New Modification Of The Gewald Reaction For The Synthesis Of Sulfur-Containing, Nucleic Base Analogs

Heterocyclic compounds are some of the most interesting compounds in medicinal chemistry. Pyrimidne is a well known heterocyclic compound and is an important pharmacophore used in medicinal chemistry. Adenine and hypoxanthine-like frameworks structurally are consistent with the pyrimidine framework, showing immense promise in the development of biologically active compounds. Highly substituted 2-aminothiophenes are a class of compounds that are excellent scaffold motifs for the synthesis of biologically active compounds. Because they are used primarily as precursors, there is a lack of research concerning their biological activity. One of the approaches in medicinal chemistry is the fusion of multiple pharmacophores into one drug. This is thought to improve activity and reduce the risk of resistance to the drug formed by the cancer cells. Fusion of 2-aminothiophene and pyrimidine gives rise to compounds known as thiophene pyrimidines, which have great implications in the drug development field. It is known that Gewald reaction schemes give rise to 2-aminothiophenes and that cyclization generates a fusion between 2-aminothiophene and pyrimidine pharmacophores to produce thiophene pyrimidine derivatives. The synthesis of thiophene pyrimidines based on rigid monoketones was established and a one-pot reaction developed.  This was used as a model for further reactions. The synthesis of thiophene pyrimidines based on flexible monoketones gave rise to a new modification of the classical Gewald reaction scheme. It allowed for the synthesis of 2-aminothiophenes easily and in acceptable yields for adenine-like compounds. The syntheses of compounds based on the hypoxanthine-like framework were not successful using the same reaction conditions. Instead, the hydrolysis and further cyclization of 2-aminothiophene derivatives from 3-cyano-2-aminothiophene derivatives allowed for the generation of hypoxanthine-like thiophene pyrimidine derivatives. A new method of synthesis for 2-aminothiophenes and thiophene pyrimidine derivatives was developed on the basis of rigid diketones.  MTT assay of anticancer activity against HeLa cells and MCF-7 cells was used and it was found that 1.) compounds containing lipophilic, halogen substituents were the most active, and 2.) cyclization of 2-aminothiophenes to thiophene pyrimidines increased activity by nearly two-fold for majority of compounds. Compounds were screened for anti-microbial activity against gram positive (S. pyogenes,  S. epidermis) and gram negative (E. coli, P. fluorescens)  bacteria, but showed no significant activity.  Compounds were also tested against C. albicans; while most showed no activity, m-Br and p-Br, hypoxanthine-like derivatives had significant activity. One fluorinated compound was tested against trypanosoma brucei and showed no significant activity.