(+)-2</b> and <b>(-)-2</b> exhibited excellent and selective antibacterial activities against <i>S. aureus</i> with a moderate antimycotic effect on <i>C. krusei</i>, only the (-)-enantiomer was active against <i>P. aeruginosa</i>. In a similar manner, most pyrimidine and purine derivatives also expressed moderate antimycotic effect against <i>C. krusei</i>. One of the purine-based derivatives <b>(-)-30</b> possessed remarkable and selective antibacterial effect against <i>P. aeruginosa</i>.