Combinatorial synthesis and biological evaluation of nitrogen-containing heterocycles as potential therapeutic agents

Abstract

<P>THIS PROJECT REPORTS THE DESIGN AND SYNTHESIS OF THREE CLASSES OF COMPOUNDS: I) 2,4-DISUBSTITUTED-5-AMINOIMIDAZOLES II) 4,5-DISUBSTITUTED-2-AMINOIMIDAZOLES AND III) 2-(BENZYLTHIO)-6,7-DISUBSTITUTEDIMIDAZO [1,2-A]PYRIMIDIN-5(8H)-ONES AS POTENTIAL DHFR ENZYME INHIBITORS. WITH THE USE OF MICROWAVE-ASSISTED ORGANIC SYNTHESIS (MAOS), WE HAVE GREATLY REDUCED THE REACTION TEMPERATURE; INCREASE THE PURITY AND THE PERCENTAGE YIELDS OF ALL THREE CLASSES OF COMPOUNDS. IN VITRO DHFR ENZYME ASSAY WAS PERFORMED ON ALL COMPOUNDS SYNTHESIZED. 10 OF THEM WERE FOUND TO BE POTENTIAL DHFR INHIBITORS WITH IC50 VALUES RANGNING FROM 6.7B5M-18.3B5M. BASED ON THE IN VITRO DHFR ASSAYS PERFORMED, 10 COMPOUNDS WERE SELECTED FOR MTT ASSAY USING A549 AND MDA-MB-231 CELL-LINES. RESULTS FROM BOTH CELL-LINES REVEALED THAT ONE COMPOUND EXHIBITED CONSISTENT IC50 IN THE RANGE OF 17-24B5M. FURTHER OPTIMIZATION OF THESE LEADS MAY LEAD TO IMPROVED DHFR INHIBITORY ACTIVITY AND THUS OFFERING A NEW CLASS OF ANTIFOLATE DRUGS